Preventing and Experiencing Ischemic Heart Disease as a Woman: State of the Science

The Institute of Medicine has defined sex as “the classification of living things, generally as male or female according to their reproductive organs and functions assigned by the chromosomal complement.”¹ The term “sex” means biological differences between women and men, including chromosomes, sex organs, and hormonal contributions.² Sex differences result from true biological differences in the structure and function of the cardiovascular systems of men and women. In contrast, gender differences ensue from a person’s self-representation resulting in psychosocial roles and behaviors imposed by society; gender implies social roles, behaviors, and cultural norms.

Gender differences play a role in treatment of cardiovascular disease (CVD) and impact outcomes, but these are very different from sex differences that arise from the genetic differences between men and women. Sex differences are a result of a single chromosomal difference between men (XY) and women (XX). Gender, however, is a social construct that differentiates men from women in a society as they assume their social roles. Gender develops on the basis of cultural norms and is articulated through values, perceptions, psychosocial characteristics, and behaviors.^3,4 Sex and gender-specific science addresses how experiences of the same disease, e.g., ischemic heart disease (IHD), are similar and different with respect to biological sex and gender. For instance, women tend to have smaller coronary arteries than men and women have less obstructive IHD than men. ^5–7 These differences affect the mechanism and expression of CVD between the sexes. Sex differences in the cardiovascular system are summarized in Table 1.

Table 1.

Sex-Related Differences in the Cardiovascular System

Parameter	Manifestations
Anatomy	Dimensions that are smaller in women (adjust for age and race): left ventricular mass, ventricular wall thickness, left atrial dimension, left ventricular end-diastolic dimension, and vessel size
Hormonal influences	Estrogen and progesterone are most influential in women; testosterone is predominant in men Menstruation can affect hematologic and electrocardiographic indices
Cardiovascular function	Stoke volume is women is 10% less Pulse rate in women is 3–5 beats/minute faster Ejection fraction is higher in women
Physiology	Women have reduced sympathetic and enhanced parasympathetic activity Women have lower plasma concentrations of norepinephrine
Cardiovascular adaptations	In response to stress, women experience an increased pulse rate, resulting in increased cardiac output; men increase vascular resistance, resulting in increased blood pressure Women are more sensitive to altitude or body positioning changes and experience more orthostatic hypotension and syncope
Hematologic indices	Women have a lower number of circulating red blood cells per unit volume of plasma (resulting in a lower hematocrit) Because of a lower hemoglobin, women have a lower oxygen-carrying capacity; this is balanced by women having a lower oxygen consumption
Electrocardiographic and electrophysiologic indices	Women on average have a longer corrected QT interval and a shorter sinus node recovery time Drug-induced torsades de pointes is more common in women Sudden cardiac death and atrial fibrillation are less common in women

Finks S. Cardiovascular Disease in Women. Pharmacotherapy Self Assessment Program Seventh Edition Book 1 Cardiology. 7 ed. American College of Clinical Pharmacy; 2010. 179–201.³⁵⁰

Need permission to use Table 1.

During the last two decades, we have learned that sex differences exist in the pathophysiology of coronary heart disease, symptom presentation, efficacy of diagnostic tests, response to pharmacological interventions, and clinical outcomes of IHD. We have also learned that sex variations exist, such as delay in seeking treatment, which may also contribute to differences in clinical outcomes and mortality rates. Several milestones have contributed to the progress that has been made thus far (See Table 2). These important milestones are instrumental in laying the foundation for evidence-based interventions to decrease the IHD burden in women to promote their cardiovascular health. However, this knowledge has accumulated slowly and often in isolation, resulting in women continuing to experience difficulty in receiving a diagnosis of IHD and timely appropriate treatment. This paper presents a through compilation of the most current research related to IHD in women. Importantly, it focuses on studies that document women’s experiences and influential factors that impact their receiving a correct diagnosis and timely treatment for IHD. In this paper, IHD is inclusive of coronary heart disease.

Table 2.

Milestones in Sex and Gender Differences in Research

1985	Public Health Service Task Force on Women’s Health was established. Recommendations for a greater focus on women’s health issues led to guidelines for inclusion of women in NIH-funded extramural research (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1424718/, accessed 1/2/2015).
1990	The NIH created the Office of Research on Women’s Health to insure that women’s health issues were appropriately addressed and women were represented in NIH-supported research (http://orwh.od.nih.gov/about/AMIssion.asp, accessed 1/2/2015).
1993	The NIH Revitalization Act included a Clinical Equity Provision to confirm that treatment effectiveness for women is not merely extrapolated from studies in men but instead is based on research in women (http://orwh.od.nih.gov/about/pdf/NIH-Revitalization-Act-1993.pdf, accessed 1/2/2015).
2001	The Institute of Medicine (IOM) Report Exploring the Biological Contributions to Human Health: Does Sex Matter? States that sex is a key biological variable that must be considered when designing and analyzing both basic and clinical research (http://www.iom.edu/Reports/2001/Exploring-the-Biological-Contributions-to-Human-Health-Does-Sex-Matter.aspx, accessed 1/2/1015).

Methods

Writing group members were nominated by the committee chair and co-chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Cardiovascular and Stroke Nursing Council’s Leadership Committee and the AHA’s Manuscript Oversight Committee. The writers used PubMed and Medline searches using the search terms listed in Table 3. We primarily searched literature from 2000–2015 but included earlier seminal studies as appropriate. All members of the writing group had the opportunity to comment and approved the final version of this document. The document underwent extensive external peer review and approval by the AHA Science Advisory and Coordinating Committee.

Table 3.

Search terms

Chest pain OR myocardial infarction OR angina OR myocardial ischemia OR heart attack OR heart infarction OR heart muscle ischemia OR ischemic heart disease OR cardiovascular disease OR coronary heart disease OR coronary artery disease OR acute coronary syndrome Women OR woman OR gender OR sex OR sex factors OR female OR sex difference Time-to-treatment OR delay OR delayed OR time OR early diagnosis OR emergency medical services OR delayed diagnosis OR patient acceptance of health care OR therapy delay Ethnic groups OR ethnicity OR racial OR race Risk factors OR smoking OR hypertension OR diabetes mellitus Behavior OR risk self-assessment OR cardiac risk awareness OR risk awareness OR awareness OR perception OR understanding OR symptom recognition OR symptom interpretation OR psychosocial Bias OR stereotyping OR prejudice OR gender attitudes OR disparities Outcomes Health care provider OR doctor OR clinician

I. Scope of the Problem: Epidemiology of IHD in Women

The epidemiology of IHD is multifactorial and includes the contribution of risk factors such as age, race, genomics, ethnicity, culture, social, lifestyle and environmental influences that may negatively impact the disease process. These factors may behave singly or interact multiplicatively to influence IHD.

Age

IHD is vast, affecting approximately 15.5 million Americans ≥20 years of age with a lower prevalence rate for women (5.0%) when compared to men (7.6%).⁸ However, after age 45 for men and after age 55 for women, the risk for IHD increases similarly in both groups. Although it has been assumed that premenopausal women (usually before age 55) possess cardio-protective effects of estrogen, surprisingly, hormone replacement therapy has not been shown to be effective in protecting against IHD in postmenopausal women, and in fact, may be harmful. ⁹

The life expectancy for women is greater than that of men contributing to an increased aged female population with greater IHD risk.¹⁰ However, it is particularly worrisome that IHD death rates in younger women aged 35 to 44 continue to increase while it is decreasing in their male counterparts.^8,11,12 Although risk factors such as obesity, diabetes, hypertension, smoking, and metabolic syndrome in younger women are thought to be the primary culprit in these troubling IHD trends, lack of recognition of prodromal symptoms and failure to assess for IHD in these younger women may contribute to this disturbing trend. ¹¹

Race

Race is construed as a biological factor determined by genetics. However, science indicates that race is best described as social rather than biological because there is more variation of genes within than between races. Genetically, the DNA sequence in all people is 99.9% identical, making race indistinguishable.^13–15 However, despite scientific evidence, a social stratum exists that distinguishes groups of people according to phenotypic characteristics (e.g. skin color, body shape, and hair texture) that impose social concerns.¹⁵

Interestingly, racial/ethnic variations in IHD exist in the United States (U.S.) and Black women have higher prevalence rates (7.0%) of IHD when compared to Hispanic (5.9%) and White (4.6%) women. Respectively, the same trend is noted with myocardial infarction (2.2%, 1.7%, and 1.8%) and angina (5.0%, 3.8%, and 2.9%).¹² AHA’s statistical data for Asian and American Indian/Alaska Native women are either not listed or did not meet the standards of reliability.⁸ According to the Centers for Disease Control and Prevention,¹⁶ the leading cause of death for Black (23.4%) and White (22.9%) women is IHD, while it is considered the second leading cause of death for Hispanic (20.5%), Asian/Pacific Islander (20.8%), and American Indian/Alaska Native (16.9%) women. Cancer is regarded as the leading cause of death for Hispanic, Asian/Pacific Islander, and American Indian/Alaska Native women. However, when Asian subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) are further delineated, IHD is the leading cause of death for Asian Indian and Filipino women.¹⁷ A plausible explanation for higher death rates in these racial/ethnic groups is that these women have more risk factors for CVD.

Genomics

While there is no genetic basis for racial classification, there may be genetic and genomic influences that place some women at increased risk of developing IHD.^18,19 A more detailed review of genetic and genomic concepts in CVD, is found in an AHA Scientific Statement.²⁰ IHD is considered a complex, multifactorial disease because it is influenced by multiple genes and the environment. With multifactorial diseases, a woman may inherit one or more alleles which put her at increased risk but environmental factors also influence disease development and progression. Environmental factors can influence the development or prevention of multifactorial disease even in the presence or absence of genetic risk factors depending on the health behaviors of the individual. In other words, a woman may inherit one or more alleles that increase susceptibility to IHD but if she is never exposed to environmental risk factors such as a high fat diet or sedentary lifestyle she may never develop IHD. Therefore, inheriting alleles that place a woman at increased risk does not mean that she is destined to develop a multifactorial disease. Interventions, even for women at great risk of developing IHD and associated complications, may prevent disease and prolong years and quality of life. Women with increased susceptibility to IHD due to genetic or environmental risk factors should receive education regarding how to reduce their risk.

Ethnicity and Culture

Identification with an ethnic group often implies shared cultural traditions. Although ethnicity is frequently associated with culture, the two are distinct terms. Ethnicity refers to ancestry and a person’s country of origin or place of parental or ancestor birth²¹ and is used to distinguish racial groups.¹³ On the other hand, culture denotes a learned pattern of behavior where beliefs, values, norms, and practices are shared from one generation to the next and influences thoughts and actions of a particular group.¹³

Women are influenced by their ethnicity and cultural background and thus, are not considered to be a homogeneous group. A woman’s ethnic or culture background creates complex norms and expectations that impact all aspects of life including marital status, childbearing, caregiving roles, food preparation, educational level, job choices, wage rates, health beliefs/practices, amount of political power, and degree of social influence.²² Therefore, health care providers must be prepared to address the influence of ethnicity and culture on a women’s health and well-being. The striking differences in IHD prevalence rates whereby Black women have the highest prevalence rates as compared to Hispanic and White women⁸ is evidence that ethnicity and culture identifies groups of women who are known to suffer a disproportionate burden of (CVD).

Social and Environmental

Social and physical environments have been implicated as major determinants of cardiovascular health. Certain social and physical environments tend to promote a cause and effect chain of events that contribute to developing CVD, including IHD.²³ Social conditions that impact cardiovascular health may include health behaviors (e.g. smoking and alcohol use), lack of social support, low educational levels, low income, menial jobs, and racial discrimination.²³ Physical environments that may contribute to poor cardiovascular health include low income neighborhoods, substandard housing, high-level noise pollution, living by high traffic freeways and other sources of air pollution,²⁴ food deserts (fast food restaurants and convenience stores with limited access to supermarkets and full service grocery stores), crime ridden neighborhoods, and lack of access to quality health services. Moreover, women are more likely to live in these undesirable neighborhoods, especially minority women.²⁵ In the WISEWOMAN study,²⁶ authors noted how community characteristics (e.g. racial segregation, community-level education, income characteristics, employment opportunities, and neighborhood safety) influenced CVD risk behaviors in different racial/ethnic groups. Blacks displayed the most CVD risk, while Hispanic and Alaska Native women displayed the least. Interestingly, some racial/ethnic disparities in CVD risk factors were explained by differences in individual and community characteristics, but other disparities persisted even after controlling for these factors. Thus, the impact of social and environment influences on women’s health deserves further attention.

Outcomes: Rates of Repeat AMIs, Re-hospitalization, Disability, and Mortality

Although the annual death rate from IHD between 2000 and 2010 declined 39.2 %,¹² disparities exist and women have notably poorer outcomes than men following the initial IHD presentation. Pooled data from the National Heart Lung and Blood Institute-sponsored cohort studies (1986–2007) indicate substantial disparities between men and women: 1 year after acute myocardial infarction (AMI), 19% of men and 26% of women aged 45 years or older will die. Within 5 years after a first AMI, 36% of men and 47% of women will die. Higher in-hospital mortality rates have also been reported for women with stable angina and acute coronary syndrome (ACS) compared with men.^27,28 This disparity in deaths following a first AMI preferentially affects older women since women tend to present with IHD at older ages, but as stated earlier, IHD death rates in younger women continue to escalate. Clearly, these startling disparities must be addressed.

Additionally, women have more complications after having a first AMI such as increased bleeding risk after a first AMI treated with PCI (2.4% versus 1.2% for men).²⁹ At 45 to 64 years of age, 15% of men and 22% of women have a recurrent AMI or fatal cardiovascular event within 5 years. Furthermore, 8% of men and 18% of women develop heart failure within 5 years of a first AMI. As women and men age, the rates of a subsequent AMI and heart failure equalize.¹²

Sex differences also exist with ACS symptoms. A greater proportion of women than men with anginal symptoms and ACS have non-obstructive IHD,³⁰ however more woman than men have adverse outcomes. Women with non-obstructive IHD and stable angina have greater major adverse event rates than men with non-obstructive IHD (adjusted HR 2.43, 95% CI 1.08–5.49).³¹ Further, data from the Women’s Ischemia Syndrome Evaluation (WISE) Study showed 5-year annualized event rates for cardiovascular events of 16% and 7.9% in symptomatic women with non-obstructive IHD and normal coronary arteries, respectively.³² Adverse outcomes continue over the long term for women in the WISE cohort with cardiovascular death or AMI at 10 years in 6.7%, 12.8%, and 25.9% of women with no, non-obstructive, and obstructive IHD (P<.0001), respectively.⁵

Women with suspected ACS are less likely to be diagnosed with ACS, which has often been attributed to atypical symptoms and less reliable electrocardiogram (ECG) findings.³³ However, a recent investigation reported the use of a high sensitivity troponin assay with sex-specific cutoffs increased diagnostic accuracy for women. In a study of 1126 ACS patients (46% women), the high sensitivity troponin I assay increased the diagnosis of AMI in women (from 11% to 22%; P < 0,001) but had a minimal effect in men (from 19% to 21%; P = 0,002) compared with contemporary assays with a single diagnostic threshold.^33,34 Additional studies are needed to determine if the use of a high sensitivity troponin I assay with sex-specific diagnostic thresholds will improve outcomes for women with ACS.

Finally, women with documented IHD and those who have experienced an AMI have poorer self-reported health-related quality of life and depression compared with men.^35–37 In the WISE study, depression, symptom severity, and history of depression treatment were associated with a greater risk of mortality and hospitalization, respectively.³⁸

Costs

The estimated direct and indirect cost for IHD in 2010 was $108.9 billion and is projected to more than double by 2030.³⁹ Investigators from the WISE Study estimated the average lifetime cost for women with non-obstructive IHD at $767,288 (95% CI, $708,480 to $826,097). The estimated cost ranged from $1,001,493 to $1,051,302 for women with 1-vessel to 3-vessel IHD (P=0.0003). The volume of repeat catheterizations or angina hospitalizations in 1 year was almost 2-fold higher in women with non-obstructive versus 1-vessel IHD (P<0.0001). Interestingly, women with non-obstructive or 1-vessel IHD required more drug treatment (P<0.0001).⁴⁰

Trends in Public Awareness

In response to women’s increasing mortality rates, the AHA has conducted a series of surveys to ascertain awareness of CVD by American women.⁴¹ The first survey was conducted in 1997 and revealed that only 30% of women recognized that CVD was the leading cause of death for women. Despite aggressive campaigns, such as Go Red for Women, to raise women’s awareness, a repeat survey in 2012 indicated that only 56% of White women currently recognize CVD as the leading cause of death, with even lower recognition in African American and Hispanic women. Although almost half of women in 2012 consider themselves very well or well informed about heart disease in women, they had difficulty identifying symptoms of IHD. Notably, chest pain was less frequently cited as a warning sign of a heart attack in 2012 compared with 1997 (56% versus 67%), however awareness of less typical signs of a heart attack remained very low (fatigue 10%, nausea 18%, shortness of breath 38%).⁴¹ Awareness of calling 9-1-1 if experiencing symptoms of a heart attack was also low (65%).⁴¹

II. How Women Experience Ischemic Heart Disease

A. Risk Factors

Increasing age is a significant risk factor for the development of IHD in both men and women. Women are typically 10 years older than men when their heart disease is diagnosed. Epidemiological studies suggest increased prevalence of IHD risk factors with aging explain up to 50% of the age-related increased risk of IHD in women.⁴² By midlife, more than 80% of women have 1 or more traditional cardiac risk factors.⁴³ Traditional risk factors for IHD in women are similar to those in men and include obesity, dyslipidemia, diabetes, older age, hypertension, inactivity, family history, and smoking.⁴⁴ It is important to note that IHD risk factors are commonly seen in conjunction with one another and the rate of IHD in women increases with the number of these traditional risk factors.^45–47 Among women 18–39 years of age, those with no IHD risk factors had 88% lower rates of cardiovascular mortality over an average of 31 years of follow-up compared to similarly aged women with 2 or more risk factors.⁴⁶ Prevention of major cardiovascular risk factors in females must occur at an early age, preferably early childhood, to significantly impact these trends

Although the overall number of risk factors is prognostic in both genders, the prevalence and outcomes associated with individual risk factors differ in women and men.^45,48–51 Further, the use of traditional risk factors alone has been criticized for underestimating IHD risk in women, particularly among women with subclinical disease.^{43,52, 53} Given this concern, several novel risk factors have been identified that may improve risk estimation and detection of IHD in women.⁴⁵ The following is a brief review of both the traditional and novel IHD risk factors for women.

Women’s Psychosocial Risks

As noted previously, women lag behind men in the manifestation and presentation of IHD. There are several other gender differences, for example the higher prevalence among women of some psychosocial states such as depression, which itself is a major risk factor for IHD and is twice as common in women compared to men.⁵⁴ Low and colleagues conducted a review of the literature on psychosocial risk and protective factors for IHD among women.⁵⁵ Results of the review revealed that depression is a reasonably consistent predictor of IHD among women, both incident and recurrent IHD events. While anxiety was associated with increased IHD risk among healthy women, a longitudinal study conducted by Stewart and colleagues found that anxiety was not associated with the common carotid artery intima-media thickness for females or males.⁵⁶ Two studies^57,58 reported that hostility was a significant predictor of increased risk for IHD events.

Stress is frequently thought to be associated with IHD. Low et al. identified 11 studies that examined stress that was based on the conventional measure of perceived high demand and low control and suggested that this measure may be less important for women compared to men.⁵⁹ What may be more important is the exposure to psychological stress in both work and home settings. Lack of social relationships in women with existing IHD^60,61 is associated with an increased risk for IHD mortality and recurrent events and specifically loneliness has been shown to be associated with increased IHD incident risk.⁶² In summary, the empirical literature suggests that for primary and secondary IHD prevention, positive reciprocal social relationships may be important for women and from a negative perspective, psychological stress in the interpersonal domains may create an important risk for IHD among women.⁵⁵ Few studies have focused on positive states or traits.^63,64 Women’s Health Initiative (WHI)⁶³ found that an optimistic disposition was associated with reduced risk while the National Health and Nutrition Examination Survey (NHANES)⁶⁴ reported that emotional control and vitality and positive well-being were associated with lower coronary heart disease risk.

Obesity, Metabolic Syndrome, Diabetes and Dyslipidemia

The increased incidence of obesity has been recognized for the past 20 years as an epidemic in all industrialized countries, and is associated with increased CVD risk.⁶⁵ The incidence of obesity is greatest in the middle of the U.S. with 24 states having a prevalence of >30%.⁶⁶ CVD prevalence and mortality is the highest in these same states.⁶⁷ With no other risk factors for CVD, Cerhan and colleagues reported that waist circumference was associated with greater risk of mortality than any other variable.⁶⁸

Women are particularly at risk for CVD and especially IHD if they are obese. The incidence of obesity may be as high as 40% in postmenopausal women.⁶⁹ There are also ethnic differences in the incidence of obesity in the U.S. For example in 2007–2008, 33% of non-Hispanic white women were obese whereas 49.6% of non-Hispanic black women were obese.^69,70 Obesity increases after surgical menopause and is increased in women who start hormone replacement therapy within 12 months of amenorrhea.⁷¹ There is also evidence that even if women do not gain additional weight after menopause, there is a redistribution of body fat favoring an increase in abdominal fat waist circumference gain rather than lower hip weight gain.⁷² This is significant since weight that accumulates in the abdominal area is associated with a higher incidence of CVD than weight that is accumulated in the lower body.⁷³

Obesity (particularly central obesity) is one component of the cluster of features known as the metabolic syndrome, that also includes insulin resistance or type II diabetes, dyslipidemia and hypertension.^69,70 Women with metabolic syndrome have an increased prevalence of subclinical atherosclerotic disease and they have higher all-cause and cardiovascular mortality compared to women without metabolic syndrome.^45,74–76 Horvei and colleagues reported that waist-to-hip ratios and waist-to-height ratios had the greatest risk for AMI in women who participated in the Tromso Study (1994–1995) and were evaluated up to 2011.⁷⁷ In another study in patients with IHD and hypertension, the majority of obese individuals were women (67.1%) and they had a higher prevalence of diabetes, dyslipidemia, and left ventricular hypertrophy and heart failure than normal weight women.⁷⁸ In addition, hypertension was only controlled in less than 35% of obese individuals, compared to 52% in normal weight individuals, and diabetes was controlled in only 18% of obese individuals compared to 43% in normal weight individuals. The investigators concluded that chronic IHD worsens as body mass index increases.

Currently it is unknown whether body weight alone or the combination of obesity and parameters of the metabolic syndrome increase the risk of CHD.^79,80 In the Louisiana State University Hospital-based Longitudinal Study with 7,414 subjects (2,926 men and 4,488 women), there was a positive correlation between body mass index at baseline and increased risk of IHD in individuals with type 2 diabetes at follow up for both men (P_trend<0.001) and women (P_trend<0.001).⁸⁰ In contrast, comparison of data from the Framingham Offspring, Atherosclerosis Risk in Communities, and Cardiovascular Health cohorts, assessed ≥ 8 years, indicated that abdominal obesity alone was not significantly associated with increased risk of CVD.⁷³ However, inclusion of 1–2 components of metabolic syndrome plus type II diabetes did significantly increase the odds ratio of developing CVD and IHD in both men and women.

Women with diabetes have over a six times higher risk of dying from CHD compared to women without diabetes.⁸¹ Numerous studies suggest that diabetes conveys higher risk for cardiovascular mortality in women compared to men.^82–90 Even women with Type I diabetes have been shown to have a 40% excess risk of fatal and non-fatal cardiovascular events, when compared with men with Type 1 diabetes.⁹¹ The increased risk from diabetes may be partially related to the greater burden of cardiovascular risk factors seen in women as compared to men, differences in their pathophysiology, as well as lower rates of recognition, treatment and control of diabetes in women compared to men.^{83,85–88,92} Although mortality rates among diabetic women and men have been declining in recent years, the magnitude of decline has been greater in men than women.⁹³ Therefore, continued research is needed to better understand how to improve cardiovascular outcomes among diabetic women.

Dyslipidemia is a significant risk factor for IHD in women and men.^48,94–97 High total cholesterol, high LDL, high triglycerides and low HDL have all been shown to be associated with increased cardiovascular risk in women.^98,99 All major international guidelines on the treatment of dyslipidemia recommend similar approaches to the management of dyslipidemia in both men and women.^94–96 High triglycerides have been shown to be a stronger predictor of IHD risk in women compared to men; although whether this relationship is related to the ratio of triglycerides to HDL is debated.^99,100 Reiner and colleagues assessed individuals who had IHD and repoted that the majority of both men and women had elevated total cholesterol, especially LDL cholesterol and 37% had reduced levels of HDL.⁹⁷ Data from the 14-year follow-up of the Nurse’s Health Study showed a significantly increased risk for non-fatal AMI and IHD among women with higher intake of saturated dietary fat.¹⁰¹ Despite similar recommended approach to treatment of dyslipidemia, many studies have shown that women are less likely to be prescribed lipid lowering therapies or to achieve recommended cholesterol goals when treated as compared to men’s outcomes.^102–107 Clearly, lack of following treatment guidelines and failure to obtain recommended treatment goals contributes to women’s poorer outcomes. This disparate treatment enhances the perception of bias in treating women with known cardiac risk factors and/or IHD.

Physical Inactivity

Physical Inactivity (PI) negatively impacts several modifiable major risk factors for IHD in both sexes. PI in women is often associated with obese and overweight states, hypertension, diabetes and certain abnormal blood lipids. Overall older women, who are more at risk for IHD, tend to be more physically inactive than men. Many older women lack experience in team activities and group exercise, contributing to their PI.¹⁰⁸ However, this is changing as more baby boomers age and participate in group activities such as water aerobics, Yoga, Pilates, and other activities. The National Institute of Aging has excellent step by step instructional material to encourage safe activity in the older population, Your Everyday Guide from the National Institute on Aging, Exercise and Physical Activity. Silver Sneakers and other local programs are increasing opportunities for both older men and women to participate in physical activity. However, despite these educational materials tailored to older adults and increasing opportunities for age-related group exercise activities, women continue to have higher rates of PI than men (33.2% compared to 29.9%), perhaps because health professionals are not encouraging them to increase activity.¹⁰⁹ Unfortunately, high risk minority women have the highest rate of PI.¹⁰⁹

Research on effectiveness of cardiac rehabilitation has consistently concluded that it is beneficial to all IHD patients in reducing cardiovascular risk factors after the occurrence of a cardiac event.^110–115 Some of these benefits include: improved exercise capacity, improvement in lipids, reduction in body mass index, reduction in morbidity and mortality, and improved psychological factors.^{111,113–116} Historically, referral rates by healthcare providers to cardiac rehabilitation have been low for both sexes, but substantially lower in women, 50% or less.¹¹⁰ and current referral rates remain severely suboptimal with a greater disparity in referrals for women as compared with men (31.1% vs 42.2%, p<0.0001)¹¹⁷, with the lowest referral rates in minority women.^{110,112–114}

If women are fortunate enough to be referred to cardiac rehabilitation, they do not fare as well as men. They typically have very low attendance rates, particularly minority women.^110–115 They report difficulty completing the recommended program due to their social roles of care taker or single parent head of household employment responsibilities.^110–115 Other barriers that may account for the disparity among women and minorities related to cardiac rehabilitation attendance and completion include lack of awareness among women about their IHD risk, low education level, psychological stress, financial barriers, language barriers, cultural differences, geographic inaccessibility, lack of transportation, physical deconditioning, and lack of significant social support system.^{110–113,115}

Completion rates for women are significantly lower than their male counterparts (50.1% vs 60.4%, p<0.0001) and minorities have decreased completion rates as compared to whites.^112,113 In a study that compared younger women (n=65) < 55 to older women (n=187) > 55 enrolled in cardiac rehabilitation, data indicated women who did not complete cardiac rehabilitation were significantly younger with more risk factors for IHD and increased levels of anxiety and depression.¹¹⁵

Another potential contributing factor for younger women is that when pre-menopausal women exercise, difference in pain perception may exist with regard to the effects of the menstrual cycle.¹¹⁸ Also among women with angina, ischemia may be more easily inducible in the early follicular phase (a low estrogen state). Pain exacerbated by exercise in women with IHD may frighten women if they do not understand how pain may be impacted by the menstrual cycle and may contribute to lower completion rates in younger women. There are other sex differences in exercise dynamics, such as peak heart rate decreases more gradually in women than men and exercise maximal heart rate is often different.¹¹⁹

Although there are mixed results regarding who benefits the most from completion of cardiac rehabilitation, all studies conclude that women benefit from attendance, regardless of age. For instance, one study found women (n=6,374) who complete cardiac rehabilitation experienced the highest reduction in mortality (HR 0.36, 95% CI 0.28, 0.45) with a relative benefit higher than men (n=19,584) (HR 0.51, 95% CI 0.46, 0.56).¹¹² Another study demonstrated that although African Americans (n=169) significantly benefited from cardiac rehabilitation, they did not benefit to the same degree as their White counterparts (n=927).¹¹⁴ They also concluded that women and diabetic patients had the least improvement after completing cardiac rehabilitation, but their improvements were significant.¹¹⁴ Therefore, women with known IHD, regardless of age or race, benefit from referral to and completion of a cardiac rehabilitation program. Interventions need to be developed that address the social constraints that prevent many women from benefitting from cardiac rehabilitation.

Tobacco Use

Cigarette smoking remains the leading cause of preventable death in the U.S.^44,120–123 In the U.S., it is estimated that ~17% of adult women currently smoke cigarettes.¹²⁰ Smoking is a potent risk factor for women as it impacts a 25% greater risk of IHD than in male smokers, independent of smoking intensity or other cardiovascular risk factors.^{48, 124, 125} In all age groups, women who smoke have a significantly higher risk of IHD events (fatal and nonfatal) compared women who do not smoke.¹²⁶ The largest difference in risk for IHD events between smokers and non-smokers was seen in young women or those age 40–49 years old; however, the absolute rate of IHD events was significantly higher in older women (≥ 60 years old) smokers compared to non-smokers.¹²⁶ Women who stop smoking at any age experience an immediate benefit as well as further longer-term declines in excess risk of IHD to the level of those who never smoked.^127–130 Therefore, promoting smoking cessation is vital to lowering CVD risk for women of all ages.

Aging and Hypertension

Systolic blood pressure is the most important modifiable risk factor contributing to the excess IHD risk that occurs with aging in men and women.⁴² Aging in both men and women is characterized by increases in blood pressure (BP), and the prevalence of hypertension in postmenopausal women is higher than in men.^131–134 Hypertension is a major risk factor for CVD in men and women.^{131, 133}

Worldwide, 25% of women are hypertensive, and in the U.S., more than 75% of women over 60 years of age are hypertensive.^135,136 The NHANES IV (1999–2002) showed more women with high BP went undiagnosed compared to men (11.7% versus 9.9%).¹³⁷ Furthermore, in a study that compared the NHANES III cohort (ending in 1994) with the NHANES IV cohort (ending in 2002), hypertension was less well controlled in women than men who were taking antihypertension medications (14.6% versus 8.3%).¹³⁷ This finding is similar to the lower number of women receiving optimal treatment and achieving recommended lipid levels. It is possible that sex bias contributes to both of these treatment outcomes.

Non-dipping of BP at night is associated with increased target organ damage in both men and women,¹³⁸ but there is evidence that non-dipping in women in general is associated with greater target organ damage than in men,^139,140 and postmenopausal women are more likely than pre-menopausal women to exhibit nocturnal non-dipping of BP.¹³⁹ Thus while antihypertensive guidelines are no different for men and women,¹⁴¹ and women are more likely to have their BP measured, hypertension may be less well controlled in women. This suggests that women may not be as aggressively treated for their hypertension as are men, but also that the mechanisms responsible for hypertension in aging women may differ from the mechanisms in men.

Roles of estradiol and consequences of Hormone Replacement Therapy

Whether the presence of estrogens protects against CVD is controversial. Estradiol has been shown to be cardiovascular protective mainly in experimental settings or where intermediate markers for CVD were used as endpoints.^142,143 Whether the lack of estrogens contributes to CVD in postmenopausal women is also controversial and unknown. Early observational studies suggested an association between the use of hormone replacement therapy (HRT), such as estradiol, and lower cardiovascular risk in post-menopausal women.^144,145 However, large clinical trials on the effect of HRT in post-menopausal women have not supported these previous findings. The results of the WHI studies,¹⁴⁶ HERS I and HERS II^117,147 trials, have not supported a role for HRT in prevention of either primary or secondary IHD, respectively. It is unknown if the mode of delivery of HRT, or the dose of HRT, or even if the preparation of the HRT itself may play a role in the efficacy. For example, conjugated equine estrogen is a common estrogenic HRT, but because of the source (urine of pregnant mares), there are a significant number of other steroids that are included in the preparation, such as androgens. Conjugated equine estrogen was the preparation used in the WHI.¹⁴⁶ Ichikawa and colleagues found that transdermal HRT for 12 and 24 months reduced diastolic and mean BP in normotensive postmenopausal women.¹⁴⁸ In contrast, Prelevic and colleagues studied healthy post-menopausal women who had been taking HRT for at least 5 years, and found that there was either no effect on BP or that BP was in fact higher in some women using HRT.¹⁴⁹ Age at beginning HRT and/or the length of time after the last menstrual period when HRT is begun may also contribute to efficacy and any adverse effects that may occur. For example, re-evaluation of women in the WHI study who were younger and randomized to the “Estrogen Only” arm showed there was a significant reduction in IHD after years 7–8.¹⁵⁰ Note that was four years after the WHI studies with conjugated equine estrogen preparation as HRT were stopped due to adverse side effects.

The prevalence of hypertension is higher in postmenopausal women suggesting a possible role of sex hormones. Olszanecka and colleagues measured ambulatory BP in normotensive and hypertensive women, aged 40–60 years, and found that BP was similar in normotensive and hypertensive groups regardless of presence or absence of menopause.¹⁵¹ Unfortunately, there have been no studies to our knowledge in which ambulatory BP has been measured serially over the perimenopausal transition in order to correlate and document any BP change with menopausal transition. Thus whether the presence of estrogens protects young women from hypertension or loss of estrogens promotes coronary disease in postmenopausal women is not clear.

There is evidence that loss of estrogens at any age contributes to endothelial dysfunction, which is common in individuals with hypertension. For example, Taddei and colleagues reported that in response to acetylcholine, an index of endothelial dysfunction, endothelium-dependent flow mediated vasodilation (FMD) was attenuated less with aging in premenopausal, hypertensive women than men, but after menopause, the FMD response was attenuated to the same extent in both women and men.¹⁵² Attenuated FMD is prognostic of CVD risk factors, including hypertension, in postmenopausal women.¹⁵³ Women with premature ovarian failure before age 40 years also exhibit reduced brachial FMD compared to age-matched cycling women, but in these women, HRT with conjugated equine estrogen and medroxyprogesterone for 6 months reversed the endothelial dysfunction.¹⁵⁴ In contrast, in the Women’s Angiographic Vitamin and Estradiol (WAVE) Trial, HRT had no beneficial effect on FMD in postmenopausal women.¹⁵⁵ The fact that HRT protected against endothelial dysfunction in young women, but not in older women, both of whom had experienced menopause, supports the contention that aging may change the response to HRT and thus may independently contribute to increases in BP.

Endothelial dysfunction is characterized by reductions in nitric oxide (NO). Estradiol stimulates NO production acutely by increasing intracellular calcium that activates endothelial NO synthase (eNOS).¹⁵⁶ In addition, estradiol increases NO chronically since it upregulates synthesis of eNOS via estrogen response elements that would promote vasodilation and thus reductions in BP.¹⁵⁷ Estradiol is a modest antioxidant since it upregulates superoxide dismutase,¹⁵⁸ which removes superoxide which reduces oxidative stress. Superoxide binds to NO with high affinity, and thus renders NO unavailable for vasodilation.¹⁵⁹ Because an intact NO system is necessary for antioxidants to reduce BP, in situations of chronic hypertension when endothelial dysfunction is present and NO levels have been reduced for long periods, estradiol may lose the ability to affect BP. Furthermore, with an estrogen-mediated increase in superoxide dismutase, it is possible that there may be an increase in hydrogen peroxide, also a powerful oxidant that offsets any beneficial effect of removing superoxide.

Reductions in estradiol with menopause could also affect the renin-angiotensin system (RAS). Estradiol down regulates angiotensin type I receptors and angiotensin converting enzyme,^160,161 thus protecting against activation of the renin-angiotensin system (RAS) and subsequent vasoconstriction. Reductions in estradiol, therefore, would tend to activation of the RAS. However, in normotensive postmenopausal women, HRT with transdermal 17β-estradiol and oral medroxyprogesterone reduced BP, but had no effect on levels or expression of RAS components such as plasma renin activity, angiotensin I or II, aldosterone or angiotensin converting enzyme activity.¹⁴⁸ In contrast, treatment of postmenopausal women with angiotensin type I receptor antagonists did improve endothelial dysfunction measured by FMD, whereas a calcium channel blockers did not,¹⁶² supporting a role for the RAS in contributing to postmenopausal CVD.

EMERGING RISK FACTORS FOR CVD

Inflammatory Markers

Research shows that there is a correlation between inflammation and IHD.^163–166 This correlation may be useful for early diagnosis of IHD because multiple biomarkers can be used to detect inflammation including high-sensitivity C-reactive protein (hs-CRP), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α). In fact, some of these biomarkers have been used to aid in the diagnosis of IHD.^164,166,167 However, some of the biomarkers are not specific for IHD, which may limit their diagnostic usefulness. Also, the exact mechanism of how biomarkers function is not clear. Therefore, the usefulness of biomarkers alone as screening tools for IHD is controversial.

Lipoprotein(a) [Lp(a)] has also been shown to be a risk factor for IHD and other CVD. For instance, one 15-year prospective study (n=826; 52% female) found that Lp(a) level was associated with occurrence of CVD. The hazard ratio (95% CI) per 1 SD higher Lp(a) for females was 1.32 (1.10–1.58). Interestingly, the addition of Lp(a) to Framingham Risk Score and Reynolds Risk Score improved prediction of CVD in this study.¹⁶⁸ The exact mechanisms are not known but the association of Lp(a) with IHD may be partially due to its proinflammatory properties. Another mechanism may be its low-density lipoprotein (LDL) component. Clinical utility of Lp(a) is controversial but the U.S. National Lipid Association and the European Atherosclerosis Society do recommend its use in select populations such as those with intermediate or high risk of developing CVD to assist in identifying their risk.^169,170

High-sensitivity C-reactive protein is the most commonly studied inflammatory marker for the detection of IHD. However, it is unknown if it is an independent risk factor for CVD: data does support that it may improve risk detection in women.^163,171,172 In the Women’s Health Study, a global risk predication model that included hsCRP improved cardiovascular risk prediction in women.¹⁷¹ Furthermore, hsCRP has been shown to be a stronger predictor of cardiovascular events in women than LDL cholesterol.¹⁷² For women with metabolic syndrome, hsCRP may add prognostic information regarding future cardiac risk. In a study of apparently healthy women, those with metabolic syndrome and hsCRP levels greater than 3.0 mg/L had almost twice the risk of a future cardiovascular event than those with metabolic syndrome and a hsCRP less than 3.0 mg/L. ¹⁷³ Measuring hsCRP is not recommended in routine risk assessment of women, but rather as an option in those with intermediate risk.¹⁷⁴ The benefits of assessing hsCRP or any treatment based on this strategy remain uncertain.

Autoimmune Disease

Atherosclerosis may be accelerated by the presence of systemic inflammation.¹⁷⁵ Rheumatoid arthritis and systemic lupus erythematosus (SLE) are associated with a significantly increased risk for CVD.¹⁷⁵ In the Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update, systemic autoimmune collagen-vascular disease was listed as a criterion for the status of “at risk”.¹⁷⁶ Examination of The California Hospital Discharge Database indicated that young women between the ages of 18 to 44 with SLE (n=3,851) were 2.27 times more likely than their age-matched peers without SLE (n=19,228) to be hospitalized because of AMI, 3.80 times more likely to be hospitalized because of congestive heart failure, and 2.05 times more likely to be hospitalized because of cerebrovascular accident.¹⁷⁷ Women in the Framingham Offspring Study aged 35 to 44 with SLE were astonishingly 50 times more likely to have an AMI than women of the same age without SLE.¹⁷⁸ Traditional risk factors such as smoking, family history of premature disease, hypertension, and elevated cholesterol do not completely account for the increased risk of IHD in patients with SLE.

Pre-eclampsia and Pregnancy-associated Hypertension

Women with a history of preeclampsia have a 3.6 to 6.1-fold greater risk of developing hypertension, and a 3.1 to 3.7-fold higher risk of developing diabetes, depending on whether the preeclampsia was mild or severe.¹⁷⁹ Preeclampsia is also a risk factor for future ischemic stroke.¹⁸⁰ One large cohort study in Northern Finland (N=12,055) found that any elevated BP during pregnancy, regardless of type, signaled a greater risk of developing CVD, chronic kidney disease and diabetes mellitus than in women without elevated BP during pregnancy.¹⁸¹ A number of meta-analyses have demonstrated that women with a history of preeclampsia have approximately double the risk for subsequent IHD, stroke and venous thromboembolic events over the 5 to 10 years following the pregnancy.^182,183 The Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update lists history of preeclampsia or pregnancy-induced hypertension as a criterion for the status of “at risk”.¹⁷⁶

Gestational Diabetes

Unique to women is the IHD risk factor of gestational diabetes. A history of gestational diabetes doubles the risk of developing diabetes in the following 4 months postpartum and remains a lifelong risk factor.¹⁸⁴ Fasting glucose levels of ≥121 mg/dl during pregnancy increase the risk for diabetes in the early puerperium by an astounding 21-fold.¹⁸⁵ Studies have also showed at least 1.5 times greater risk of CVD in women with a history of gestational diabetes compared to women without gestational diabetes.¹⁸⁶ The Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update incorporated a history of gestational diabetes as an “at risk” criterion, requiring attention to CVD risk factors and the implementation of therapeutic lifestyle changes in these women throughout their life.¹⁷⁶ Women must be educated about their ongoing risk imparted by experiencing gestational diabetes.

Reproductive Hormones

Oral Contraceptive Therapy

The American College of Obstetricians and Gynecologists and the World Health Organization have published guidelines on medical eligibility for contraceptive use.¹⁸⁷ For most women, who are healthy and free of CVD and cardiovascular risk factors, the use of combination estrogen-progestin oral contraceptives is associated with low relative and absolute risks of developing CVD.¹⁸⁸ Nonetheless, women who are smokers over the age of 35, women with uncontrolled hypertension, and women with a history of IHD have an unacceptable high risk associated with oral contraceptive use.^{189, 190}

Post-menopausal Hormone Therapy

A majority of CVD occurs after menopause in older women, which is associated with an increased burden of risk factors for CVD.¹⁹¹ As stated earlier, it was thought that post-menopause HRT should reduce the risk of CVD, and initial observational data supported this hypothesis. Nonetheless, randomized trials, such as Heart and Estrogen/Progestin Replacement Study (HERS) I, HERS II, WHI and Raloxifene Use for The Heart (RUTH) did not support that HRT or selective estrogen receptor modulators prevented CVD, regardless of use for primary and secondary prevention.^{146,192–194} The AHA Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 2011 Update states that HRT and selective estrogen receptor modulators should not be used for the primary or secondary prevention of CVD and are a Class III, level of evidence A, intervention.¹⁷⁶

Polycystic Ovarian Syndrome

Unique to women, polycystic ovarian syndrome (PCOS) is associated with the development of metabolic syndrome and insulin resistance. A meta-analysis concluded that women with PCOS have an increased prevalence of impaired glucose tolerance, the metabolic syndrome and diabetes compared to women without PCOS.¹⁹⁵ It remains unclear if PCOS is an independent risk factor for premature CVD in women, but recent data suggests an elevated risk in women with PCOS independent of established risk factors in older postmenopausal women.¹⁹⁶ Furthermore, in the WISE study of post-menopausal women with PCOS, cumulative 5-year CVD event-free survival was 79% for women with PCOS compared to 89% for women without PCOS.¹⁹⁶

Functional Hypothalamic Amenorrhea

It is estimated that up to 10% of premenopausal women have documented ovarian dysfunction with a larger proportion having subclinical hormonal dysfunction that may result in an increased risk of developing CVD. Functional hypothalamic amenorrhea (FHA) is a cause of a premenopausal ovarian dysfunction and occurs when gonadotropin-releasing hormone increases thereby increasing luteinizing hormone in a pulse frequency causing both amenorrhea and hypoestrogenemia. FHA can be induced by psychological stressors or a metabolic insult such as caloric restriction or excessive exercise. In a large cohort study, women with menstrual irregularities had a 50% increased risk of nonfatal and fatal IHD compared to women with regular menstrual cycling.¹⁹⁷ Data suggest an association between FHA and premature coronary atherosclerosis in women undergoing coronary angiography,¹⁹⁸ and that use of oral contraceptive therapy may offer protection.¹⁹⁹ These findings suggest that amenorrhea and cycling irregularity may be a risk factor for CVD in women, but further research is still needed to understand this association.

Breast Cancer Therapy

As a result of advancements made in breast cancer treatment, there has been an improved survival in women with breast cancer, yet these women have an elevated risk of developing CVD.²⁰⁰ Breast cancer therapies (including anthracycline therapies, trastuzumab and radiation therapy) are associated with varying degrees of direct cardiovascular injury, in addition to significant indirect lifestyle changes that also reduce cardiovascular reserve.²⁰⁰ It remains unclear whether it is the presence of breast cancer itself or the specific therapies for treatment of breast cancer that increase the risk for CVD. The risks to the heart can be related to many cardiovascular issues but radiation therapy seems to have an established association with the development of IHD. Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the rate of developing IHD. The risk is directly proportional to the mean dose of radiation to the heart, with and increase in CVD events of 7.4% per Gray (Gy) of radiation (95% CI, 2.9 to 14.5; P<.001). The mean radiation dose to the heart, in a study of 2,168 women, who received radiotherapy treatment for breast cancer, was 4.9 Gy. The risk of IHD begins within a few years after exposure and appears to continue for at least 20 years after the exposure. As expected, the abosolute risk for IHD is highest in those women with pre-existing CVD risk factors.²⁰¹ This increased risk for IHD may be under appreciated. Nonetheless, this is an increasingly important issue in the management of women surviving breast cancer. Further work is needed to determine the relative and absolute risk of breast cancer and its specific therapies to guide cardiovascular healthcare providers who will increasingly be called upon to evaluate and treat these women.

Sleep Apnea

Although sleep apnea is more prevalent in men compared with women, it is a very common issue in women and under-recognized in terms of its impact on CVD. In women, untreated obstructive sleep apnea is associated with an increased risk of hypertension, coronary artery disease, stroke, and atrial fibrillation.²⁰² Central sleep apnea occurs mainly in patients with heart failure. Regardless of type, sleep apnea is believed to induce severe intermittent hypoxemia and CO2 retention during sleep, with oxygen saturation sometimes dropping to ≤60%, disrupting the normal autonomic and hemodynamic responses to sleep.²⁰³ Apnea often occurs repetitively through the night and towards the end of an apneic episode, BP can reach levels as high as 240/130 mm Hg.²⁰⁴ This hemodynamic stress occurs simultaneously with severe hypoxemia, hypercapnia, and adrenergic activation which in turn acts to promote CVD. Importantly, untreated sleep apnea in women is associated with 3.5 times greater risk of dying from CVD, yet this risk was reduced to the same as a woman without sleep apnea with appropriate treatment with continuous positive airway pressure.²⁰²

B. Cultural Diversity in Self-Risk Assessment

A gap in racial/ethnic awareness of IHD as the number one cause of death in women was noted in 1997 among White (33%), Black (15%) and Hispanic (20%) women. In 2012, awareness of heart disease as the leading killer of women improved for all racial/ethnic groups with White (65%) women’s awareness superseding that of Black (36%) and Hispanic (34%) women.⁴¹ Although awareness of heart disease has improved over the past 15 years, the gap in awareness is alarming. Clearly, efforts to inform minority women of their risk for developing IHD are insufficient. Further research is needed to determine the most effective ways to reduce this disparity.

Because IHD is the leading cause of mortality, morbidity, and disability among women in the U.S.,¹² it is vital that women have an accurate perception of their risk for IHD. Major causative factors for heart disease are credited to modifiable risk factors (e.g. hypertension, dyslipidemia, diabetes, smoking, obesity, physical inactivity, unhealthy diets). Rarely do cardiac risk factors occur in isolation, but rather there is a synergistic action among several risks factors that exacerbate the disease burden. Therefore, treatment should be holistic and not singly focused on individual risk factors.²⁰⁵

It is vital that health care providers accurately use cardiovascular risk assessment tools and effectively treat cardiac risk using recommended guidelines. In addition, it is equally vital that health care providers teach all patients about their cardiac risk in simple terms they can understand and provide lifestyle management counseling.²⁰⁶ In a systematic review, intervention intensity and repetitive presentations improved risk perception accuracy and intent to adhere to preventive strategies.²⁰⁷ Whether this intent translated into action is not known. Longitudinal studies that focus on repetitive risk presentation at delivery levels are needed to determine suitable impact on cardiac outcomes.

Even when clinicians suspect IHD, accurately estimating women’s risk is challenging. Perhaps the most used risk assessment tool is the Framingham Risk Score and this includes traditional risk factors such as age, gender, BP, tobacco use, and cholesterol levels. However, it does not include family history or pregnancy related problems such as preeclampsia, and other emerging risk factors discussed earlier in this paper. Therefore, it may underestimate IHD risk in women. The Reynolds Risk Score was developed to detect risk of CVD²⁰⁸ and includes the Framingham components but adds family history, Hemoglobin A1c (HgbA1c) in diabetics, and one inflammatory marker,: hsCRP. Inflammatory markers may be especially important in the detection of IHD in women, who tend to have more microvascular disease than men. A more recent risk score published jointly by the AHA and the American College of Cardiology is the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator.²⁰⁹ This risk score includes age, gender, BP, tobacco use, cholesterol, race, and diabetes status and was developed with Pooled Cohort Equations from several large cohort studies of White and Black men and women. A mobile application is available that includes the risk score and most recent cardiovascular prevention guidelines so clinicians can easily access this information. These risk scores can aid in decisions regarding prevention and treatment of IHD. However, health care providers tend to underestimate the risk of IHD in women regardless of the risk assessment used.

Currently, risk assessment tools are available for 5, 10 year, or lifetime risk estimate of coronary disease electronically^{209,209, 210} and the risk estimate is relevant for vulnerable populations such as women and Blacks. However, modification to current risk assessment tools are needed since most under or overestimate risk for non-White racial/ethnic groups.²⁰⁹

C. The Diagnostic Experience

Recognizing IHD in women is a long-standing two-pronged problem for both women and health professionals. First, women have to recognize symptoms as indicative of potential disease and seek treatment, and secondly, when they seek treatment, health professionals must recognize symptoms as potential prodromes of heart disease or acute symptoms indicative of impending AMI and respond appropriately.^211,212 Although progress is evident on both fronts, too many women continue to have difficulty recognizing symptoms as potentially indicative of heart disease and for those who do and seek medical attention, many continue to report that providers ignore their concerns and/or minimize importance of their symptoms. This in turn undermines women’s confidence in their ability to recognize the importance of their symptoms and may deter women from seeking additional healthcare for prodromal symptoms.²¹³ This lack of recognition of symptoms leads to delay in seeking treatment and contributes to women’s disability and mortality rates.

Women’s Viewpoint

Early qualitative studies of women’s experiences in seeking medical assistance for troubling symptoms of unknown origin, later diagnosed as IHD when women experienced an AMI, began appearing in the literature in the late 1990s.²¹⁴ At this time, research on women’s IHD symptoms was in its infancy and women’s mortality rates were increasing at alarming rates and eventually surpassed men’s rates.¹² In recognition of these statistics, a concerted effort was initiated to improve women’s IHD outcomes. These early qualitative studies reported that women were often recognizing symptoms were not normal but they did not attribute them to potential IHD as they thought it was primarily a disease that occurred in men. Additionally, elusive and vague intermittent prodromal symptoms made it difficult for women to recognize these symptoms as indicative of IHD. The AHA embarked on a project, Go Red for Women, to increase women’s awareness of heart disease as the number one killer of women so that women would suspect it and seek prompt medical attention. However, studies continue to report that many women frequently attribute symptoms to non-cardiac reasons, minimize importance of symptoms, and/or put meeting social and role responsibilities ahead of their seeking medical attention for themselves.^211,213,215 Equally troubling, when women recognize that something is not right and they seek timely medical attention, they often report difficulty receiving a diagnosis and accurate treatment. Unfortunately, this is not just a problem in the U.S. Similar experiences are reported by women in a variety of studies conducted world-wide, making this a universal problem.^{213,215–218}

Two recently published small qualitative studies^213,215 N=10, N=20, conducted in different countries reported similar accounts of women’s diagnostic experiences. In both studies, over one-half of women sought medical care during the prodromal period for troubling symptoms. Although a few received recommended diagnostic tests and treatments, many reported their symptoms were not taken seriously, downplayed, and contributed to their delaying seeking treatment when symptoms became more severe. They doubted their ability to recognize important symptoms requiring immediate attention. Even when health professionals correctly identified symptoms as needing immediate treatment, some women were instructed to go to a hospital emergency department by private automobile or taxi, not by emergency transportation. This further decreased women’s confidence in health care providers. These experiences are not remarkably different than those reported by McSweeney et al. more than a decade earlier in a sample of women in the U.S.²¹⁹ The study by McSweeney et al. was conducted with 40 women aged 27 to 79 years (58.5 ± 12.5 years) who had previously experienced an AMI.²¹⁹ Most women were unaware they were at risk for IHD, but sought medical attention when troubling symptoms appeared. When the women sought treatment for their prodromal symptoms they reported trouble with getting diagnosed, perceived they were not taken seriously by providers, and were often treated for depression or indigestion.²¹⁹ This delay in treatment and diagnosis lead many of the women to grow frustrated with seeking treatment for their symptoms and angry with the delay in receiving a diagnosis prior to their AMI.²¹⁹ Some women expressed relief at the diagnose of AMI because they finally understood what was “wrong” with them. These studies document a trend of missed opportunities to prevent and/or delay AMI due to lack of recognition of prodromal symptoms. Unfortunately, this lack of recognition of prodromal symptoms in women continues to persist despite studies identifying women’s most frequent prodromal symptoms.

Health Care Providers’ Viewpoint

Although awareness regarding the prevalence of IHD among women has improved in recent years, many health care providers still view it primarily as a man’s disease or one that affects older women after menopause and others are uncertain even when they correctly diagnose IHD.^220–222 This uncertainty often results in less aggressive and/or less timely treatment for women with possible IHD. In fact, research shows that women are consistently treated less intensely than men before and after the diagnosis of IHD in the U.S. and other countries.^222–226 There are many reasons for this such as bias and lack of education related to the non-traditional symptom presentation often related by women to their healthcare providers. For instance, many clinicians do not entertain IHD as a diagnosis when a woman complains of fatigue or shortness of breath. In addition, many women who undergo coronary angiography are negative for obstruction. In fact, among women who present with “chest symptoms”, only about 50% have obstructive IHD.^{5, 6} This procedure is not without risk and expense, and clinicians may be reluctant to offer it for women who are typically older at diagnosis of IHD. The diagnosis of IHD may be missed or delayed when coronary angiography is not performed in a timely manner.

Symptoms/Presentation

Woman’s decision to seek care for possible IHD is directly related to their symptoms. Research shows that women are less likely to experience chest pain than men,²²⁷ but the majority experience prodromal symptoms, such as shortness of breath or unusual fatigue, for weeks or even months prior to an acute cardiac event. Prodromal symptoms are defined as symptoms that are new and intermittent prior to an acute cardiac event and resolve after the event.²²⁸ McSweeney et al have published a series of studies identifying U.S. women’s most frequently reported prodromal symptoms (see Table 4) and racial/ethnic differences between these symptoms.

Table 4.

Significant Differences in Frequency of Women’s Prodromal Symptoms by Race

	Black (N=545) No. (%)	Hispanic (N=186) No. (%)	White (N=539) No. (%)	Raw p-value	Adjusted p-value
Generalized Symptoms
Unusual fatigue	421(77.2)	124(66.7)	385(71.4)	0.009	0.174
Anxious	27 (51.2)	95(51.1)a	199(36.9)b	<0.001	<0.001
Frequent indigestion	235(43.1)a	50(26.9)b	209(38.8)a	<0.001	0.004
Heart racing	233(42.8)a	68(36.6)ab	153(28.4)b	<0.001	<0.001
New vision problems	217(39.8)a	43(23.1)b	132(24.5)b	<0.001	<0.001
Change in thinking or remembering	202(37.1)a	60(32.3)ab	135(25.0)b	0.001	0.001
Loss of appetite	183(33.6)a	50(26.9)ab	124(23.0)b	<0.001	0.006
Difficulty breathing at night	182(33.4)a	38(20.4)ab	107(19.9)b	<0.001	<0.001
Hands/arms tingling	172(31.6)	47(25.3)	125(23.2)	0.007	0.064
Numbness or burning in hands/fingers	171(31.4)a	45(24.2)ab	104(19.3)b	<0.001	<0.001
Cough	147(27.0)a	59(31.7)a	98(18.2)b	<0.001	<0.001
Increased frequency of headaches	109(20.0)	29(15.6)	68(12.6)	0.005	0.055
Increased intensity of headaches	91(16.7)a	36(19.4)a	48(8.9)b	<0.001	<0.001
Discomfort/pain symptoms
Centered high in chest	102(18.7)ab	46(24.7)a	76(14.1)b	0.004	0.004
Leg(s)	61(11.2)a	29(15.6)a	22(4.1)b	<0.001	<0.001
Both arms	30(5.5)	24(12.9)	33(6.1)	0.003	0.014
Right arm or shoulder	24(4.4)ab	16(8.6)a	13(2.4)b	0.002	0.004
Jaw/teeth	17(3.1)b	20(10.8)ab	23(4.3)b	<0.001	0.001

Note: Values with the same superscript letter indicate non-significant post hoc differences. Bonferroni adjusted (≤ 0.003).²⁵⁸

A study in Korea reported that 145 out of 271 women experienced prodromal symptoms prior to their first AMI.²¹⁶ The most common reported prodromal symptoms were chest symptoms (34.5%), indigestion (19.3%), shortness of breath (9.7%), and fatigue (8.3%). Almost 64% of those who experienced fatigue or weakness and approximately 38% of those who experienced chest or epigastric symptoms recognized that something was wrong but either did not think it was serious or attributed it to their age or other comorbidities. Only 40% of the women with prodromal symptoms visited a clinic or hospital for those early symptoms.

A prospective longitudinal study conducted in the U.S. with 1097 women indicated four prodromal symptoms were significantly associated with an increased risk of experiencing a cardiac event.²¹⁷ These symptoms were: discomfort in jaw/teeth, unusual fatigue, discomfort in arms, and shortness of breath.²¹⁷ Additionally, women reporting one or more of these prodromal symptoms were four times more likely to experience a cardiac event within the two year follow up.²¹⁷ Recognition of these prodromal symptoms by women and health care providers could improve the diagnosis of IHD and thus, promote timely treatment to prevent/delay progression to AMI.

Recognition of Symptoms as Cardiac

Women may have difficulty identifying prodromal symptoms as cardiac because they may not experience chest pain, the most publicized symptom of heart disease. A meta-analysis of 26 studies examining sex differences in IHD symptom presentation reported that women with AMI had lower odds of presenting with chest pain than men (OR 0.63; 95% CI, 0.59–0.68).²²⁹ Instead, women were more likely to present with fatigue, nausea, neck pain, right arm pain, jaw pain, dizziness, and syncope than men. Other differences were that women were older than men at symptom presentation by a mean of 6.58 years (95% CI, 5.42–7.74) and women were more likely to have a history of congestive heart failure than men (RR 1.64; 95% CI, 1.44–1.88).

Two qualitative studies examined women’s recognition of IHD symptoms. One study included 9 women (4 Black, 5 White) with recently diagnosed IHD who were interviewed within 2 weeks after hospital discharge.²³⁰ Five of the 9 women experienced “atypical” symptoms of IHD and had difficulty identifying the cause of the symptoms. The women reported a lack of acute symptoms and did not initially realize the need to seek care. Four of the women had what they recognized as IHD symptoms. All women tried to identify a symptom pattern and only when they were able to do so did they recognize their symptoms as cardiac in nature.

A descriptive study using vignettes in Lima, Peru examined sex differences in health care seeking behavior for AMI (N=90; 54.4% women).²¹⁸ Women in this sample were 4 times less likely than men to identify chest pain as a symptom of IHD in the vignette labeled “typical chest pain” after adjusting for demographic variables (OR=0.23; 95% CI, 0.063–0.87). After watching the same vignette, women were more likely to respond that a man would seek help (OR=4.54; 95% CI, 1.21–16.90) and that a women would be less likely to seek help (OR=3.26; 95% CI, 1.13–9.41 after adjustment). Both of these studies demonstrate that women may be reluctant to attribute symptoms to heart disease even when they experience “typical” chest symptoms.

Women also underestimate their risk of IHD,²³¹ which can influence their decision to seek care. Most women still view IHD as a man’s disease and perceive breast cancer as a greater health threat for them than IHD. One integrative review found that lack of communication between women and their health care providers regarding risk of IHD contributes to this misunderstanding.²¹²

Delay in Seeking Treatment

Obtaining timely treatment for AMI is crucial for survival and optimal clinical outcomes, yet women continue to delay longer than men.²³² Delay is defined as the time between symptom onset and accessing health care for those symptoms, referred to here as treatment-seeking delay. This difference is often attributed to the difference in symptoms or women’s interpretation of symptoms when compared to men. While much success has been achieved in reducing the components of delay once a patient enters the health care system, little has changed in treatment-seeking delay times for women. This behavior is universal across cultures including women in Saudi Arabia,²³³ China²³⁴, Brazil²³⁵, and Norway²³⁶ and across racial groups, including African American women.²³⁷ Recent studies continue to demonstrate that treatment seeking delay is associated with worse outcomes.²³⁸ Clearly, new methods to educate women are urgently needed, to assist women to recognize symptoms earlier and to immediately seek medical assistance.

Numerous studies have attempted to elicit causes of why women delay seeking treatment longer than men. Many attribute this to misinterpretation of symptoms by women²³⁹ or their providers²⁴⁰, as well as differences in symptoms.²⁴¹ Qualitative studies have helped to elucidate the types and reasons for women’s symptom behaviors during the treatment-seeking delay time. Rosenfeld et al²⁴² described two main decision trajectories that women used when responding to AMI symptoms: knowing (knowing almost immediately they would seek help) and managing (treating an alternate hypothesis or minimizing their symptoms). Davis et al.²³⁰ described a process that women went through when making decisions about seeking care. This process included noticing symptoms, forming a symptom pattern, using a frame of reference, finding relief, and assigning causality. Some women who were uncertain delayed seeking care while others were certain also delayed seeking care.

Women who report prodromal symptoms often experience the same symptoms during an acute event.²¹⁷ Prodromal symptoms by definition are intermittent and resolve spontaneously.²¹⁷ In a recent study comparing prodromal and acute symptoms in women; over 50% of the women reported experiencing the same prodromal and acute symptoms.²²⁸ Two of the symptoms from this study had over 80% agreement: chest pain/discomfort and shortness of breath.²²⁸ Additionally, the prodromal and acute symptom of arms weak and heavy had over 65% agreement.²²⁸ These women may delay seeking treatment until they determine symptoms are unrelenting.²¹⁷

The state of the science of intervention research to decrease delay has been disappointing. Neither the REACT study²⁴³ of a community level intervention nor the PROMOTION trial²⁴⁴ of an individual intervention for both men and women resulted in a decrease in delay time. No effective interventions have been tested for women.

Differences in IHD pattern (obstructive vs non-obstructive)

Initially women who did not fit the classic (or male) pattern of IHD were diagnosed with cardiac syndrome X (CSX), which has a female predominance of about 70%.²⁴⁵ CSX is defined as the triad pattern of chest pain, abnormal stress test consistent with ischemia and the absence of significant obstructive IHD on angiography.²⁴⁶ In stable IHD, women are five times more likely to be diagnosed with normal coronary arteries than men.²⁴⁷ Recent data from the Dallas Heart Study demonstrated that angina in the general population is not associated with subclinical atherosclerosis as measured by coronary artery calcification scores on cardiac electronbeam computed tomography.²⁴⁸ Normal to non-obstructive IHD is twice as likely in women who present with ACS, unstable angina, NSTEMI or STEMI compared to men.^249–253 Several paradoxes are identified in women; despite lower rates of obstructive disease and less extensive IHD and decreased incidence of AMI compared to men, women tend to have increased prevalence of angina, higher rates of myocardial ischemia and more adverse cardiac events (re-hospitalization and death).^28,249–253

The current characterization of angina (“typical chest pain”) is largely based on data in men, however this definition has been generalized to women as well. However, gender differences exist in terms of the type, pattern and quality of symptoms.²⁵⁴ Until recently the diagnosis and treatment of IHD in women has largely centered on whether or not their symptoms fit the typical angina definition and pattern. Regardless of sex disparities in symptoms upon presentation to the emergency room, typical angina symptoms in women are predictive of AMI and warrant further investigation.²⁵⁵ Data from 69 AMI/ACS studies that assessed IHD symptoms indicated that women frequently present with typical angina, but when “atypical” symptoms are present, the prevalence of these symptoms is higher in women than men.²⁵⁶ Higher rates of atypical chest pain in women may be partly explained by the increased prevalence of ischemia from vasospastic and microvascular disease in women. Additionally women experience angina during periods of mental stress or rest whereas angina in men is most frequently related to exertion.²⁵⁴

There appears to be an interaction with age and symptom presentation in patients hospitalized for chest pain. Older women often present similar to men with typical angina patterns and rates of ACS are similar between the genders. Younger women (<65 years of age) are more likely to be discharged with a diagnosis of unstable angina compared to similar age matched cohort of men. Regardless of age, women have less atherosclerotic burden compared to men which may contribute to these differences. ²⁵⁷

In a study by McSweeney et al of 1270 ethnically diverse women, 545 (43%) Black, 186 (15%) Hispanic, and 539 (42%) White, the most frequent prodromal symptom among all women was unusual fatigue (73%).²⁵⁸ The other most commonly reported prodromal symptoms among all women were: sleep disturbances (50%), anxiety (45%), shortness of breath (44.5%), and frequent indigestion (38.9%).²⁵⁸ Chest discomfort/ pain was only reported by 37.7% of women in the prodromal period.²⁵⁸ During the acute phase of AMI, shortness of breath was reported most often (62.8%), then weakness (54.9%), unusual fatigue (48.3%), dizziness (44%), and cold sweat (40%).²⁵⁸ When four locations of chest discomfort/pain were combined, chest discomfort/pain was frequently reported during the AMI. When women did report chest discomfort/pain, they frequently used terms other than pain to describe their symptoms: pressure (44.8%), tightness (28.9%), ache (28.5%), sharpness (27.7%), fullness (14.7%), burning (10.5%), crushing (8.9%), spasm (8.5%), soreness (8.1%), and tingling (7.3%).²¹⁷ Importantly, 42% of Whites, 38% of Blacks, and 28% of Hispanics did not report any chest discomfort/ pain when experiencing their AMI.²⁵⁸ See Table 5 for women’s acute symptoms that were significantly different by race. Thus there is research to support both differences^259–261 and similarities²⁶² in symptoms of IHD in men and women.

Table 5.

Significant Differences in Frequency of Women’s Acute Symptoms by Race

	Black (N=545) No. (%)	Hispanic (N=186) No. (%)	White (N=539) No. (%)	Raw p-value	Adjusted p-value
Generalized Symptoms
Unusual fatigue	277(50.8)ab	109(58.6)a	227(42.1)b	<0.001	0.003
Dizzy or faint	269(49.4)	76(40.9)	214(39.7)	0.004	0.028
Hot, flushed	252(46.2)a	51(27.4)b	173(32.1)b	<0.001	<0.001
Indigestion	224(41.1)a	48(25.8)b	154(28.6)b	<0.001	<0.001
Heart racing	194(35.6)a	67(36.0)ab	125(23.2)b	<0.001	0.005
Numbness in hands/fingers	149(27.3)a	50(26.9)ab	97(18.0)b	<0.001	0.007
Vomiting	149(27.3)a	42(22.6)ab	101(18.7)b	0.004	0.014
Loss of appetite	145(26.6)	53(28.5)	106(19.7)	0.008	0.076
New vision problems	145(26.6)a	37(19.9)ab	77(14.3)b	<0.001	<0.001
Headache	125(22.9)ab	50(26.9)a	80(14.8)b	<0.001	0.005
Coughing	89(16.3)a	36(19.4)a	52(9.6)b	<0.001	0.002
Choking sensation	83(15.2)	34(18.3)	50(9.3)	0.001	0.016
Discomfort/pain symptoms
Centered high in chest	177(32.5)b	87(46.8)a	166(30.8)b	<0.001	<0.001
Left breast	133(24.4)a	44(23.7)ab	73(13.5)b	<0.001	<0.001
Back/between shoulder blades	84(15.4)c	70(37.6)a	112(20.8)b	<0.001	<0.001
Neck/throat	71(13.0)b	44(23.7)a	87(16.1)b	0.003	0.001
Generalized chest	70(12.8)b	41(22.0)ab	110(20.4)a	0.001	0.003
Leg(s)	40(7.3)a	27(14.5)a	9(1.7)b	<0.001	<0.001
Both arms	38(7.0)b	34(18.3)a	77(14.3)a	<0.001	<0.001
Top of shoulders	36(6.6)b	33(17.7)a	57(10.6)ab	<0.001	<0.001
Right arm or shoulder	34(6.2)b	24(12.9)a	25(4.6)b	<0.001	0.001
Jaw/teeth	26(4.8)c	36(19.4)a	54(10.0)b	<0.001	<0.001

Note: Values with same superscript letter indicate non-significant post hoc difference. Bonferroni adjusted (p≤0.003).²⁵⁸

Women report angina more frequently than men despite women having lower rates of obstructive IHD.²⁸ Interestingly in the WISE study, more than 50% of women with angina were found to have no IHD or minimal IHD on coronary angiography.²⁶³ In patients without obstructive IHD, women with persistent chest pain had worse cardiac outcomes compared to asymptomatic women,²⁶⁴ including higher rates of repeat hospitalization and repeat coronary angiography which in turn results in higher health care resource consumption.⁴⁰ Additionally those women from the WISE study who had persistent chest pain despite no obstructive IHD had higher mortality rates than asymptomatic women. This highlights the importance of recognizing and treating the signs and symptoms of ischemia in patients without obstructive IHD, as ongoing ischemia is not a benign entity and places these women at increased CVD risk. Equally important, lack of chest pain as a presenting symptom of AMI contributes to missed diagnoses and is associated with higher in hospital mortality rates.^227,265

Subsequent researchers have since identified a subset of CSX patients to have microvascular angina, also labeled as female pattern of IHD.^43,266 There are several features of microvascular angina or the female pattern of IHD: angina, abnormal stress testing indicative of ischemia, no obstructive IHD on angiography, and abnormal coronary microcirculation dysfunction.²⁶⁷ Microvascular angina can be secondary to endothelium dependent or endothelium-independent microvascular coronary dysfunction, which can be detected on coronary angiography.^43,267

The WISE study was instrumental in our current understanding of IHD in women and subsequent ancillary studies will provide us more insight.^45,268 More than half the patients in this study cohort had no or minimal IHD, and persistent chest pain despite no obstructive IHD in these women was associated with worse prognosis (increased re-hospitalization, revascularization, death).^263,264,269 Microvascular angina is neither benign nor inexpensive. Care of the symptomatic female with non-obstructive IHD is costly and places an economic burden on the health care system.⁴⁰ The pathophysiology, presentation, evaluation and treatment of microvascular angina are complex and challenging, further research is needed to help clarify many unanswered questions regarding this entity.

Disparities in Guideline-based Diagnosis of IHD

Utilizing Bayes’ theorem in the assessment of myocardial ischemia, the pretest likelihood of angiographic IHD in symptomatic women is lower than in men, regardless of typical or atypical symptoms.²⁷⁰ Women are less likely to be assessed for cardiac symptoms but when assessment is performed, sex based differences exist. Exercise ECG is the first line diagnostic tool to evaluate for IHD in symptomatic women who have a normal resting ECG, an intermediate pretest probability, and an ability to perform maximal exercise.²⁷¹ The sensitivity and specificity for detection of obstructive IHD with exercise ECG is lower in women than in men but the negative predictive value of the exercise ECG is very high.^272,273 The reduced accuracy in women is related to increased functional impairment that inhibits women to achieve maximal levels of exercise, lower QRS voltage and hormonal factors (endogenous estrogen in younger women and hormone replacement therapy in postmenopausal women).^{271,274–276} The Duke treadmill score provides additional diagnostic and prognostic information in women undergoing evaluation for IHD.²⁷⁷

Addition of cardiac imaging to assess for stress induced wall motion or myocardial perfusion abnormalities supports the evaluation of IHD in women with an abnormal resting ECG, diabetes, questionable functional capacity or intermediate risk treadmill findings.²⁷¹ In women, stress echocardiography provides better specificity and diagnostic accuracy than standard exercise electrocardiography.^272,278 The diagnostic accuracy of exercise and dobutamine echocardiography appears to be comparable in women and men (i.e. sex neutral accuracy).²⁷¹ Prognostic information with stress echocardiography is also similar between men and women.^279,280

Stress gated myocardial perfusion single-photon emission computed tomography (SPECT) with contemporary nuclear imaging agents provide high specificity and diagnostic accuracy^281–283 as well as high prognostic accuracy regardless of sex.²⁸⁴ In patients with left bundle branch block pharmacologic nuclear stress testing is more accurate than exercise perfusion imaging regardless of sex.²⁸⁵ Challenges of SPECT imaging in women include breast attenuation artifact as well as possible unobserved minor perfusion defects in women with smaller hearts, in addition to radiation exposure.²⁸⁶ The labeling of false positive stress tests in women with non-obstructive IHD on angiography should be avoided if there are any objective signs or symptoms of ischemia during the stress portion of the test.

Only a few specialized centers currently perform stress MR imaging to assess for subendocardial ischemia or wall motion abnormalities in the evaluation of IHD.^287,288 Stress MR demonstrated diffuse subendocardial perfusion defects in patient with cardiac syndrome X.²⁸⁷ In the WISE study, ³¹P MR spectroscopy identified women with metabolic myocardial ischemia which also provided important prognostic information.^269,289 Stress CMR is a relatively newer imaging test and with further research will hopefully provide promising diagnostic and prognostic data for IHD.

Even after appropriate diagnosis of IHD, disparities exist in the treatment of IHD in women despite female specific guidelines for CVD prevention.¹⁷⁶ Disparities exist in regards to physician adherence to evidence based guidelines in the treatment of CVD and prescribing patterns have shown that women are less likely to be prescribed lipid lowering medications, antiplatelet agents, and beta-blockers at the time of hospital discharge than men.^290–293 Hospitals participating in AHA Get With the Guidelines-CAD program have had increased rates of guideline adherence over a 5 year period regardless of gender and age.²⁹⁴ This demonstrates the powerful impact quality improvement projects can have upon adherence, yet more data are necessary to determine if it will effect clinical outcomes.

Emotional/Affective Response and Behavior Change

When women receive a diagnosis of IHD or AMI, they often express disbelief and react in a variety of ways. Even when women are able to identify common CVD risk factors, they often do not personalize this information, meaning they do not perceive themselves at risk even though they have multiple risk factors.²³¹ An integrative review of the literature supported these findings, in particular, that women underestimate their cardiovascular risks and that communication between the female patient and physician is less than therapeutic. These perceptions can influence a patient’s decision-making process related to making healthy behavior changes and seeking healthcare.²¹² Thanavaro et al²⁹⁵ examined the best predictors of risk reducing and health promoting behaviors among women without a prior history of CHD in a cross-sectional study of 119 women. Results indicated that women had low levels of knowledge related to IHD and did not regularly practice health promoting behaviors although they perceived benefits to these behaviors were good. Those who were more likely to engage in healthful behaviors perceived fewer barriers to reducing risk of IHD, had greater knowledge of IHD and a negative history for smoking.

Moore et al. used qualitative methods to examine perceptions of risk for IHD as well as perceptions of risk-reducing behaviors among seven women with known CVD.²⁹⁶ Three major themes emerged from the data: that absence of symptoms was interpreted as an absence of disease, that women desired a relationship with their physician in which they could have an open discussion, and expressed fear of the effects of the disease on their daily lives and relationships. To further elaborate on the three themes, the women did not interpret their IHD as a chronic disease but rather one that was corrected by the acute intervention and thus did not necessitate a change in behavior to reduce their risk of a recurrent event. They did not see their patient-provider relationship as one that fostered dialogue with the physician and reported that there was no discussion about risk reduction. Since the provider did not discuss risk reduction, this supported the women’s ideas that behavior changes were not necessary. The fear the women expressed was manifested in varying ways, one woman expressed fear about unknown dangerous changes occurring in her heart while others feared the effects of IHD on their relationships. One woman reported that being diagnosed with IHD served as a motivator for her to make behavior changes, targeting her specific risks.

Other studies have linked specific personal CVD risk factors with behavior change in women. Murphy and colleagues ²⁹⁷ conducted studies among 239 women post-AMI and monitored self-initiated changes in diet. Using the Short Fat Questionnaire, they demonstrated over 4 time points that the women significantly reduced their dietary fat intake, and while there was some regression over the subsequent months, the 12-month score remained significantly lower than at baseline; also the scores were lower than the scores of a randomly selected sample of healthy women and older adults in the same time period.

While Murphy and colleagues’ study was conducted in Australia and revealed positive self-initiated behavior changes in post-AMI women’s diets,²⁹⁷ increasing physical activity is often a more problematic self-initiated behavior change pre or post-AMI. Adults in several countries have received and adopted the low fat diet message to some extent;^298,299 however, less than 50% of adults in the U.S. are physically active at the recommended level.³⁰⁰ Mozumdar and colleagues³⁰¹ examined the relationship of occupational and leisure physical activity with IHD risk among working women. They did not find a relationship between IHD risk and occupational physical activity, however they reported that there was a greater prevalence of high risk for IHD among those with low levels of leisure time physical activity. This study was conducted in India, a country where there may be more physically demanding occupations for women compared to the U.S. Thus, these reported relationships might not be the same among women in the U.S.

An area where attention is needed for both primary and secondary prevention of IHD is medication adherence, particularly for the control of hypertension and dyslipidemia. Moss and colleagues³⁰² studied the financial burden of cardiac medications among older women post AMI. Results of the cross-sectional study revealed that 89% of a sample of 83 were taking at least one cardiac medication, costs per day varied ($0.13–$6.75), and the total number of pills taken per day was between one and 19. Providers need to be sensitive to the financial burden of medications to enhance adherence. Other factors that contribute to non-adherence are frequency of medications, perceived and actual side effects, etc. Still other studies have shown that medication frequency may be related to low adherence rates and recommend that providers consider daily dosing formulas to increase medication adherence.^303,304 Multiple medications prescribed (polypharmacy) to patients and the increased accompanying cost are associated with decreased adherence.³⁰⁵ Other reasons for non-adherence to medication are patient choice to make lifestyle changes instead of taking prescribed preventative medications or previous experience with CVD.³⁰⁶ Increased income and education levels have been well established as associated with increased compliance rates. Inversely, lower socioeconomic status and education levels are associated with decreased compliance levels. Adherence is a multifactorial concern that requires assessment of the patient’s abilities and willingness to participate in the plan of care.

III. Explanations for the unique experience: The role of sex

Clinician Behavior as a Source of Gender/Sex Disparities

The Institute of Medicine’s Unequal Treatment report defines disparities as differences in treatment that remain after accounting for patient characteristics including clinically appropriate needs, the demands of coexisting conditions, and patient preferences.^307,308 Determinants of residual gender/sex disparities include health system and clinician factors.³⁰⁷ From the clinician perspective, 1) greater clinical uncertainty when interacting with female patients; 2) beliefs or stereotypes about the behavior or health of female patients; and 3) bias or prejudice toward women have all been proposed as potential contributors to health disparities.^307–315 Physician uncertainty for CVD diagnosis has been shown to vary by patient sex and influence clinical decisions.^220,222,316 Indirect evidence also indicates that healthcare clinicians’ interpretation of symptoms are influenced by patient demographics, including sex/gender.^317–319 For example, physicians are more likely to interpret a man’s symptoms as organic and a woman’s as psychosocial.^220,320 Importantly, clinicians’ beliefs about a patient may directly influence their clinical decision-making. Clinician sex/gender bias has been commonly inferred when sex/gender differences in care persist after adjusting for different patient, clinician and health system characteristics.^103,321,322 For example, Schulman demonstrated that physicians were less likely to refer hypothetical female than male “patients,” with the same symptoms and stress test results for cardiac angiography.¹⁰³ Although these studies indirectly suggest that clinician gender/sex bias explains the observed variation in clinician recommendations, to our knowledge, no studies have directly measured clinician gender/sex beliefs and the extent to which these attitudes are associated with clinical decisions.

Explicit (conscious) stereotypes about the traits that women and men possess are common. Women are traditionally felt to be more selfless and concerned with others and men are viewed as being self-assertive and motivated to master.^323–326 The unjust application of these stereotypes, or gender bias, is also felt to be common and primarily implicit.^324,326,327 As its name suggests, implicit gender bias is less intentional, even unconscious, and it operates in a relatively automatic manner.^324,328,329 Clinicians are not immune to bias; levels of implicit bias among clinicians towards different groups have been shown to be similar to those seen in the general population.^330–335 Tools have been developed in other fields that measure explicit gender attitudes, such as the Trait Stereotype measure, and implicit gender attitudes such as the Implicit Association Test (IAT).^336–340 These tools have been widely used to explain gender differences in social outcomes including hiring decisions, job promotions and performance evaluations, but they have less widely applied to the study of health care disparities.^341–344 A few studies have used these tools among clinicians to examine the role of race and ethnicity bias in clinical decisions and outcomes.^345–349 Further work is needed to understand whether clinician gender/sex attitudes and bias plays a role in treatment decisions and potentially contribute to disparities in care of women.

As discussed earlier, many other factors may make it more difficult to diagnose IHD in women. Lack of appropriate risk assessment tools that do not incorporate women’s novel risk factors plus vague intermittent symptoms compound the diagnostic problem. Furthermore, women’s terms to describe symptoms, such as chest pressure or burning or fatigue may not match provider’s expectations of IHD symptoms. Also, since women are often older at the time of initial IHD diagnosis, they often have other comorbid conditions, confounding diagnosis. Even when providers suspect IHD in women, many diagnostic tools are not as sensitive and specific in women. Combined, this makes it challenging to diagnose IHD in women. Studies contained in this paper should assist clinicians in recognizing IHD in women.

IV. Gaps in Science of Ischemic Heart Disease in Women

Although there is clear evidence that women experience IHD differently from men due to both sex and gender differences, significant gaps in scientific knowledge regarding risks, mechanisms, assessment, interventions, and symptoms for women with IHD remain.

Risks, mechanisms and assessment

The reasons for women’s worse outcomes are likely multifactorial and studies are needed that incorporate comprehensive theoretical frameworks. Inadequate information is available about hypertension across the lifespan in women. Whether the presence of estrogens protects young women from hypertension or loss of estrogens promotes coronary disease is unclear. Also, data are needed to explain why hypertension in aging women differs from men. Exciting findings about emerging risk factors for heart disease in women are emerging, but the precise use of biomarkers such as hsCRP and other novel risk factors needs further study. Commonly used risk scores may not be as sensitive for women and thus clinicians may not have adequate knowledge to accurately assess women’s risks. Further, the existence of clinician gender bias and its influence on clinicians’ decisions is not fully understood. Significant gaps in our understanding of the pathophysiology, presentation, evaluation, and treatment of microvascular angina exist, despite that fact that this is a predominantly female phenomenon. The impact of the use of sex specific troponin cutoff values on diagnostic accuracy for women is a crucial question.

Interventions

Many studies show that women do not benefit as much as men in intervention trials related to depression, physical activity, cardiac rehabilitation, diabetes, treatment-seeking delay and other outcomes. Interventions developed for women only are more effective¹¹¹ and thus more trials are needed to test interventions tailored for women with IHD. Further, interventions targeted to specific racial and ethnic groups of women also are needed. Regardless, interventions that have proven beneficial in women need to be offered to all women, for both primary and secondary prevention.

Symptoms

There is strong evidence regarding the typical and “atypical” symptoms that women experience. The precise mechanisms for those symptoms are not fully understood. The identification of symptom phenotypes in women is needed.

V. Future Directions

Although tremendous progress has been made in building the science of how women experience IHD, much remains to be done to translate the science into practice and education and to continue to expand the science.

A. Practice

• Increased education for providers and women on emerging risks for IHD and routine assessment of individual risk of IHD

• Routine assessment of sex-specific risks for IHD in screening, history and physical examination by all primary care providers and gynecologists

• Population health approaches to decreasing women and girls’ risks

B. Research

• Powering of all clinical trials to allow for analysis by sex/gender and reporting of sex-specific differences

• Broadening of inclusion criteria that focus on IHD symptoms to include more than chest pain

• Testing of interventions tailored for women and women of different ethnicities; in particular, cardiac rehabilitation programs designed to increase women’s participation and completion

• Use of community based participatory research methods to develop culturally sensitive approaches to meeting the needs of underserved populations of women

C. Policy

• Research funding targeted to improving the evidence for guidelines for prevention of IHD in women

• Randomized clinical trials of diagnosis, treatment, and/or outcomes of IHD in women with non-obstructive coronary artery disease

• Interventions to identify and eliminate sex bias in treatment and use of clinical guidelines

• Devise measures to assess the effectiveness of guidelines for prevention, diagnosis and treatment of women with or at risk for IHD

D. Public health education

• Improved methods to disseminate information about women’s risk, symptoms and behaviors and necessary responses to symptoms of ischemia