Cardiovascular disease (CVD) remains the leading cause of death in women.¹ Nearly half-a-million women die each year in the United States from ischemic heart disease (IHD) and its related conditions with the most recent annual statistics on mortality reporting that CVD accounted for 421,918 deaths among women in the United States.² In fact, current projections indicate this number will continue to rise with our aging population^2,3,4 (Figure 4-1). Since 1982 more women than men have died annually from IHD² (Figure 4-2), which is the leading killer of women with annual mortality rates exceeding those due to breast cancer in women of any age^2,5 (Figure 4-3). Although in the last decade, there have been significant declines in female mortality due to coronary heart disease, these reductions lag behind those seen in men¹ (see Figure 4-2). In addition, women under 65 suffer the highest relative sex-specific cardiovascular heart disease mortality (Figure 4-4). A study from the Journal of American Clinical Cardiology in 2007 noted that although mortality from coronary heart disease (CHD) in men across all age groups has decreased, there has been a notable increase in mortality among women belonging to youngest age group (<55 years).⁶ This group of women, in particular, also have increased risk factors for CHD.⁶ Additionally, women were more likely to die of cardiac arrest before hospital arrival compared to men, 52% and 42% respectively.³ This prehospital death rate represents a worsening trend among women and a significant change from prior decades.^7,8 Though there have been declines in sudden cardiac deaths in men, the condition of women has changed little⁹ (Figure 4-5), even those who are living with cardiovascular disease suffer greater morbidity and mortality than men. Upon examination of the specific diagnoses of CVD and comparison of their effects on gender, it has been proved that women not only suffer greater mortality, but greater morbidity as well. When compared with men, women suffer 2 times greater mortality and morbidity from angina and coronary artery bypass graft surgery (CABG).¹⁰ There is a 2 times greater incidence of congestive heart failure (CHF) and 1½ times greater 1-year mortality from myocardial infarction (MI) in women than men.¹⁰ Lastly, women with proven coronary artery disease (CAD) but stable angina have a higher probability of death or MI than men¹¹ (Figure 4-6).

There are differences in the prevalence, symptoms, and pathophysiology of myocardial ischemia in women when compared to men.¹ This chapter reviews the sex-specific issues related to myocardial ischemia in women in relation to traditional and novel risk factors, presentation, diagnosis, treatment, and outcomes. Based on the sex-specific differences it may be easier to identify women who are at risk and those who are diagnosed with ischemic heart disease under a female pattern of disease versus our traditional understanding of male-pattern disease as women can have both patterns.

Discussion of CAD in women, with focus on gender differences in diagnosis.

The graph in Figure 4-7 shows a cumulative change (in percentage) in mortality rate for males versus black and white females. It shows that the trend is decreasing more rapidly in men and there are more deaths in women from IHD than men despite the overall decrease in mortality over the past 3 decades (Figure 4-7).

Traditionally, evaluation and management of IHD has been approached by defining and treating a “culprit” lesion. There are a vast array of diagnostic tools specifically designed to determine the likelihood of a “culprit” obstructive coronary lesion as well as evidence-based guidelines for treatment traditionally applied to both men and women. However, there is a greater prevalence of nonobstructive disease in women than men.¹ The prevalence of obstructive CAD in women is relatively low before menopause and equal to the prevalence in men in the seventh decade. In general, the comparable incidence rates are achieved with women who are 10 years older than men, so women at age 65 have the same incidence of CAD as men at age 55. As a result, there is lower likelihood of obstructive coronary disease in the women we evaluate.

Overall, the prevalence and incidence of all forms of ischemic heart disease are lower in women compared to men, and the age at presentation is delayed (Figure 4-8). However, after 75 years of age, women outnumber men and the total number of elderly female IHD patients is greater than men¹² (Figure 4-9).

TRADITIONAL RISK FACTORS

The presence of any cardiovascular risk factor increases the lifetime risk of developing IHD^13,14 (Figure 4-10) and >80% of women have >1 cardiac risk factor present.¹⁵ It is possible that many of the traditional cardiac risk factors in women have a greater impact or higher prevalence.¹ In regards to specific risk factors, women have higher cholesterol levels than men after their fifth decade of life and elevation in their triglycerides is a more potent risk factor in women compared with men.^15,16,17,18 In women, diabetes and hypertension appear to confer a higher risk of coronary events, as diabetes is more prevalent in women.^15,19 This could potentially be secondary to smaller coronaries in women and the more aggressive nature of coronary disease in diabetics or, alternatively, because women may require a greater risk factor burden compared to men before developing IHD, or the “higher risk factor burden” hypothesis.¹² As seen in Figure 4-11, men and women who present with unstable ischemic syndrome have similar high-risk profiles based on the Thrombolysis in Myocardial Infarction (TIMI) risk scores, but women have a different cardiovascular risk profile. Specifically, women were more likely to present with a history of cardiovascular risk factors (including hypertension and diabetes mellitus), prior angina episodes, ST depression on their ECGs, and increased age, whereas men were more likely to present with prior coronary artery disease and elevated markers of myonecrosis (P <0.001 for each; see Figure 4-11).²⁰ But, certainly, the reason why the CHD death rates in US women aged 35 to 54 appears to be increasing is likely because of the obesity epidemic, which is more prevalent in women than men^21,22 (Figure 4-12). With nearly 2 of every 3 US women >20 years of age now overweight or obese (Figure 4-13), the rate of diabetes is more than double in Hispanic women compared to non-Hispanic white women.²² Lastly, metabolic syndrome is more common after menopause and women with the combination of central obesity, glucose intolerance, hypertension, and dyslipidemia are at the highest risk of developing IHD compared to men.²³ From a 2007 meta-analysis, the data demonstrated that the cardiovascular risk conferred by the metabolic syndrome was three times higher in women than it was in men.²³

WOMEN WHO PRESENT WITH ACS

In 60% of cases, the initial presentation of IHD in women is acute MI or sudden cardiac death (SCD).^2,16,22,24 For those women who do present with an initial fatal ischemic event, there are morphologic differences in the etiology by age and gender.^25,26,27,28 The postmortem examination reveals plaque rupture in men and older women. There is usually a large necrotic core and disrupted fibrous cap infiltrated by macrophages and lymphocytes.²⁹ In younger women, however, there is a greater tendency toward plaque erosion. In this scenario, the fibrous cap is absent and the exposed intima consists mostly of smooth muscle and proteoglycans (Figure 4-14). Other unique pathophysiologic features in women with ischemic heart disease include adverse coronary reactivity,³⁰ microvascular dysfunction,³¹ and distal microembolization³² in addition to the plaque erosion. This is unlike men who are more likely to have obstructive coronary disease.¹

SYMPTOMS

The definition of “typical” or male-pattern symptoms has been established from mostly male populations.³³ However, women suffer as much or more from angina than men,³⁴ and they have fewer “typical” symptoms than men. But the majority of women still present with these typical symptoms.³⁵ In a recent report there appeared to be no difference in diagnosing acute coronary syndromes in men and women presenting with typical symptoms, including chest pain or discomfort, dyspnea, diaphoresis, and arm or shoulder pain.³⁶ However, women often present with a different symptom complex than men. Women generally report more acute than prodromal symptoms and up to half of women with acute myocardial infarction had no chest pain prior to the event.³⁷ Among Acute Coronary Syndrome (ACS) patients, women have more frequent unstable angina and “atypical” symptoms (Figure 4-15). After sudden cardiac death (SCD), the most common presentation is atypical including fatigue, shortness of breath, and atypical chest pain.^{33,38,39,40,41} Even though women are more likely than men to have “atypical” symptoms, they present almost 2 times as frequently than men for evaluation and hospitalization of chest pain (4 million versus 2.4 million).⁴

GENDER DIFFERENCES IN DIAGNOSIS

In cardiovascular medicine, an exercise stress test is often the initial test to diagnose CAD in both men and women. The exercise ECG is the recommended first test of choice in the evaluation of symptomatic, intermediate-risk women who are able to exercise and have a normal baseline ECG.⁴² Stress ECG has lower accuracy (60%-70%) compared to men (80%) (Table 4-1). The sensitivity and specificity of ST-segment depression are lower in men⁴³ but given the lower incidence of obstructive CAD in women, this influences the accuracy of the stress ECG. To better predict the presence of CAD and IHD mortality in women, the Duke Treadmill score should be used.^44,45 This takes into account exercise duration and symptoms during the stress test. The DTS has been shown to have a good diagnostic and prognostic value in both men and women.^44,45,46,47 Overall, survival for women appears to be better at all levels of the DTS compared with men.^44,47 The DTS is a valuable tool to predict the risk of future myocardial infarction, revascularization, cardiac survival, and all-cause mortality in both genders, but it does not appear effective at assessing prognosis in the elderly (those aged ≥75 years).⁴⁸ For asymptomatic women, the Women Take Heart Project showed that the DTS was an independent predictor of all-cause and cardiac mortality.⁴⁹

Exercise capacity can be estimated during an exercise stress test. Predictors of MI, IHD death, and all-cause mortality in women can be determined from an exercise capacity <5 metabolic equivalents (METs) or inability to achieve >85% age-predicted fitness level.^42,50,51 Although the focus of stress exercise ECG has centered mainly on ST-segment depression as a method of diagnosing CAD, the use of additional exercise parameters in women improves the diagnostic accuracy of the exercise stress test, as well as the prognostic assessment. In women, exercise capacity, percentage of age-predicted exercise capacity, chronotropic response, heart rate recovery (HRR), blood pressure response, and the DTS can all be used to enhance the diagnostic and prognostic value of exercise ECG ⁴² (Table 4-2). Even in asymptomatic women, METs can be a predictor of annual mortality rate. Importantly, women who are referred for pharmacologic stress test have the highest annual mortality rate (Figure 4-16) compared to those symptomatic or asymptomatic women who undergo an exercise stress test.

For the women with an abnormal ECG, stress testing may lead to cardiac imaging. Stress-induced perfusion abnormality assessment detects reductions in myocardial perfusion that occur prior to ECG or wall motion abnormalities seen on ECG. Most commonly, myocardial perfusion single-photon emission computed tomography (SPECT) is a nuclear-based technology that is most commonly used for women and men presenting with chest pain. Large observational series have noted similar abilities to risk-stratify women and men with chest pain symptoms.^{52,53,54,55,56,57}

Stress-induced wall motion abnormality assessment by echocardiography has been associated with high diagnostic specificity, seen in Table 4-2. This testing assesses for wall motion abnormalities that appear after perfusion abnormalities. In women who cannot exercise, pharmacologic stress can be used in both SPECT and stress echocardiography. SPECT imaging has been effective in risk-stratifying women. Women who have a normal myocardial perfusion study have a low annual IHD event rate (0.6% per year) and those with an abnormal myocardial perfusion have a much higher event rate of (5% per year).⁵⁷ However, there are several limitations to SPECT in women including reduced sensitivity because of severe multi-vessel disease, “balanced ischemia” or as a result of microvascular disease, limited resolution where smaller abnormalities are not detected because of a smaller heart, breast attenuation, and radiation exposure.⁵⁸

This figure summarizes the work-up algorithm for noninvasive testing in symptomatic women as discussed in more detail in testing chapter of this atlas (Figure 4-17).

Table 4-1 lists the sensitivity and specificity of exercise ECG, stress Echo, and stress SPECT in women.

TREATMENT AND OUTCOMES