Sex differences in Cardiac Diseases: Pathophysiology, Presentation, Diagnosis and Management

Significant biological differences exist between men and women that contribute to sex-specific differences in cardiovascular disease (CVD) risk factors, pathophysiology, presentation, response to therapy, and prognosis. It is essential for clinicians to be cognizant of these sex-specific differences in order to reduce the disparity in diagnosis and management of cardiovascular diseases in both genders.Sex Differences in Cardiac Disease provides a timely review of the contemporary data on these sex-specific differences in pathophysiology, clinical presentation, diagnostic evaluation, and management of cardiovascular diseases that fills a void for clinicians in practice and training. With contributions from renowned experts in the field and guideline writers, the text provides a state-of-the-art review of each topic encompassing the full spectrum of CVD in men and women. Sex-specific guideline-based recommendations are highlighted when available. Tailored to meet the needs of the busy clinicians and researchers, this text provides concise practical data to care for men and women at risk for or with CVD. The book serves as an essential resource for researchers, cardiologists, obstetricians, gynecologists, internists, family practitioners, nurse practitioners and physician assistants, and respective trainees who treat men and women with CVD.

• Provides a comprehensive state-of-the-art text written by internationally renowned experts in the field of CVD disease, serving as an indispensable resource for clinicians and researchers
• Enables the reader to understand the sexual dimorphism in the pathophysiology, diagnosis, management, and outcomes of the full spectrum of cardiovascular issues including ischemic heart disease, valvular disorders, arrhythmias, and heart failure
• Provides a concise evidence-based practical review of medical topics, with key points and eye-catching visual infographics to meet the needs of the busy clinicians, policy makers and researchers

• Language: English
• Publisher: Elsevier Science
• Release date: Jan 29, 2021
• ISBN: 9780128193709

Book preview

Introduction

Chapter 1: Introduction: Past, Present, and Future of Heart Disease in Men and Women

Nanette K. Wenger

For most of the 20th century, cardiovascular disease was addressed as a problem for men, with coronary disease and myocardial infarction the foremost morbid and mortal problems. Women were widely considered protected from heart disease (absent evidence-based data) by their hormones in the premenopausal years and by the subsequent widespread application of menopausal hormone therapy. Although women in the Framingham Heart Study had a higher incidence of angina, this was overwhelmed by the predominance of myocardial infarction in men, with its attendant 40% hospital mortality. Angina was not viewed as a serious problem. Hypertension had yet to be accepted as a lethal condition, and heart failure prevalence would only increase in subsequent years consequent to the increased survival of both women and men from more acute cardiovascular problems. Not surprisingly, the emergence of clinical research studies and in particular randomized controlled trials of cardiovascular prevention and therapies involved exclusively or predominantly men and typically middle-aged white men. Stroke was considered untreatable and not widely accepted as a common consequence of uncontrolled hypertension. Rheumatic heart disease with its surgically amenable mitral stenosis predominated in women, and the problem of cardiac arrhythmias, and in particular atrial fibrillation, had yet to receive widespread acknowledgment. Ignored was the fact that the more women than men died annually from cardiovascular disease, a statistic that persisted until 2013–2014 (Figure 1).

Figure 1 The Past, Present, and Future of Heart Disease in Men and Women. CV, cardiovascular; CVD, cardiovascular disease; FDA, Food and Drug Administration. Image courtesy of Niti R. Aggarwal.

The 1992 NHLBI Conference: Cardiovascular Health and Disease in Women highlighted the flawed assumption that women did not experience heart disease until elderly age and were not as seriously at risk as men. It presented new information appropriate for clinical application but identified knowledge gaps that impeded quality cardiovascular care for women, displaying a research agenda for the next decades [1]. The importance of sex and gender differences in cardiovascular disease was promulgated by the 2001 IOM report Exploring the Biological Contributions to Human Health. Does Sex Matter? [2], which advocated the need for the evaluation of sex-based differences in human disease and in medical research, with translation of these differences into clinical practice.

Not until the late 1990s and early 2000s did the randomized controlled trials of menopausal hormone therapy including the Heart and Estrogen Progestin Replacement Study (HERS) in women with heart disease and the hormone trials of the Women’s Health Initiative (WHI) in healthy women [3–5] identify that menopausal hormone therapy did not prevent incident or recurrent cardiovascular disease and thus was not indicated for primary or secondary prevention. The importance of these trials was the refocusing of attention on established cardiovascular preventive therapies for women.

Yet, as recently as 2003, the AHRQ Report on the Diagnosis and Treatment of CHD in Women [6, 7] displayed that most contemporary recommendations for the prevention, diagnostic testing, and medical and surgical treatment of CHD in women were extrapolated from studies conducted predominantly in middle-aged men and that there remained fundamental knowledge gaps regarding the biology, clinical manifestations, and optimal management strategies for women.

Advocacy also increased the awareness of cardiovascular disease in women, beginning with the NHLBI Heart Truth Campaign in 2004 and the American Heart Association’s Go Red for Women Initiative in the same year, as well as the work of WomenHeart, the National Coalition for Women with Heart Disease.

Subsequent clinical research studies provided data specifically for women, such as the Women’s Health Study, showing that aspirin provided stroke protection but not protection from MI [8], contrary to data for men in the Physician’s Health Study.

Gender-specific data derived from the CRUSADE Quality Improvement Registry of women with non-ST elevation acute coronary syndrome [9] demonstrated that the prognosis with an acute coronary syndrome was worse in women who incurred an increase in hospital death, myocardial infarction, heart failure, stroke, and the need for transfusion. Yet women were less likely to receive coronary interventions and guideline-based medical based therapies despite their high-risk status. The question was raised as to whether the worse prognosis for women was related to their raised baseline risk or to suboptimal admission and discharge therapies: was this biology, bias, or both?

A concept-changing paradigm derived from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE) study. At the time, women with abnormal noninvasive diagnostic studies, in the absence of obstructive disease of the epicardial coronary arteries at angiography, were considered to represent a false-positive noninvasive test, based on the male model of disease [10, 11]. Subsequent data from the WISE cohorts identified that myocardial ischemia was the villain, associated with adverse clinical outcomes in women in the absence of obstructive coronary disease, today termed INOCA [12]. This highlighted the importance of microvascular disease and nonobstructive coronary disease in women, with current research actively targeting the optimal diagnostic procedures to identify this complex pathophysiologic spectrum. Clinical studies are currently underway to attempt to improve the outcome of women with microvascular disease and nonobstructive coronary artery disease, with unimpressive data yet forthcoming [13, 14].

The Women’s Antioxidant Cardiovascular Study (WACS) and the Women’s Antioxidant with Folic Acid Study (WAFACS) [15, 16] identified that vitamin C and beta carotene as well as folic acid and vitamin D supplements did not prevent incident or recurrent cardiovascular disease in women and removed these ineffective therapies from the recommended regimens. Shortly thereafter, the AHA Women’s CVD Prevention Guideline 2011 Update [17] highlighted that pregnancy complications, specifically preeclampsia, gestational diabetes, pregnancy-induced hypertension, preterm delivery, and small for gestational age infants were all early indicators of an increase in cardiovascular risk, placing a detailed history of pregnancy complications as a routine component of risk assessment for women. At the same time, this guideline identified an increased risk of cardiovascular disease with systemic autoimmune collagen vascular disease, warranting screening for conventional coronary risk factors and interventions as appropriate. The 2011 Update of the Cardiovascular Prevention Guideline also addressed stroke prevention in women with atrial fibrillation, stating that atrial fibrillation increased the stroke risk 4–5 fold and that undertreatment with anticoagulants doubled the risk of recurrent stroke.

More recently, a report from the Get With the Guidelines CAD database [18] showed women to have a doubled STEMI mortality compared with their male peers, 10.2% vs. 5.5%. This was predominantly an initial 24-h increase in mortality and was associated with a decrease in the application of early aspirin, beta blockers, reperfusion therapy, and timely reperfusion. It was not that physicians chose to treat their women patients differently, but rather this represented a lack of recognition of ST-elevation myocardial infarction; remediation of this problem offered opportunities to lessen gender disparities in care and improve clinical outcomes for women.

The Institute of Medicine (IOM) 2010 Report on Women’s Health Research: Progress, Pitfalls, and Promise [19] further highlighted that medical research historically neglected the health needs of women, even though there was major progress in reducing cardiovascular mortality. It identified that women were not a homogeneous group, with disparities in disease burden among subgroups of women, particularly those socially disadvantaged because of race, ethnicity, income level, and educational attainment. The IOM highlighted that the lack of analysis and reporting of sex-stratified analyses limited the ability to identify potentially important sex and gender differences, including differences in care, and advocated for translation of women’s health research findings into both clinical practice and public health policies, with effective communication of research-based health messages to women, the public, providers, and policy makers.

The result of the emerging sex-specific research and recommendations was stunning. Until the year 2000, the decline in cardiovascular mortality in the United States occurred predominantly in men, but beginning in 2000, the cardiovascular mortality decline was more prominent in women and, as previously noted, for the first time in 2003–2014 fewer women than men died annually from cardiovascular disease.

But all this may not bode well for the future—since that time there has been a leveling or increase of cardiovascular mortality for both women and men, predominantly in the younger age groups 35–50 years of age, likely reflecting the US epidemic of obesity and sedentary lifestyle.

Women’s participation and data in clinical trials remains a challenge, with a Cochrane review of 258 cardiovascular clinical trials showing that only one-third examined outcome by sex, although among those with sex-based analyses, 20% reported significant differences in outcomes between women and men [20]. Worthy of mention is that the exclusion of elderly patients from clinical trials doubly disadvantages women, who have their predominance of coronary and other cardiovascular events at older age. Promise for the future is offered by HR2101: The Research for All Act of 2015, 114th Congress (2015–2016). In addition to the mandate by the Government Accountability Office to update reports on women and minorities in medical research at both the NIH and the FDA, the National Institutes of Health were legislatively ordered to update guidelines on the inclusion of women and minorities in clinical research. Of equal importance, they were mandated to ensure that both male and female cells and tissues, as well as animals, be included in basic research, with the results disaggregated according to sex and sex differences examined. Similarly, the FDA 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, with the outcomes supported by the results of clinical trials that separately examined outcomes for women and men.

The past decade has seen Scientific Statements on women and peripheral artery disease [21]. Guidelines for the Prevention of Stroke in Women [22] define sex-specific stroke risk factors including pregnancy, preeclampsia, gestational diabetes, oral contraceptive use, menopausal hormone use and changes in hormonal status, as well as risk factors that were stronger or had an increased prevalence in women. The role of noninvasive testing in women for the clinical evaluation of suspected ischemic heart disease received repeated attention [23, 24], as did the sex differences in the cardiovascular consequences of diabetes mellitus showing that the gender advantage of a decrease in cardiovascular events in women compared with comparably aged men was lost in the context of type 2 diabetes [25].

Also highlighted was the intersection of cardiovascular disease and breast cancer, targeting their overlapping risk factors and the risk that current breast cancer treatments may accelerate cardiovascular disease and resultant left ventricular dysfunction, and identifying the need for surveillance, prevention, and secondary management of cardiotoxicity during breast cancer treatment [26]. Most recently, a cooperation between the American Heart Association and the American College of Obstetricians and Gynecologists [27] cited that 90% of US women have at least one risk factor for cardiovascular disease, with women less likely to receive guideline-recommended therapies and advocating that healthy lifestyles and behaviors should be discussed at each OB/GYN visit with enhanced screening for cardiovascular disease and cardiovascular risk factors. Shared information should be used to assess risk, initiate interventions, and facilitate significant lifestyle changes.

The ideal vision for women’s cardiovascular health research in the next decade is that the landscape must be expanded to include beliefs and behaviors; local, national, and global community issues; economic and environment issues; ethical aspects; legislative and political issues; public policy; and societal/sociocultural variables. All these can only be ascertained by examining gender differences in cardiovascular disease, with the application of personalized or individualized medicine beginning with sex-based examination of differences.

References

[1] Wenger N.K., Speroff L., Packard B. Cardiovascular health and disease in women. N Engl J Med. 1993;329:247–256.

[2] Wizeman T.M., Pardue M.-L., eds. editors, Committee on Understanding the Biology of Sex and Gender Differences, Board on Health Sciences Policy, Institute of Medicine. Exploring the biological contributions to human health. Does sex matter?. National Academy Press; 2001.

[3] Hulley S., Grady D., Bush T., Furberg C., Herrington D., Riggs B. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613.

[4] Rossouw J.E., Anderson G.L., Prentice R.L., LaCroix A.Z., Kooperberg C., Stefanick M.L. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.

[5] Anderson G.L., Limacher M., Assaf A.R., Bassford T., Beresford S.A.A., Black H. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701–1712.

[6] Agency for Healthcare Research and Quality. Results of systematic review of research on diagnosis and treatment of coronary heart disease in women. Evidence report/technology assessment number 80. AHRQ Publication. No. 03-E034, DHHS. Washington, DC: U.S. Department of Health and Human Services; 2003.

[7] Agency for Healthcare Research and Quality. Diagnosis and treatment of coronary heart disease in women: systematic review of evidence on selected topics. AHRQ, No. 03-E036. Washington, DC: U.S. Department of Health and Human Services; 2003.

[8] Ridker P.M., Cook N.R., Lee I-M., Gordon D., Gaziano J.M., Manson J.E. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293–1304.

[9] Blomkalns A.L., Chen A.Y., Hochman J.S., Peterson E.D., Trynosky K., Diercks D.B. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Pectoris Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol. 2005;45:832–837.

[10] Bairey Merz C.N., Shaw L.J., Reis S.E., Bittner V., Kelsey S.F., Olson M. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Part II. Gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. 2006;47(3 Suppl):S21–S29.

[11] Pepine C.J., Ferdinand K.C., Shaw L.J., Light-McGroary K.A., Shah R.U., Gulati M. Emergence of nonobstructive coronary artery disease: a women’s problem and need for change in definition on angiography. Am J Cardiol. 2015;66:1918–1933.

[12] Herscovici R., Sedlak T., Wei J., Pepine C.J., Handberg E., Bairey Merz C.N. Ischemia and no obstructive coronary artery disease (INOCA): what is the risk?. J Am Heart Assoc. 2018;7(17):doi:10.1161/JAHA.118.008868.

[13] AlBadri A., Bairey Merz C.N., Johnson B.D., Wei J., Mehta P.K., Cook-Wiens G. The impact of abnormal coronary reactivity on long-term clinical outcomes in women. J Am Coll Cardiol. 2019;73:684–693.

[14] Wenger N.K. The feminine face of heart disease. Challenges and opportunities. J Am Coll Cardiol. 2019;73:694–697.

[15] Cook N.R., Albert C.M., Gaziano J.M., Zaharris E., MacFadyen J., Danielson E. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610–1618.

[16] Albert C.M., Cook N.R., Gaziano J.M., Zaharris E., MacFadyen J., Danielson E. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–2036.

[17] Mosca L., Benjamin E.J., Berra K., Bezanson J.L., Dolor R.J., Lloyd-Jones D.M. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123:1243–1262.

[18] Jneid H., Fonarow G.C., Cannon C.P., Hernandez A.F., Palacios I.F., Maree A.O. Sex differences in medical care and early death after acute myocardial infarction. Circulation. 2008;118:2803–2810.

[19] Committee on Women’s Health Research, Institute of Medicine. Women’s health research: progress, pitfalls, and promise. Washington, DC: National Academies Press; 2010.

[20] Wenger N.K., Ouyang P., Miller V.M., Bairey Merz C.N. Strategies and methods for clinical scientists to study sex-specific cardiovascular health and disease in women. J Am Coll Cardiol. 2016;67:2186–2188.

[21] Hirsch A.T., Allison M.A., Gomes A.S., Corriere M.A., Duval S., Ershow A.G. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012;125:1449–1472.

[22] Bushnell C., McCullough L.D., Awad I.A., Chireau M.V., Fedder W.N., Furie K.L. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:1545–1588.

[23] Mieres J.H., Gulati M., Bariey Merz N., Berman D.S., Gerber T.C., Hayes S.N. Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association. Circulation. 2014;130:350–379.

[24] Regensteiner J.G., Golden S., Huebschmann A.G., Barrett-Connor E., Chang A.Y., Chyun D. Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2015;132:2424–2447.

[25] Baldassarre L.A., Raman S.V., Min J.K., Mieres J.H., Gulati M., Wenger N.K. Noninvasive imaging to evaluate women with stable ischemic heart disease. JACC Cardiovasc Imaging. 2016;9:421–435.

[26] Mehta L.S., Watson K.E., Barac A., Beckie T.M., Bittner V., Cruz-Flores S. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137:e30–e66.

[27] Brown H.L., Warner J.J., Gianos E., Gulati M., Hill A.J., Hollier L.M. Promoting risk identification and reduction of cardiovascular disease in women trough collaboration with obstetricians and gynecologists: a presidential advisory from the American Heart Association and the American College of Obstetricians and Gynecologists. Circulation. 2018;137:e843–e852.

Section II

Epidemiology and Prevalence

Chapter 2: Epidemiology and Prevalence

Mariana Garcia; JoAnn E. Manson

Abstract

Cardiovascular disease (CVD) is the leading cause of death in both men and women in the United States and most other developed countries. In 2016, CVD claimed the lives of 412,244 women in the United States. Growing knowledge of sex differences in symptoms/clinical presentation, pathophysiology of CVD, reliability of diagnostic tests, and responses to treatments, as well as an improved recognition of nontraditional risk factors specific to women, have resulted in improved clinical outcomes in women. However, despite these advances, CVD continues to be the leading cause of morbidity and mortality in both women and men in the United States. Women face disparities in diagnosis, treatment, and research related to heart disease. Persistent differences in risk factor prevalence, healthcare access, low levels of awareness by both the public and medical communities leading to underdiagnosis, delayed adoption of evidence-based guidelines in women, and major knowledge gaps are some of the factors contributing to CVD disparities. The objective of this chapter is to address the known sex differences in CVD based on epidemiologic and clinical data, characterize current sex-specific health disparities, discuss challenges, and identify strategic pathways to improve the cardiovascular health of women.

Keywords

Cardiovascular disease; Heart disease; Sex differences; Incidence; Prevalence; Equity; Disease burden; Gender; Women

Abstract

Definitions

Sex‐Specific Awareness of Heart Disease in the Public and Medical Community

Public Awareness

Medical Awareness

The Burden of Heart Disease in Men and Women

Prevalence and Epidemiology of Risk Factors in Women

Diabetes

Hypertension

Dyslipidemia

Obesity

Physical Inactivity

Smoking

Psychological Stress

Risk Factors Unique to Women

Early Menopause

Adverse Pregnancy Outcomes

Multiparity

Incidence and Prevalence of Coronary Heart Disease

Incidence and Prevalence of Heart Failure

Incidence and Prevalence of Atrial Fibrillation

Incidence and Prevalence of Peripheral Arterial Disease

Temporal Trends

Cardiovascular Health Disparities Persist

Race/Ethnicity

Contemporary Challenges

Opportunities for Equitable Outcomes

Methodologic Limitations of CVD Research in Women

Womeńs Heart Centers

Government Mandates, Policies, and Advocacy

Key Points

Acknowledgment

Sources of Funding

References

Acknowledgment

We graciously acknowledge the graphical assistance of Eduardo Garcia and Dr. Niti Aggarwal in preparation of the figures.

Sources of Funding

Dr. JoAnn Manson receives funding from the National Institutes of Health (HL34594, CA138962, and U01 HL145386).

Definitions

The terms coronary heart disease (CHD), coronary artery disease (CAD), and cardiovascular disease (CVD), as used in this topic, are defined as follows:

●Coronary artery disease: general disease process affecting the coronary arteries (usually caused by atherosclerosis).

●Coronary heart disease: includes specifically the diagnosis of angina, myocardial infarction, silent myocardial infarction, and coronary death. It may also include coronary revascularization.

●Cardiovascular disease: represents several heart and blood vessel diseases, including CHD (as above), hypertension, atrial fibrillation, heart failure, cerebrovascular disease (including stroke and transient ischemic attack), peripheral arterial disease (PAD), and aortic atherosclerosis (including thoracic and abdominal aortic aneurysm).

CVD is the leading cause of death for both men and women in the United States (US), resulting in one of every four male deaths and one of every five female deaths, and accounting for 840,678 deaths in 2016 (Figure 1) [1, 2]. Moreover, nearly half (48%) of US adults aged 20 and older have some form of CVD, which includes CHD, heart failure (HF), stroke and/or hypertension, and other vascular conditions. This percentage is projected to continue to rise [1, 3].

Figure 1 Epidemiology of Cardiovascular Disease in the United States. GDP, gross domestic product.

There is a need to increase the awareness of CVD in women, as nearly half of women in the United States do not recognize that heart disease is the leading cause of death in women [1].

Furthermore, CVD mortality in young women (<  55 years of age) remains high and even greater than that in men [1]. The latest heart disease and stroke statistics (2019 update) indicates that while there has been a decline in CVD related mortality among older women, there has been relative stagnation in CHD mortality among young women over the last decade [1]. Moreover, the CVD risk burden is greater in young women compared to men of similar age, although hospitalization rates are lower [4]. The CVD burden is increasing due in part to the increasing prevalence of obesity, poor diet, sedentary lifestyle, and the rise in type 2 diabetes—all major risk factors for heart disease (Table 1).

Table 1

BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; DM, diabetes mellitus; HF, heart failure; HTN, hypertension; LDL, low-density lipoprotein; MI, myocardial infarction; PAD, peripheral arterial disease.

Reproduced with permission from [5].

Between 2000 and 2011, the annual rate of decline for all CVD mortality in the United States averaged 3.8%. The annual rates (percent [95% confidence interval (CI)]) of decline of all CVD was 4.0% (3.8–4.1%) for females and 3.7% (3.5–3.9%) for males between 2000 and 2011 [6].

However, since 2011, this progress has plateaued with the overall decline in CVD mortality rates flattening to less than 1% per year [7]. More alarmingly, in 2015, the death rate from heart disease increased by 1% for the first time since 1969, according to the Centers for Disease Control and Preventiońs National Center for Health Statistics [8].

According to data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 cycle, among US women age 20 and older (mean age 48 years), 44.7% had some form of CVD. This prevalence constitutes ~  60 million American women living with CVD. In addition, CVD accounted for 412,244 female deaths in 2016, which is more than the total combined female deaths from cancer, accidents, and diabetes combined [1]. CVD in women is still underrecognized and undertreated, and women face disparities in diagnosis, treatment, and research. The risk in women is often underestimated due to the misperception that females are protected against heart disease. This underrecognition of heart disease and differences in clinical presentation in women leads to less aggressive treatment strategies and a lower representation of women in clinical trials. Women generally make up only about 20% of enrolled patients, even though women represent 40–50% of participants in longitudinal studies and registries of CVD [9, 10].

Despite recent increases in awareness, many women are still uninformed about their CVD risk. A 2012 survey conducted by the American Heart Association (AHA) found that only 36% of black women and 34% of Hispanic women knew that heart disease is their leading cause of death, compared to 65% of white women (Figure 2). Less than 25% of women could name hypertension and high cholesterol as risk factors for heart disease, and less than 50% knew the major symptoms of heart disease. Black and Hispanic women were less likely than white women to be aware of heart attack symptoms [12].

Figure 2 Awareness That Cardiovascular Disease Is the Leading Cause of Death in Women. According to 2012 survey conducted by the American Heart Association, only 55% of women were aware that CVD was the leading cause of death in women, with even further decreased awareness in black and Hispanic women. Data from [11].

Major strides aimed at improving the understanding of sex and gender differences in CVD have been implemented over the past 20 years (Figure 3). Scientists, healthcare professionals, the public, and policy makers have initiated educational campaigns focusing on increased awareness of sex and gender differences in the presentation of disease and on recognizing the impact of heart disease in women. The rate of awareness of heart disease as the leading cause of death in the United States nearly doubled between 1997 (when the AHA launched its first campaign for women) and 2009 [14–16]. The extent to which efforts to close gaps and heighten awareness of heart disease in women are causally linked to lower CVD mortality or improved clinical outcomes for women is not established.

Figure 3 Professional and Patient‑Lead Advances Regarding Cardiovascular Disease in Women. ACC, American College of Cardiology; AHA, American Heart Association; ASA, American Stroke Association; CAD, coronary artery disease; CVD, cardiovascular disease; IOM, Institute of Medicine; JACC, Journal of the American College of Cardiology; NEJM, New England Journal of Medicine; NHLBI, National Heart, Lung, and Blood Institute; WISE, Womeńs Ischemic Syndrome Evaluation. Reproduced with permission from [13].

The goal of this chapter is to review the trends in awareness of heart disease in women, to evaluate the distribution and determinants of CVD in women, characterize contemporary sex differences in the burden of CVD, and discuss health disparities and current challenges.

Sex‐Specific Awareness of Heart Disease in the Public and Medical Community

Public Awareness

In 1994, an AHA statement reported that 45.2% of deaths in women were from CVD [17, 18]. In 1995, the AHA published the brochure Silent Epidemic and started encouraging greater awareness of CVD in women. Three years later, the AHA commissioned a national survey to assess awareness and knowledge of CVD in women. In this poll of 1000 women, only 8% of those surveyed knew that CVD was a womańs greatest health threat and only one in three women correctly identified heart disease as their leading cause of death [19]. The results of the survey were presented in Washington, DC, against a background of the Capitol building and 500,000 red carnations, representing the number of women who died annually of CVD. Consequently, the AHA has conducted triennial surveys to monitor national trends in awareness of heart disease among women.

The remarkable decrease in CVD mortality starting in 2000 among women in the United States coincided with the combined efforts to raise awareness by many organizations and the results of the landmark trials on primary and secondary prevention of CHD in women [20, 21]. In 2002, the National Heart, Lung, and Blood Institute (NHLBI) launched The Heart Truth, the first federally sponsored national campaign to raise awareness and to reduce mortality in women in the United States. The Red Dress symbol was released as part of this campaign and has now become a national symbol for women and heart disease. Subsequently, the AHA partnered with NHLBI and other organizations to launch the Go Red for Women initiative in February 2004. The campaign incorporated awareness of heart disease in women through celebrity speakers, National Wear Red Day, Go Red Luncheons, and events that prompted and empowered women to take action. Since the launch of the Red Dress Campaign, dedicated to increasing recognition of CVD in women, awareness of heart disease as a leading cause of death among US women has almost doubled at 54% in 2012, in comparison with 30% in 1997 [22]. These activities coincided with the release of the first-ever evidence-based guidelines focused on the prevention of heart disease in women [23]. The AHA Go Red for Women campaign has expanded its scope to encompass the creation of risk-assessment tools, disease-management guidelines and their implementation, and sex-specific research to decrease the high morbidity of CVD in women.

Despite recent advances, public awareness of CVD remains suboptimal. This is particularly true among women. In 2014, the Womeńs Heart Alliance conducted a nationwide survey of women ages 25–60 years. Overall, 45% of women were unaware that heart disease is the number one killer of women in the United States, and this knowledge gap is worse among younger women (58% of women between the ages of 25 and 29 vs. 35% of women between 50 and 60). The results also showed low awareness in women with lower levels of education: 55% of women with some college or less vs. 28% of women with college degrees and a similar gradient by income levels. Hispanic women (73%) and African American women (55%) were more likely to be unaware of heart disease being the leading cause of death than non-Hispanic (NH) white women (34%) [11].

Public awareness among women is also low regarding linkages between heart disease and risk factors such as diabetes (43%), autoimmune disease (19%), pregnancy complications (21%), early menopause (10%), and irregular periods (5%) [11].

Even though the awareness of atypical signs of a heart attack has risen due to national awareness initiatives, with 18% in 2012 [12] up from 10% in 1997 [22], the overall recognition levels remain quite low. In the Womeńs Heart Alliance survey, less than half the women knew that jaw pain, cold sweats, nausea, or anxiety could be symptoms of heart disease and/or heart attack [11].

Even when women correctly recognized the symptoms of heart disease, not all women reported they would seek medical attention or call 9-1-1 if they had these symptoms. According to a poll conducted by the AHA in 2012 among US women >  25 years of age, when asked what they would do first if they thought they were experiencing signs of a heart attack, 65% of women in 2012 reported that they would call 9-1-1 compared with 53% in 2009. When asked what they would do first if they thought someone else were experiencing signs of a heart attack, 81% of women reported that they would call 9-1-1 [12].

The 2014 Womeńs Heart Alliance survey also showed that nearly 71% of women rarely raised the issue of heart health with their physicians even if they had risk factors for CVD [11]. Reasons for this low prioritization were most frequently lack of knowledge and competing demands. However, the underlying reasons for the misperception of CVD risk, suboptimal prioritization of cardiovascular health, and avoiding medical care are poorly understood. Women reported that factors influencing these behaviors included prioritizing others over self, caretaker responsibilities, tendency to minimize personal health concerns to avoid placing a burden on others, inadequate financial resources, and lack of personal confidence to make a lifestyle change [11]. Social stigma, in particular regarding body weight, constituted a significant barrier to women discussing heart health and taking action to reduce risk. Nearly half the women surveyed canceled or postponed healthcare visits because of weight issues [11] (Figure 4).

Figure 4 Potential Barriers for Women Seeking Care. Women often do not prioritize their cardiovascular health and reported several barriers that account for this behavioral trend. Data from [11].

Patients’ perceptions of discussions with their healthcare providers regarding heart disease issues have changed over time. In 2003, 38% of women reported discussing heart disease with their doctor, and, after the AHA Go Red for Women Initiative, this number rose to 54% in 2005 [22]. Alarmingly and for unclear reasons, the percentage of women reporting discussions with their providers about heart disease risks has markedly declined, from 48% in 2009 [15] to 21% in 2012 [12]. These rates are even lower among Hispanic women than among white or black women [11].

In a study of young and mid-life women (ages 18–55) hospitalized with acute myocardial infarction (MI), ~  50% perceived themselves to be at low risk for heart disease despite nearly all patients (98%) having at least one established risk factor, and 64% having three or more risk factors [24]. Furthermore, in those patients with acute MI and no previous history of CHD, women were 21% less likely to report prior provider discussions about heart disease and ways to modify CVD risk than men who were hospitalized with acute MI [24].

Medical Awareness

In February 2004, AHA released Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women to assist healthcare providers in determining appropriate preventive CVD care based on a womańs future risk. Successful adoption of practice guidelines is related to physician awareness and agreement, self-efficacy, outcome expectancy, and practice habits, in addition to patient- and system-related factors [25]. That same year, a national online survey of physicians demonstrated that fewer than one in five physicians were aware that more women died each year of CVD than men [26]. Ten years later, in 2014, the Womeńs Heart Alliance surveyed 200 primary care providers (PCPs) and 100 cardiologists to determine their self-reported preparedness to address CVD risks in their female patients [11]. PCPs reported CVD as a top health concern in women, but less important than weight-related health concerns and breast health. Most physicians reported suboptimal training in assessing CVD risks in women (22% PCPs and 42% cardiologists) [11]. A single-center survey of 80 postgraduate trainees demonstrated that although 60% recognized the importance of and need for the implementation of gender-based concepts in their formal curriculum, nearly 70% of respondents reported no or only minimal formal training regarding sex- and gender-specific medicine concepts in their education programs or didactic lectures [27].

The perception of lower CVD risk in women than in men has been implicated as the primary factor in underutilization of preventive recommendations [26, 28]. The 2004 online survey assessed knowledge and incorporation of national CVD prevention guidelines in 300 PCPs, 100 obstetricians/gynecologists (Ob/Gyns), and 100 cardiologists [26]. Cardiologists and PCPs had a high level of awareness of contemporary hypertension and lipid guidelines (>90% for both), but a lower awareness of the AHA’s CVD prevention guidelines for women (80% and 60%, respectively) [26]. Ob/Gyns reported 60% awareness of hypertension guidelines, 45% awareness of lipid guidelines, and 60% awareness of CVD prevention guidelines for women. Incorporation of CVD prevention guidelines for women into practice was <  42% in all three groups [26].

Similarly, the Womeńs Heart Alliance survey demonstrated that 16% of PCPs and 22% of cardiologists were implementing the AHA’s guidelines for CVD risk assessment in women. Specifically, they reported that they: (1) discussed personal and family medical history and pregnancy complications that further increase heart disease risk; (2) asked about any heart disease symptoms; (3) asked about smoking, diet, and physical activity habits; (4) screened for depression among women with heart disease; (5) conducted a physical examination that included blood pressure, body mass index (BMI), and waist circumference; (6) measured cholesterol, triglycerides, and glucose levels; (7) calculated 10-year and lifetime heart disease risk; and (8) talked with women about what each of these means for their heart health [11]. Only one in four PCPs and one in five cardiologists reported implementing at least five of the eight recommended CVD risk assessments in women [11]. Physician utilization of the American College of Cardiologists/AHA Atherosclerotic Cardiovascular Disease pooled cohort equation risk estimator was better (44% PCPs and 53% cardiologists) [11]. Despite medical society-endorsed guidelines for CVD prevention, major gaps remain in physicians’ self-perception of preparedness to assess womeńs CVD risks and in the application of guidelines in clinical practice [11].

The Burden of Heart Disease in Men and Women

Despite enormous declines in the burden of CVD in the past decades, mainly due to improvements in primary and secondary prevention, CVD disease remains the main cause of premature death and disability among men and women worldwide. Statistics from the Global Burden of Disease Study show that CVD in 2013 accounted for 35% of all deaths in women and 32% in men throughout the world [29]. In the United States, CVD is not only the leading cause of death, but also one of the costliest chronic conditions, constituting 17% of overall national health expenditures [30, 31].

Based on NHANES 2013–2016 data, the prevalence of CVD (comprising CHD, HF, stroke, and hypertension) in adult women ≥  20 years of age was 44.7% (60 million) vs. 51.2% (61.5 million) in adult men [1]. In 2011, the AHA commissioned a report that showed that by 2035, ~  40% of the US population would suffer from CVD. Unfortunately, that prediction came true in 2015. That same year, the death rate from heart disease rose by 1% for the first time since 1969 [8]. The AHA repeated its projections of the prevalence and economic burden of hypertension, CHD, HF, stroke, atrial fibrillation, and other heart diseases from 2015 to 2035 [3]. This latest study projects that by 2035, in the US, there will be:

●123.2 million with hypertension

●24 million with CHD

●11.2 million suffering from stroke

●7.2 million with atrial fibrillation

●8.8 million with HF

The prevalence of total CVD is higher among men than women; however, the prevalence of hypertension, HF, and stroke is higher among women than among men. The prevalence is expected to increase for all conditions among both sexes [3]. Total costs of total CVD in the United States in 2015 were higher among males ($325 billion) than females ($252 billion) and are projected to increase to $591 billion and $525 billion, respectively, by 2035. However, for congestive heart failure, stroke, and atrial fibrillation, the costs are higher among women than among men.

Most of the burden of CVD can be explained by a set of traditional risk factors that affect both men and women, including smoking, overweight and obesity, hypertension, diabetes, and elevated cholesterol. Increased recognition of the prevalence of traditional CVD risk factors, and their differential impact on women, as well as emerging, nontraditional risk factors unique to or more common in women, contribute to a new understanding of mechanisms leading to worsening outcomes for women (Figure 5).

Figure 5 Traditional and Nontraditional Cardiovascular Risk Factors in Women. BP, blood pressure; DM, diabetes; HDL, high-density lipoprotein; HTN, hypertension; IHD, ischemic heart disease; LDL, low-density lipoprotein; MI, myocardial infarction; SLE, systemic lupus erythematosus; TG, triglycerides. Reproduced with permission from [32].

Prevalence and Epidemiology of Risk Factors in Women

Diabetes

More than 11.7 million US women have a diagnosis of diabetes mellitus (DM) and ~  95% of these women have type 2 diabetes mellitus (T2DM) [33]. The increasing prevalence of T2DM is concerning because it is a potent risk factor for CVD and has long been recognized to confer greater risk for CVD death in women compared with men [34]. A growing body of literature shows that there are appreciable and clinically relevant differences in how diabetes affects the risk of CVD in men and women.

A recent pooled analysis summarizing data from 64 cohorts, including nearly 900,000 individuals and more than 28,000 incident CHD events, showed that the presence of diabetes nearly tripled the risk of incident CHD in women (RR 2.82 [95% CI 2.35; 3.38]), whereas it little more than doubled the risk in men (RR 2.16 [95% CI 1.82; 2.56]) [35]. Therefore, diabetes conferred a 44% (95% CI 27–63%) greater excess risk for incident CHD in women compared with men.

Moreover, there is a threefold excess fatal CAD risk in women with T2DM compared with nondiabetic women (95% CI, 1.9–4.8) [36]. In addition, a pooled analysis on data from 750,000 individuals and more than 12,000 incident stroke events provided strong evidence that women with DM have a 27% (95% CI 10, 46%) greater increased risk of stroke compared with their male counterparts; the pooled relative risk of stroke associated with diabetes was 2.28 (95% CI 1.93, 2.69) in women and 1.83 (95% CI 1.60, 2.08) in men, independent of sex differences in other major cardiovascular risk factors [37].

Women who progress from normoglycemia to prediabetes have higher levels of endothelial dysfunction, higher blood pressure, and more abnormalities in their fibrinolysis and thrombosis pathways compared with those who do not, and such differences are more pronounced than in men [38].

Early diagnosis of diabetes is essential, particularly in racial/ethnic groups at high risk for diabetes, such as African Americans, Hispanics, American Indians, and Pacific Islander Americans. The burden of diabetes varies greatly by race/ethnicity, with blacks having the highest age-adjusted prevalence, followed by Hispanics, Asians, and then NH whites [39]. Compared with white postmenopausal women in the United States, there is a more than twofold higher risk of diabetes in blacks and approximately twofold higher risk in Hispanics and Asians [40].

Hypertension

Hypertension significantly increases the risk of MI, HF, atrial fibrillation, and stroke. Premenopausal women are at a higher risk of hypertensive end-organ damage than age-matched men, including microalbuminuria (13.7% vs. 6.2%, P = 0.002) and left ventricular hypertrophy (26.4% vs. 8.8%, P < 0.0001) [41]. According to NHANES 2013–2016 data, the prevalence of hypertension is higher in women than men (77.8% in women vs. 70.8% in men in the 65–74 age group, 85.6% in women vs. 80% in men in the >  74 age group), but less than half receive adequate treatment [42]. Hypertension is often poorly controlled in older women; only 23% of women vs. 38% of men >  80 years have a BP <  140/90 mmHg [43]. The prevalence of hypertension is 25.3% among Hispanic women, and only 37.5% have controlled BP [44].

Dyslipidemia

Elevated serum lipid levels are the greatest contributor to development of ischemic heart disease worldwide, and clinical trials have shown that low-density lipoprotein cholesterol reduction with statins leads to improved CVD outcomes [45]. Statin therapy has similar proportional benefits for women and men in CVD event reduction [46].

Nevertheless, sex differences in statin treatment and adherence to guideline-recommended lipid management are well documented [47–49]. Female patients have historically received less aggressive lipid management than male patients, and the reasons underlying this remain poorly understood. A recent study comprising a large sample of US adults seen in community practice found that women were less likely than men to receive guideline-recommended statin therapy (67.0% vs. 78.4%; P < 0.001) or to receive a statin at the guideline-recommended intensity (36.7% vs. 45.2%; P < 0.001). Potential causes of these disparities include the following: women were less likely to report having been offered statin therapy, more likely to decline statin therapy when offered, and more likely to discontinue statin therapy after starting [50].

Obesity

More than two in three adults in the United States are classified as overweight or obese, and the prevalence of obesity is higher among women than among men [51]. While elevated BMI is associated with increased fatal and nonfatal ischemic heart disease in both women and men, sex differences in fat distribution have been implicated in ischemic heart disease. Women predominantly accumulate subcutaneous fat, whereas men accumulate significantly more visceral fat.

It is established that abdominal or central adiposity is an important predictor of chronic disease risk independent of total adiposity [52]. For example, individuals with a higher proportion of abdominal fat have a greater risk of developing CHD [53, 54], T2DM [55, 56], and cancer [57].

The trunk-to-leg fat ratio can be considered a marker of body shape. Studies have reported heterogeneity of body fat distribution across racial groups. Abdominal visceral adiposity has been reported to be significantly greater in white men and women compared with black men and women, and white women have lower measures of subcutaneous adipose tissue than black women [58]. Black women tend to have more pear-shaped bodies, i.e., they tend to have more subcutaneous fat deposited in the hips and thighs vs. in the abdominal areas [59].

BMI, waist circumference, and waist-to-hip ratio are common surrogate measures of adiposity in clinical and public health practice. Body fat distribution changes according to menopausal status, with central obesity more pronounced in postmenopausal women [60]. Postmenopausal women have increased visceral fat accrual, which has implications for development of insulin resistance, inflammatory responses, lipolysis, and CVD [61]. A recent study of postmenopausal women aged 50–79 years participating in the Womeńs Health Initiative found that in this age group across all racial/ethnic groups, waist circumference was a better predictor of diabetes risk (compared with waist to hip ratio or BMI), especially for Asian women [62].

The prevalence of obesity among US women varies markedly by race/ethnicity. According to the Centers for Disease Control and Prevention, the prevalence of obesity among adults and youth in the United States in 2015–2016 was 38.0% in NH white, 54.8% in NH black, 14.8% in NH Asian, and 50.6% in Hispanic women [63]. Based on a recent US Department of Health and Human Services Office of Minority Health report, American Indian or Alaska Native adults are 50% more likely to be obese than NH whites (43.7% vs. 28.5%) [64].

Physical Inactivity

According to data from a 2011 National Health Interview Survey in adults, inactivity was higher among women than men (33.2% vs. 29.9%, age-adjusted) and increased with age from 26.1% to 33.4%, 40.0%, and 52.4% among adults 18–44, 45–64, 65–74, and ≥  75 years of age, respectively [65].

Smoking

Tobacco use increases CVD risk, including progression of atherosclerosis, MI, and sudden cardiac death. Importantly, in women, the combination of smoking with oral contraceptive use has a synergistic effect on risk of acute MI, stroke, and venous thromboembolism.

A meta-analysis conducted in 2011 reported that in all age groups, with the exception of the youngest (30–44 years), women had a 25% increased risk for CAD conferred by cigarette smoking compared with men [66]. A meta-analysis to estimate the effect of smoking on stroke according to sex showed evidence of a more harmful effect of smoking in women than in men in Western (relative risk ratio [RRR], 1.10 [1.02–1.18]) but not in Asian (RRR, 0.97 [0.87–1.09]) populations [67]. A large population-based case-control study found that women who were current smokers and used oral contraceptives had an 8.8-fold higher risk (odds ratio [OR] 8.79, 95% CI 5.73–13.49) of venous thrombosis than nonsmoking women who did not use oral contraceptives [68].

Psychological Stress

Psychological stress remains an understudied, underappreciated and poorly managed cardiovascular risk factor. The INTERHEART study provided the first substantive data supporting the relationship between stress (OR 1.45), depression (OR 1.55) and first MI [69]. After an MI, depression, trauma, and perceived stress are disproportionately common in younger women compared with their male counterparts or older patients [70, 71] and are powerful predictors of cardiovascular risk in young women [72–74]. Moreover, young women after MI have a twofold likelihood of developing mental stress-induced MI compared with men (22% vs. 11%, P = 0.009) [75]. Future research will be vital to better address this important association and develop strategies to mitigate this major risk factor.

Risk Factors Unique to Women

Early Menopause

After menopause the incidence of CVD increases substantially. One systematic review found an increased risk of CVD, CVD mortality, and all-cause mortality in women who experienced early menopause [76].

Adverse Pregnancy Outcomes

Pregnancy is a metabolic stress test and provides a unique opportunity in women to analyze their future risk of developing CVD. The 2011 guidelines for CVD prevention in women incorporated adverse pregnancy outcomes as cardiac risk factors [77]. These include gestational diabetes, preeclampsia, eclampsia, hypertensive disorders of pregnancy, and preterm delivery, all associated with increased future heart disease risk [78]. A diagnosis of preeclampsia doubles the risk of future diabetes and stroke [79] and is associated with a nearly fourfold elevated risk for developing hypertension within 14 years of pregnancy [80]. Gestational DM increases the risk of developing T2DM by sevenfold, which is a major risk factor for subsequent atherosclerotic cardiovascular disease, but also raises CVD risk (twofold for stroke and fourfold for MI) independently of the interim development of overt T2DM [81].

Multiparity

According to a recent study, multiparity is associated with poorer cardiovascular health, especially among women with five or more live births. The Life’s Simple 7 cardiovascular health score, defined according to AHA criteria, was recently examined in relation to parity (a score of 0–8 was considered inadequate, 9–10 average, and 11–14 optimal). Among women with a mean (SD) age of 62 (10) years, the mean (SD) cardiovascular health score was lower with higher parity (8.9 [2.3], 8.7 [2.3], 8.5 [2.2], and 7.8 [2.0] for 0, 1–2, 3–4, and ≥ 5 live births, respectively) [82].

Incidence and Prevalence of Coronary Heart Disease

According to the Heart Disease and Stroke Statistics 2019 update from the AHA, using data from 2013 to 2016, an estimated 18.2 million Americans >  20 years of age have CHD, with a prevalence of 9.4 million (7.4%) in men and 8.8 million (6.2%) in women [1]. Based on data from 1995 to 2012, 23% of women age 45 and older who have an initial recognized MI die within a year compared with 18% of men. However, within 5 years after a first MI, 47% of women and 36% of men will die [1] (Figure 6).

Figure 6 Burden of Coronary Artery Disease in the United States. Data from [1].

Observed sex differences in the incidence and presentation of CHD in population might be partially explained by distinct pathophysiological processes leading to MI [1]. Women have less obstructive and extensive epicardial artery disease than men but are more prone to have impaired coronary vasomotor function and microcirculatory dysfunction. Population-based studies reported a lower calcium score [83] and atheroma volume [84] in women when compared with men.

A study, performed within the Rotterdam cohort, investigated sex-based differences of the vascular tree. Median coronary calcium scores, mean carotid intima-media thickness, and carotid plaque scores were higher in men than in women in all age groups. The findings of this study showed that sex differences in the coronary vessels were larger than in the other vascular beds; moreover, the observed sex differences in atherosclerosis of the coronary arteries were particularly pronounced in younger participants but still present in the older age groups. The age-adjusted male:female odds ratios of having a calcium score above 1000 in the two lowest age tertiles were 6.9 (95% CI: 3.4, 13.9) and 7.4 (95% CI: 4.3, 12.7), showing that men have a substantially higher burden of coronary calcification than women [83].

A systematic analysis demonstrated that women have less plaque in terms of percent atheroma volume (33.9 ± 10.2% vs. 37.8 ± 10.3%, P < 0.001) and total atheroma volume (148.7 ± 66.6 mm³ vs. 194.7 ± 84.3 mm³, P < 0.001). With medical therapy, the rate of change in both measures did not differ between sexes [84].

On the other hand, based on available experimental and clinical data, microvascular dysfunction is considered as a major etiological factor for CHD in the absence of significant coronary obstruction, particularly in women [85]. Further clarification of the pathophysiological processes underlying CHD may help with tailoring sex-specific strategies for the prevention, detection, and management of CHD. Due to sex differences in pathophysiology and clinical manifestation of CHD (discussed in Chapter 3), clinical symptoms of myocardial ischemia in women are often regarded as atypical and likely to be ignored or misdiagnosed [86]. As a consequence, women with overt CHD may have delays in diagnosis and treatment, contributing to worse prognosis and outcomes [87].

Data from 44 years of follow-up in the original Framingham Study cohort and 20 years of surveillance of their offspring have allowed ascertainment of the incidence of initial coronary events including both recognized and clinically unrecognized MI, angina pectoris, unstable angina, and sudden and nonsudden coronary deaths [88–90]. The following observations were noted:

●For adults aged 40 years, the lifetime risk of developing CHD is 49% in men and 32% in women. At age 70 years, this risk increases to 35% in men and 24% in women.

●For total coronary events, the incidence rises steeply with age, with women lagging behind men by 10 years. For the more serious manifestations of coronary disease, such as MI and sudden death, women lag behind men in incidence by 20 years, but the sex ratio for incidence narrows progressively with advancing age [91]. The incidence at ages 65–94 compared to ages 35–64 more than doubles in men and triples in women.

●In premenopausal women, serious manifestations of coronary disease, such as MI and sudden death, are relatively uncommon. Beyond menopause, the incidence and severity of coronary disease increases abruptly, with rates three times those of women the same age who remain premenopausal [88].

Incidence and Prevalence of Heart Failure

According to data from NHANES 2013–2016, an estimated 6.2 million Americans ≥  20 years of age had HF [1]. By 2030, the incidence of HF is projected to rise by 46%, affecting more than 8 million individuals. HF affects both sexes equally and is a leading cause of morbidity and mortality.

By the age of 40, men and women have equal lifetime risks of developing HF. At 40 years of age, the lifetime risk of developing HF for both men and women is one in five [1, 92]. Occurrence of HF increases with advancing age, and women at older ages are at greater risk than men [93].

Incidence rates of HF in men approximately double with each 10-year increase in age from 65 to 85 years; however, the HF incidence rate triples for women between ages 65–74 and 75–84 years [1].

In the Atherosclerosis Risk in Communities Study (ARIC), the age-adjusted incidence rate per 1000 person- years was lowest for NH white women (3.4) compared with all other groups, including NH white men (6.0), NH black women (8.1), and NH black men (9.1) [94].

Incidence rates in black women were more similar to those of NH black men than of white women [94].

The lifetime risk of developing HF differs by sex and race. Data from the NHLBI-sponsored Chicago Heart Association Detection Project in Industry, ARIC, and the Cardiovascular Health Study cohorts indicate that lifetime risks for HF were 30–42% in white males, 20–29% in black males, 32–39% in white females, and 24–46% in black females [95].

Patients with HF and preserved ejection fraction are more often female and older compared to those with HF and reduced systolic function [96, 97]. According to the 2019 AHA Heart Disease and Stroke Statistics Update, white women had the highest proportion of hospitalized HF with preserved ejection fraction (59%), whereas black men had the highest proportion of hospitalized HF with reduced ejection fraction (70%) [1].

Over the past 50 years, the incidence of HF has declined among women but not among men [98]. Survival after the onset of HF has improved in both sexes, however (~  12% per decade; P = 0.01 for men and P = 0.02 for women) [98]. Men and younger adults have experienced larger survival gains compared to women and the elderly [99].

Incidence and Prevalence of Atrial Fibrillation

Estimates of the prevalence of atrial fibrillation in the United States ranged from ~  2.7 million to 6.1 million in 2010 [100, 101].

In the Framingham Heart Study, atrial fibrillation incidence (per 1000 person-years) was 3.8 in men and 1.6 in women [102]. The Olmsted County Minnesota Study reported the atrial fibrillation incidence (per 1000 person-years) in men to be 4.7 compared with 2.7 in women [101]. Despite higher incidence of atrial fibrillation in men, lifetime risks of atrial fibrillation in women and men are similar owing to longer life expectancy for women. In the Framingham Heart Study [103], the lifetime risks of atrial fibrillation in women and men at age 60 years were 23.4% and 25.8%, respectively.

Atrial fibrillation incidence has been shown to increase markedly with increasing age in both women and men, reaching as high as 30.4 per 1000 person-years in women and 32.9 per 1000 person-years in men by age 85–89 years [104]. In a Medicare sample, per 1000 person-years, the age- and sex-standardized incidence of atrial fibrillation was 27.3 in 1993 and 28.3 in 2007, representing a 0.2% mean annual change (P = 0.02). Of individuals with incident atrial fibrillation in 2007, ≈  55% were females, 91% were white, 84% had hypertension, 36% had HF, and 30% had cerebrovascular disease [105].

Atrial fibrillation is associated with worse symptoms and quality of life [106], and increased risk of complications such as stroke [107, 108] and mortality [109], in women compared to men.

Incidence and Prevalence of Peripheral Arterial Disease

According to data from several US cohorts during the 1970s to 2000s and the 2000 US Census, 6.5 million Americans ≥  40 years (5.5%) are estimated to have low ankle-brachial index (ABI) (<  0.9) [110]. Of these, one-fourth have severe PAD (ABI <  0.7) [110]. The population-based prevalence of PAD in women has been incompletely evaluated. In contrast to the abundant data defining the sex-specific prevalence of CHD and stroke, few population surveys of PAD have been performed, and ongoing PAD surveillance is not currently conducted in any state or nation. Thus, in calculating the relative prevalence of PAD, it has been noted that many population-based studies of PAD do not report prevalence for women separately. In the published literature, the results are mixed with respect to differences in prevalence by sex. In a systematic review, the prevalence of PAD in women 45–93 years of age was reported to range from 3% to 29% [111].

In-hospital mortality was higher in females than males, regardless of disease severity or procedure performed, even after adjustment for age and baseline comorbidities: 0.5% vs. 0.2% after percutaneous transluminal angioplasty or stenting for intermittent claudication; 1.0% vs. 0.7% after open surgery for intermittent claudication; 2.3% vs. 1.6% after percutaneous transluminal angioplasty or stenting for critical limb ischemia; and 2.7% vs. 2.2% after open surgery for critical limb ischemia (P < 0.01 for all comparisons) [112].

Temporal Trends

Over the past few decades, the incidence of CHD has decreased in developed nations. An analysis of the NHANES 1 Epidemiologic Follow-up Study examined the incidence of CHD in two cohorts: one comprised 10,869 patients between 1971 and 1982, and a second included 9774 patients between 1982 and 1992 [43]. A decrease was found in the incidence of CHD from 133 to 114 cases per 10,000 people per year of follow-up, as well as an overall decline in CVD from 294 to 225 cases per 10,000 patients. The Mayo Clinic, as part of the Rochester Epidemiology Project, utilized a population-based data resource including the complete medical records of all of the residents of Olmsted County, Minnesota to analyze the incidence of newly diagnosed CHD in the local population, over a 10-year period from 1988 to 1998 [44]. The study reported a decline, from 57 to 50 cases per 10,000 people, in the age-adjusted incidence of new CHD, including CHD diagnosed by angiography, unstable angina, MI, and sudden death.

Temporal trends in sudden cardiac death and nonsudden CHD death in the Framingham Heart Study original and offspring cohorts, from 1950 to 1999, were examined. From 1950–1969 to 1990–1999, overall CHD death rates decreased by 59% (95% CI 47–68%, P(trend) < 0.001). Nonsudden CHD death decreased by 64% (95% CI 50–74%, P(trend) < 0.001), and sudden cardiac death rates decreased by 49% (95% CI 28–64%, P(trend) < 0.001). These trends were seen in both men and women, in those with and without a prior history of CHD, and in smokers and nonsmokers [113].

Although the numbers are remarkable—mortality rates due to CHD between 1980 and 2002 fell almost 52% for men and 49% for women [45]—CHD remains the number one cause of death in the United States, and these trends are not experienced equally among different demographic groups. The overall decline in CHD mortality rates have flattened to less than 1% per year since 2011, and rates have even worsened for the most at-risk populations. While decline in mortality rates have slowed in men, from −  6.2% between 1980 and 1989 to −  0.5% in 2000–2002, the plateauing of the decline in mortality rates is even more marked in women, from −  5.4% to 1.5%