Cardiovascular disease is one of the leading causes of death worldwide. Since 1984, the total number of deaths from cardiovascular disease has been greater for women compared with men. This might be, in part, related to gender-specific differences in the presentation of people with chest pain but, importantly, the risk of heart disease in women is often underestimated owing to the misperception that women are ‘protected’ against cardiovascular disease. Studies have shown that medical services are underused, delays occur in health-care seeking behaviour, resource use patterns are less intensive, and it takes longer to diagnose women compared with men. This often leads to less aggressive treatment strategies which, in turn, may translate into poorer outcomes compared with those in men. In this chapter, we review the gender-specific differences in epidemiology, diagnosis, and management of people with ischaemic heart disease, and focus particularly on the effect of ageing and menopause in ischaemic heart disease.
Introduction
Cardiovascular disease is one of the leading causes of death and disability in women worldwide. Historically, despite the high prevalence of ischaemic heart disease (IHD) in women, most available data on the clinical presentation, clinical outcomes and preferred methods of treatment in IHD were based on clinical trials and studies focusing exclusively on men. More recently, interest in gender differences and female-specific recommendations has increased, leading to the documentation of epidemiological and pathophysiological differences, and differences in the presentation, diagnosis, and management of IHD between men and women. Over the past decade, randomised-controlled trials, such as the Women’s Health Initiative, have significantly influenced the development of gender-specific awareness in the diagnosis and treatment of women with IHD.
Gender-related epidemiological differences
Women with IHD are generally about 10 years older than men, but they carry a greater burden of risk factors and have higher prevalence of symptoms, myocardial ischaemia, and mortality relative to men. Despite being the leading cause of death of women at all ages, the prevalence of obstructive coronary artery disease (CAD) in women is relatively low before menopause (average age 51 years), and this delayed onset of the disease results in relatively lower likelihood of obstructive CAD in their lifetime. In particular, the prevalence of IHD in premenopausal women is about 5% in women younger than 35 years; however, younger women may have worse prognosis than men.
Paradoxically, although women have less anatomical obstructive CAD and relatively more preserved left ventricular function, the rates of myocardial infarction and mortality are higher compared with men, even when adjusting for age. Data from WISE study implicate adverse coronary reactivity, microvascular coronary dysfunction, and plaque erosion or distal microembolisation, as it is at least, in part, responsible for a female-specific myocardial ischaemia pathophysiology.
Gender-related epidemiological differences
Women with IHD are generally about 10 years older than men, but they carry a greater burden of risk factors and have higher prevalence of symptoms, myocardial ischaemia, and mortality relative to men. Despite being the leading cause of death of women at all ages, the prevalence of obstructive coronary artery disease (CAD) in women is relatively low before menopause (average age 51 years), and this delayed onset of the disease results in relatively lower likelihood of obstructive CAD in their lifetime. In particular, the prevalence of IHD in premenopausal women is about 5% in women younger than 35 years; however, younger women may have worse prognosis than men.
Paradoxically, although women have less anatomical obstructive CAD and relatively more preserved left ventricular function, the rates of myocardial infarction and mortality are higher compared with men, even when adjusting for age. Data from WISE study implicate adverse coronary reactivity, microvascular coronary dysfunction, and plaque erosion or distal microembolisation, as it is at least, in part, responsible for a female-specific myocardial ischaemia pathophysiology.
Risk factors and primary prevention
The traditional risk factors for ischaemic heart disease are smoking, hypertension, dyslipidaemia, and diabetes mellitus. Although most risk factors for IHD are similar in men and women, substantial gender-related variability occurs in the prevalence and outcome associated with these. Although the overall rates of hypertension and smoking are higher in men, elderly women with hypertension and young female smokers are prominent at-risk subsets. Epidemiological studies have reported that cholesterol measurements are higher in men until the fifth decade of life but beyond this age women have greater values, and this has an adverse effect in their prognosis.
Johnston et al. studied 12,200 people with stable chest pain that were referred for a first-time elective diagnostic coronary angiography between 2006 and 2008. They documented that, among people with significant CAD, women were older and had higher rates of diabetes, hypertension, peripheral vascular disease and chronic obstructive pulmonary disease. In fact, the strongest association with significant CAD in women is diabetes, and it seems to be the most important risk factor in predicting significant CAD and increased mortality in women. Women have a similar or even higher prevalence of angina compared with men, but do seem to have fewer typical symptoms; they are more likely to have atypical pain, and are more likely to present with symptoms of chest pain rather than a clearly defined event, such as a myocardial infarction.
In addition, obesity, sedentary lifestyle, and poor nutrition have also been described as risk factors that increase the likelihood of CAD; these factors exert much of their adverse effect through the major risk factors. Although they are not included in the risk-assessment algorithms, they are of paramount importance as targets for the prevention of CAD. Prospective epidemiological studies and randomised prevention trials have shown the importance of modification of dietary and lifestyle risk factors (e.g. maintaining a healthy weight, daily physical activity and healthy diet) in the prevention of CAD.
Investigations
The evaluation of a woman with suspected IHD should begin with a careful and thorough assessment, consisting of a detailed history of the chest pain complaints and potential risk factors, physical examination, laboratory investigations, electrocardiogram, and assessment of overall cardiac risk (categorised as low, intermediate or high risk). If the woman is established to be at intermediate risk, a stress test is normally requested. The exact choice of test will depend on a variety of clinical factors, such as patient risk, ability to exercise, body habitus, prior test information for comparison, and non-clinical factors, such as local test availability and expertise.
Exercise tolerance test
Current guidelines for the detection of CAD in women who present with chest pain recommend the use of the exercise tolerance test (ETT) as the preferred initial method for evaluating women with stable chest pain if they are able to exercise and have an interpretable electrocardiogram (ECG). In women, stress echocardiography is preferred over ECG stress testing. Other modalities, such as magnetic resonance imaging perfusion scanning and radionuclide testing, also provide useful information. The latter, however, is associated with considerable exposure to radiation. If an ETT is chosen, the stress is adequate (maximal), the ECG interpretable, and the test shows no evidence of myocardial ischaemia, no further evaluation is necessary. Reproducibility of symptoms and exercise capacity (fitness level) can also be assessed with an ETT and, in particular, an exercise capacity of less than five metabolic equivalents or the inability to achieve at least 85% of age-predicted fitness level has been shown to be predictor of myocardial infarction, IHD, death, and all-cause mortality in women. High false-positive rates have been reported as a result of limitations of the accuracy of the ECG in women, challenging this common practice. Other factors contributing to lower accuracy of the exercise tolerance test in the diagnosis of CAD in women are older age at presentation, with inevitable higher frequency of concomitant co-morbidities, limited exercise capacity, and autonomic influences. In a meta-analysis of 19 studies, the ETT carried a mean sensitivity of 61% and mean specificity of 70%, lower than the sensitivity of any imaging method used. Therefore, on the basis that further testing would be necessary if the ETT was used as an initial diagnostic tool, significant variation has resulted in the use of ETT as an initial diagnostic strategy for the detection of CAD in women.
In the WOMEN trial, 842 symptomatic women with suspected CAD were randomised to ETT or exercise myocardial perfusion imaging (MPI) to assess comparative effectiveness. No difference in major adverse cardiac events (e.g. cardiac death, myocardial infarction or acute hospital admission for an acute coronary syndrome or heart failure) were reported at 2 years.
In low-risk women able to exercise, ETT was as effective as exercise MPI as the initial step for assessing women with stable chest pain, although a significant cost saving (48%) was made for ETT compared with MPI. Therefore, although the WOMEN trial supports the use of ETT as an index procedure followed by MPI only in cases of indeterminate or abnormal ETT findings, this means that additional testing may be required in many cases.
Stress testing with imaging techniques
Imaging modalities, such as echocardiography and cardiac magnetic resonance (CMR) are preferred options to be used to assess IHD risk in women. The advantages over the conventional ETT include superior diagnostic performance for the detection of obstructive CAD, the ability to quantify and localise areas of ischaemia (e.g. hibernating myocardium), the ability to provide diagnostic information in the presence of resting ECG abnormalities, or its use when the individual is unable to exercise. Stress imaging is also more appropriate in people with established CAD who have had previous percutaneous coronary intervention or coronary artery bypass graft because of the ability to localise ischaemia.
Myocardial perfusion can be assessed in women using single-photon emission tomography, positron-emission tomography, or CMR. The effectiveness of single-photon emission computed tomograhy stress imaging in the risk-stratification of women with suspected IHD has been well documented previously, but certain limitations should be taken into consideration, such as lower sensitivity in multi-vessel CAD, breast attenuation artefact, and radiation exposure. Stress perfusion imaging is extremely valuable in the evaluation of subendocardial perfusion in the context of a normal angiogram, as a number of publications have reported subendocardial hypoperfusion in women with chest pain and unobstructed coronary arteries. In a small sub-study from the WISE study, women with unobstructed coronary arteries and abnormal stress CMR result (presumably due to microvascular coronary dysfunction) had an increased rate of adverse cardiovascular events.
Stress-induced regional wall-motion abnormalities and myocardial perfusion have relatively similar sensitivities and specificities for the detection of IHD in women.
Coronary artery calcium scoring
The assessment of coronary artery calcium (CAC) score has been proposed in recent years as a screening test for CAD. The CAC scoring aims at identifying and quantifying coronary atherosclerotic plaque using thin slice fast computed tomography imaging. A zero CAC score indicates absence of atheroma and is associated with an extremely low likelihood (<1%) of CAD. Conversely, higher CAC scores, especially those greater than 400, have been shown to be associated with obstructive CAD and events. Coronary artery calcium scoring is a screening test for coronary atheroma, but it is not able to provide information about coronary artery stenosis, severity or plaque activity. As such, it is a robust marker of coronary atherosclerotic burden, which has been found in several studies to be useful for the prediction of cardiovascular and all-cause mortality. Hence, individuals with high CAC scores should be considered for further evaluation, usually coronary angiogram.
This is reflected in current international recommendations, such as the American Heart Association European Society of Cardiology guidelines, which indicate that it is reasonable to carry out CAC scoring in intermediate risk (10–20% 10-year risk) women. In young and elderly people who are at intermediate risk of CAD, CAC scoring is a useful prognostic tool. A CAC score of zero in elderly people signifies an excellent prognosis, making further investigations unnecessary, potentially reducing healthcare expenditure. Similarly, CAC scoring has the potential to identify younger people who may be classified as low risk according to conventional risk assessment, but are, in fact, at increased risk of CAD and events, and who would benefit from aggressive preventative measures.
Coronary angiography
Coronary angiography remains the gold standard test for the investigation of chest pain in women and men. Women with any symptoms suggestive of myocardial ischaemia still have a lower probability of IHD than men. Johnston et al. studied 12,200 people with stable chest pain that were referred for a first-time elective diagnostic coronary angiography between 2006 and 2008. The proportion of people undergoing coronary angiography was similar in this study, although there is a documented underuse of invasive investigations in women. Normal coronaries or non-significant coronary artery disease were more common in women than men across all age groups. Computed tomography angiography is another option available for the investigation of coronary artery anatomy that should be considered for assessment in women with suspected CAD.
Ischaemic heart disease and menopause
The observed cardio-protective effects of endogenous oestrogen and postmenopausal oestrogen replacement have been debated and thoroughly investigated to date. The beneficial effects of oestrogen on lipid metabolism, endothelial function, and other factors involved in the pathogenesis and progression of coronary atherosclerosis are established. It has been reported that postmenopausal oestrogen replacement therapy is more effective in CAD prevention than in slowing the progression of disease once it is established. In a study of 309 women with verified CAD at baseline, women were randomised to receiving unopposed oestrogen, oestrogen plus medroxyprogesterone acetate, or placebo, and were followed up with coronary angiography after 3 years. Hormone replacement treatment did not slow down disease progression in women with established CAD. In the WISE study the relationship between total oestrogen exposure time (endogenous reproductive hormones and hormone replacement therapy [HRT]) with CAD was examined by measuring quantitative coronary angiography and prospectively assessed adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected CAD. No significant differences were found between the groups in the age of menarche or menopause, or years since the final menstrual period. As with previous epidemiological studies, the study failed to demonstrate a role of endogenous oestrogen-related reproductive factors in CAD. Total time of oestrogen exposure was also not related to major adverse cardiovascular events; however, women who used HRT for more than 5 years had a lower prevalence and severity of obstructive CAD. Those results suggest that the paradigm of oestrogen protection from CAD in women may be more complex than oestrogen exposure duration alone. Recent studies are focusing more on the ‘timing hypothesis’, suggesting that HRT initiated closer to the age of menopause may have a cardioprotective effect but only after several years of treatment; however, HRT initiated over a decade after menopause may actually lead to increased cardiovascular disease risk. The later could be explained by the fact that first pass liver metabolism of oral oestrogens increases thrombotic factors and decreases thrombolytic factor synthesis, which may accelerate thrombosis of pre-existing coronary plaque and lead to increased risk of developing venous thromboembolism or stroke.
Oestrogen may, therefore, have positive and negative effects on the coronary arteries and carries both risks and benefits; it is, therefore, essential to tailor its use according to individual patient’s circumstances. Hormone replacement therapy is not recommended for primary or secondary prevention of CAD. It is currently recommended only for symptomatic women, close to the age of menopause, and the use of the lowest effective dose for the shortest duration of time is advised.
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