Cardiovascular disease (CVD) is by far the leading cause of death of women in the United States and most developed countries, accounting for almost 39% of all female deaths in the United States. In 2007, CVD caused 421,918 deaths in women in the United States, approximately 1 per minute, more than those claimed by cancer, chronic lower respiratory disease, Alzheimer disease, and accidents combined. Despite aggressive campaigns by the American Heart Association (AHA) and other organizations, only 54% of the women surveyed in 2009 spontaneously listed coronary heart disease (CHD) as a woman’s leading cause of death, and only 13% of the women surveyed identified CHD as a risk for them personally. Minority women are even less aware of their cardiovascular (CV) risk, which is higher than for age-matched white women.

Some important gender-related differences exist in the presentation and outcome of CVD. In a national registry of over 300,000 patients (40% women) admitted with acute myocardial infarction (MI) between 1994 and 1998, female patients were found to be older compared with males (approximately 72 years vs. 66 years, respectively). Women also had higher in-hospital mortality compared with men (17% vs. 12%). Risk of death is particularly high in younger women, more than twice that of men in the under-50 age group, and also in women who presented with ST-elevation myocardial infarction (STEMI). These differences highlight an urgent need to better understand and treat heart diseases in women. This chapter summarizes current understanding of the gender-specific features of CVD based on large-scale clinical trials and existing and emerging molecular science.

Briefly, coronary artery disease (CAD) begins with nascent atheroma, the coalescence of small lipoprotein particles within the arterial intima. Over time, these lipoprotein particles become oxidized, inducing local cytokine elaboration. These inflammatory cytokines cause the increased expression of adhesion molecules for leukocytes, leading to leukocyte attraction and migration into the intimal layer. Blood monocytes become macrophages upon entering the intima and express scavenger receptors on their surface, owing to their interaction with certain cytokines present locally. These scavenger receptors promote the uptake of modified lipoprotein particles, leading to the formation of foam cells. Foam cells further elaborate inflammatory and attractant cytokines and other effector molecules. In response, smooth muscle cells migrate into the intima from the media, where they proliferate and form fatty streaks. Smooth muscle cell proliferation and extracellular matrix accumulation lead to the progression from a fatty streak to a fibrofatty plaque. Later stages are characterized by calcification and fibrosis, occasionally with smooth muscle cell death. This creates an acellular fibrous cap surrounding a lipid-rich core.

The process of atherosclerosis progresses slowly, and patients often remain unaware and asymptomatic for many years. This is likely attributable to the capacity of the arteries to remodel—expanding outwardly as the intima expands, thereby preventing plaque encroachment on the lumen of the vessel. However, at some point the plaque
burden exceeds the ability of the vessel to remodel, and narrowing of the lumen begins. Eventually, if unimpeded, atherosclerosis will progress until the degree of luminal narrowing impedes blood flow. Initially, this luminal narrowing is apparent mostly under the conditions of stress, where arterial oxygen supply is unable to meet demand. Once this occurs, the patient begins to develop symptoms, typically stable angina.

In some cases, however, the first manifestation of the underlying CAD is MI, unstable angina, or sudden death. In these instances, the underlying stenosis is usually < 50% of the lumen diameter. The inciting event leading to symptoms in these cases is either physical disruption of the fibrous cap of the plaque or superficial erosion of the intima. Either setting exposes the underlying lipid-rich core to blood components and initiates thrombosis (see Chapters 1 and 2 for more detailed discussions). Women, especially younger women, are twice as likely to have plaque erosion as the underlying cause of MI, whereas men and older women more often have plaque rupture. Compared to men, whose plaques tend to be more dense fibrous, women also tend to have more cellular fibrous plaques.

There appears to be other gender-based differences in the atherosclerotic process. Hormones have also been proven to influence many of the underlying pathophysiologic processes, including vasoreactivity, thrombosis and inflammation. Women have smaller coronary arteries than men and, interestingly, women taking androgens have much larger coronary arteries than their age-matched controls. For years it was noted that premenopausal women appeared to be protected from CAD and estrogen emerged as the most likely reason. A recent animal study suggests that estrogen appears to decrease oxidative stress via upregulation of the production of prostacyclin PGI₂, a molecule known to retard the progression of atherosclerosis. The full spectrum of sex hormone effects on the heart and vascular system has yet to be fully determined. In addition, there have been genetic links to the development of CAD that are noted to vary according to gender, with different single-nucleotide polymorphisms noted in men and others in women. There are also differences in terms of endothelial function and hemostasis (women have higher levels of fibrinogen and factor VII). Some of these or other mechanisms may eventually be identified as the reason for gender differences in the development and progression of CAD.

In recent years, microvascular dysfunction has been postulated as the underlying process leading to symptoms of CHD in some women. It is postulated that estrogen withdrawal in perimenopausal and postmenopasual women leads to impaired vasodilatation and/or enhanced vasoconstriction. This hypothesis stems from the diagnosis of cardiac syndrome X, in which patients, predominantly postmenopausal women, exhibit symptoms of typical angina pectoris with transient abnormal electrocardiogram (ECG) and/or stress perfusion studies, yet most have minimal angiographic evidence of CAD when undergoing left heart catheterization (LHC). Further studies are needed to better define the populations at risk for microvascular dysfunction and determine potential therapeutic interventions.

Stress (Takotsubo) cardiomyopathy is another novel disease entity affecting predominantly postmenopausal women, accounting for over 80% of cases. Alternatively known as apical ballooning syndrome or broken heart syndrome, stress cardiomyopathy is diagnosed when patients, often in the setting of severe emotional distress or physical trauma, present with chest pain, anterior ST elevations, mildly abnormal cardiac biomarkers, and characteristic appearance of an akinetic, ballooning apex on echocardiography or left ventricular (LV) ventriculogram. Angiography often reveals normal-appearing coronary vessels. The etiology of stress cardiomyopathy and the reason behind such strong female predilection are unclear. Catecholamine surge with stress has been implicated in a number of patient cohorts with this cardiomyopathy. The prognosis of stress cardiomyopathy is quite good, as the majority of patients regain systolic function within 6 months.

A. Diabetes mellitus. Diabetes affects more women than men after the age of 60. It is associated with a higher incremental risk for CAD (two to four times the risk of women
without diabetes) and drastically increases the mortality of MI in women, much more so than in men. Type 2 diabetes is associated with other components of the metabolic syndrome, all of which increase risk for CAD. Diabetes is also strongly associated with the development of heart failure, with or without preserved ejection fraction.

B. Hypertension (HTN). More than 73% of women aged 65 to 74 years have HTN. The risk of developing HTN increases for women if they are 20 pounds or more overweight, have a family history of HTN, or have reached menopause. Risk for CVD related to HTN rises steeply with age, although most studies show that treatment attenuates this risk.

C. Hyperlipidemia. Lipid fractions in women are affected by their menopausal status. Premenopausal women have lower low-density-lipoprotein cholesterol (LDL-C) levels and higher high-density-lipoprotein cholesterol (HDL-C) levels than agematched men. With aging, LDL-C increases and HDL-C decreases, causing the risk of CAD to increase. Total cholesterol and LDL-C are less predictive in women, unlike HDL-C, which is inversely associated with the risk. Non—HDL-C and total cholesterol to HDL-C ratio are more predictive in women than in men. In addition, triglycerides are a more potent independent predictor of CAD, especially in older women.

D. Cigarette smoking. This is the single most preventable risk factor. Smoking leads to more CVD deaths than any other risk factor, likely owing to its effects of increasing inflammation, thrombosis, and oxidation of LDL-C. Smoking also has an antiestrogen effect, inducing unfavorable changes in lipid levels. There is a sixfold to ninefold increased risk of MI in female smokers compared with age-matched nonsmokers; in fact, the risk from smoking is equivalent to the risk of weighing about 42 kg more than a nonsmoking woman. However, with smoking cessation, risk is cut in half after 1 year without smoking and eventually declines back to baseline nonsmoker’s risk.

E. Obesity and metabolic syndrome. More than 30% of American women are obese, and this number continues to climb. In women, obesity and body fat distribution (i.e., abdominal location) are independent risk factors for CAD. As shown by an examination of a cohort of 115,195 women from the Nurses’ Health Study, risk of death from CVD increased with increasing body mass index (BMI). Abdominal fat accumulation leads to the development of other components of the metabolic syndrome, such as HTN, diabetes, and hypertriglyceridemia. Obesity is also associated with elevated levels of C-reactive protein (CRP), more so in women.

Women with the metabolic syndrome more often have subclinical CAD than men. A substudy from the National Heart, Lung, and Blood Institute-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study revealed that women with the metabolic syndrome have twice the risk for CHD-related events compared with age-matched women without the metabolic syndrome. The metabolic syndrome is defined by the National Cholesterol Education Program Adult Treatment Panel-III in women as the presence of three or more of the following components:

(1) Waist circumference > 35″

(2) Fasting triglycerides > 150 mg/dL

(3) HDL-C < 50 mg/dL

(4) HTN (systolic blood pressure > 130 mm Hg, diastolic blood pressure > 85 mm Hg, or use of antihypertensive drug therapy)

(5) Fasting glucose > 110 mg/dL

F. Estrogen/menopause. Postmenopausal women have more CVD risk factors, such as obesity, HTN, and hyperlipidemia, likely owing to the changing hormonal environment (estrogen levels are one-tenth the premenopausal level). The predominant source of estrogen changes from estradiol in the premenopausal state to the much weaker hormone estrone (produced by the conversion of androgens in peripheral adipose tissue) during menopause. Animal studies have shown that estrogen can have favorable CV effects, reducing cellular hypertrophy, enhancing vessel wall elasticity, and providing antioxidative and anti-inflammatory actions.

As part of the WISE study results, endogenous estrogen deficiency in young women was shown to be a strong risk factor for CHD, with a 7.4-fold increased risk. Because of the protection from CAD afforded for premenopausal women, there was early enthusiasm for the use of hormone replacement therapy (HRT) to prevent CVD in postmenopausal women, sparked by data from observational studies. However, multiple randomized, placebo-controlled trials over recent years have shown evidence of increased risk for CVD with HRT, such that it is no longer recommended for primary or secondary prevention of CVD (see Section VI.F).

G. Physical inactivity. As women age, they become less physically active than their male counterparts. This contributes to weight gain and predisposes to the development of diabetes and HTN. In addition, with the cessation of estrogen production with menopause, there is increased abdominal fat deposition, further predisposing to CAD. There is a strong inverse association between the activity level and incidence of CV events (see Table 46.2).

H. Novel risk factors. It has been increasingly realized that the traditional risk factors underestimate CHD risk in women. For this and other reasons, research has been focused on identifying other novel biomarkers that can better define a person’s risk. Multiple biomarkers have been investigated to various degrees (e.g., high-sensitivity C-reactive protein [hsCRP], brain natriuretic peptide, and fibrinogen), but the greatest promise appears to be with hsCRP. As part of the Women’s Health Study, over 27,000 healthy American women had their CRP and LDL-C levels measured. The women were then followed for a mean of 8 years for the occurrence of the primary end point (MI, ischemic stroke, coronary revascularization, or death from CVD). Although minimally correlated with each other, both CRP and LDL-C levels had strong linear relationships with CVD events, with CRP being the stronger predictor. Each biomarker tended to identify different high-risk groups, but better prognostic values were obtained when both were used together. These data suggest that CRP shows promise when added to traditional risk factors for prediction of long-term risk.

Women often present differently than men, potentially because of differences in underlying pathophysiology. This is particularly true for diabetic women. Women usually present at an older age, usually 5 to 10 years later than men, and have more comorbidities on presentation than men do. As such, once the diagnosis of CAD is made, women are at higher risk for adverse outcomes.

A. Like men, women can present with typical symptoms of angina, such as substernal chest pain and dyspnea on exertion that is relieved by rest. These symptoms more often occur in older women, who present more similarly to men.

B. Women can also present with atypical chest pain; shortness of breath; neck, shoulder, or arm pain; diaphoresis; and nausea/vomiting.

C. Women are more likely to have subtle symptoms that require detailed history-taking to elicit, such as chest “pressure or tightness,” lightheadedness, palpitations, or fatigue. Women most often have symptoms that occur at rest, wake them from sleep, or occur in times of psychological stress.

D. Women more often present acutely without preexisting prodromes of symptoms or with sudden cardiac death.

A. Exercise electrocardiography. Exercise electrocardiography, the most frequently employed diagnostic modality, is useful only in women with normal baseline ECGs and with the ability to undergo moderate or high levels of exercise (generally on the treadmill). An abnormality is identified if there is >1 mm of ST-segment depression or elevation. Generally, exercise ECG has lower sensitivity and specificity than other modalities, and this is even more prominent in women (sensitivity and specificity
60% to 70% in women vs. 80% in men). This difference is not well understood, but it has been attributed to several factors, such as lower overall prevalence of CAD in women or more submaximal stress tests, owing to the inability of women to exercise to sufficient levels to produce a diagnostic test. If women are unable to achieve at least five metabolic equivalents (METS), studies have shown that they are at increased risk for future CV events.

B. Stress echocardiography (transthoracic echocardiography [TTE]). Stress TTE tends to have higher specificity and lower sensitivity than stress perfusion imaging, as wall motion abnormalities occur later than perfusion abnormalities. However, stress TTE has the advantages of eliminating radiation exposure, decreasing cost, and providing the ability to assess LV function and cardiac structures. It has been shown to be a cost-effective initial strategy for determining CV risk in patients at intermediate risk as compared with stress electrocardiography, and we now use it as a first-line diagnostic test for CAD in women.

C. Stress myocardial perfusion scan. Because of the limited sensitivity and specificity of exercise ECG in women, other modalities are frequently employed to assess the risk of CAD. The most frequently used test is the single-photon emission computed tomography (SPECT) scan, a radionuclide-based technique. Because alterations in myocardial perfusion generally occur earlier than electrocardiographic changes or wall motion abnormalities, this test is more sensitive than exercise ECG or echocardiography for estimating risk in either gender. For those individuals unable to exercise or attain target heart rates, adenosine or dipyridamole can be used as a pharmacologic stress agent. To increase specificity, the higher energy isotopes (technetium 99m) are recommended in women to reduce the soft tissue attenuation artifacts (influenced by both breast tissue and obesity) that tend to occur anteriorly and laterally. Other limitations of SPECT can be critical in women. Because women have smaller hearts, the limitations in spatial resolution of SPECT can lead to small areas of hypoperfusion being missed.

D. Magnetic resonance imaging (MRI).

Stay updated, free articles. Join our Telegram channel

Join