Despite the worldwide reduction in mortality from cardiovascular diseases (CVDs) in women and men in the past ten years, unfavorable outcomes, such as higher in-hospital mortality rates from ischemic heart disease (IHD) following percutaneous and surgical interventions, are more frequent among women.
Anatomical and pathophysiological differences, such as smaller epicardial coronary arteries adjusted for body surface, lower coronary vasomotor tonus with functional changes even in the absence of obstructive coronary artery disease, and higher microcirculation dysfunction, could explain the different IHD phenotypes in women.
The IHD clinical manifestations and characteristics of the complementary diagnostic methods are different in women, with false-negative or false-positive results, misinterpretations, and, consequently, inappropriate women's IHD management and treatment.
CVD remains the major cause of death in adults, thus, the development of new strategies is required to mitigate CVR, mainly in women.
The difference in clinical presentation of IHD in women, whose symptoms are triggered by emotional or mental stress, the higher prevalence of symptoms other than chest pain, as well as the presence of nonclassical risk factors not considered in usual risk scores make CVR stratification a challenge in the female sex.
A growing body of evidence suggests that traditional cardiovascular risk factors (CVRFs), such as hypertension, diabetes, dyslipidemia, and obesity, pose a differential risk to women as compared to men. For example, diabetes poses a 40% higher risk of IHD to women as compared to men. Premenopausal women have a lower risk of CVD than men at the same age, but women lose that advantage in the menopausal transition.
For younger adults, CVDs account for 10.3% and 20.9% of the deaths in the age ranges of 25-44 years and 45-64 years, respectively. In young women, recognition of adverse pregnancy outcomes (APOs) as a women-specific CVRF is critical for CVR stratification. Women with history of pregnancies complicated by hypertension, gestational diabetes, premature delivery, low birth weight, and fetal growth restriction are at a higher risk for short- and long-term cardiovascular complications. Women with history of APOs can have increased risk for CVD even after achieving normoglycemia and standard control of postpartum blood pressure.
At rest, coronary blood flow is maintained by autoregulation up to the development of critical stenosis, defined as the capacity to preserve blood flow during perfusion pressure changes, with constant metabolic needs. When an atherosclerotic plaque occludes more than 70% of the luminal cross-section, with a 50% reduction in the coronary diameter, it significantly increases proximal resistance and decreases distal coronary perfusion pressure. In that situation, autoregulation can maintain baseline coronary blood flow, but coronary reserve is impaired. Thus, at rest, the condition is asymptomatic, but, at high metabolic demands during physical exercise, the coronary flow is insufficient.
A large percentage of women with IHD has minimal or no epicardial coronary artery disease. Coronary microvascular disease, however, plays an important role in the etiology of IHD in the female sex, regulating blood flow and oxygen delivery and energetic substrates in the microcirculation-myocardium interaction. Myocardial ischemia is directly dependent on a balance between myocardial energy
The ET is an accessible, safe, reproducible, low-cost, radiation-free functional test that provides information to support IHD diagnosis, CVR stratification, therapeutic assessment, and physical exercise prescription. It is recommended as the initial method to assess symptomatic women at low/intermediate CVR for IHD who have normal electrocardiogram (ECG) at rest and who can exercise.
In addition to assessing segmental contractility abnormalities, transthoracic echocardiography is a valuable tool to screen for cardiomyopathies, such as hypertensive, hypertrophic, and Takotsubo cardiomyopathies, and other causes of chest pain.
The wall contractility abnormalities detected on echocardiography appear later in the ischemic cascade, being preceded by perfusion abnormalities detected on SPECT (
The investigation of atherothrombosis of the carotid system and femoral arteries with VUS has an excellent cost-benefit ratio for CVR stratification, because it is a noninvasive, widely available, and easily performed test.
The carotid and femoral atherosclerosis assessment has been recently suggested to improve the early detection of the disease, and the presence of a femoral plaque in women is more indicative of IHD than that of a carotid plaque.
The myocardial perfusion tests SPECT and PET play an important role in the assessment of women with symptoms suggestive of IHD and at intermediate/high CVR,
Stress myocardial perfusion scintigraphy (MPS) provides information on the perfusion deficit extension and severity, ischemic burden, and myocardium at risk, as well as the LVEF and wall motility at rest and under stress. For women at intermediate risk with ECG changes at rest or those who cannot exercise, MPS can be the first test requested. Technetium-99m is the radionuclide of choice because it involves less radiation exposure for the patient.
In the assessment of IHD in women, the MPS has shown sensitivity ranging from 78% to 88%, specificity, from 64% to 91%, and lower accuracy as compared to that in men.
The MPS with pharmacological stress with vasodilators (dipyridamole, adenosine, regadenoson) is the best option for women who cannot exercise, with sensitivity of 91% and specificity of 86%.
Women have a higher prevalence of microvascular disease and lower prevalence of obstructive coronary disease than men, and, for that analysis, complementary tests other than luminography are required. The combination of MPS and PET is a technique appropriate to assess coronary flow reserve (CFR), but it is not widely available. Evidence of reduced CFR (defined as <1.9–2.0) suggests underlying vascular dysfunction and can help detect microvascular IHD. Abnormal CFR is associated with diastolic dysfunction and can play a role in the assessment of heart failure with preserved ejection fraction (HFpEF), more prevalent in women. A study with 64.7% of women without obstructive IHD has shown an independent association of CFR reduction and diastolic dysfunction. Imaging protocols with hybrid equipment (PET/CT or SPECT/CT) add the assessment of anatomical changes to the coronary artery calcium score (CAC) quantification, thus increasing the sensitivity for the diagnosis of IHD in a single test.
Symptomatic women with positive functional tests are often submitted to invasive methods, such as coronary angiography, that evidence no atherosclerotic plaque, which, when present, is not severe (stenosis < 50%).
The CAC plays an important role in CVR stratification, mainly in asymptomatic patients at low/intermediate risk. In symptomatic women, its role is controversial, because women's have fewer calcified vessels and/or plaques and lower coronary calcium volume. A CAC of 0 practically excludes obstructive IHD, with negative predictive value > 96.5% for lesions ≥ 50% (CONFIRM registry), in addition to indicating low CVR in both sexes (< 1%).
CCTA has high diagnostic accuracy for obstructive IHD, even after sex-specific analysis. Sensitivity, specificity, and positive and negative predictive values increase with the increase in the stenosis degree. Because women's epicardial coronary arteries are thinner than those of men, the CCTA accuracy is lower (70% × 90%; p < 0.05), mainly in distal coronary arteries and branches.
In addition to detecting the presence of plaque, CCTA provides the assessment of calcium volume and load, presence of remodeling, and plaque vulnerability. Women have lower volumes of calcified or noncalcified plaques, regardless of age. The PROMISE study (n = 5007; 51% women) has compared anatomical and functional tests in patients with chest pain and low/intermediate risk, showing that, in women, positive
Regarding the characteristics of atherosclerotic plaques, those with higher risk for MACE in women have low attenuation, positive remodeling, punctate calcification, and napkin-ring sign (suggesting a thin fibrous cap) (adjusted OR: 2.41; 95% CI 1.25-4.64).
CMR plays an important role in the assessment of women with suspected or known IHD because it is noninvasive and involves neither ionizing radiation nor nephrotoxic contrast media. In addition, it has high spatial resolution, wide visual field, excellent reproducibility, and provides the assessment of cardiac and vascular anatomy, ventricular function, ischemia, viability, and tissue characterization with high accuracy. CMR has been increasingly used in the assessment of suspected IHD in symptomatic women or those at intermediate/high risk.
The CMR with stress has good accuracy for IHD diagnosis, risk stratification, and prognosis.
CMR is an important strategy in suspected MINOCA (myocardial infarction with non-obstructive coronary artery), providing the location of inflammation, edema, and myocardial fibrosis, differentiating ischemic from nonischemic etiologies, identifying the underlying etiology in up to 87% of the cases, and providing the CVR stratification and management definition in women.
One of the great advantages of CMR is its ability to overcome the technical limitations of other conventional stress imaging modalities, such as breast tissue, obesity, pulmonary disease, and low exercise capacity of the patients.
Mammography can identify BACs or arteriosclerosis by showing radiopaque structures involving the entire circumference of the artery (
The estimated prevalence of BAC ranges from 8.2% to 12% in women aged over 50 years. There is an association between the presence of BAC and kidney disease, stroke, peripheral vascular disease, carotid artery disease, and IHD. The finding of BAC on mammographies of women under the age of 59 years has been reported to be an additional risk factor for CVD, mainly in women with diabetes, even asymptomatic.
A retrospective cohort study of women assessed for breast cancer in a 23-year follow-up has estimated that those with BAC had higher relative risks as follows: 1.66 (95% CI 1.31–2.10) for cardiovascular events; 3.25 (95% CI 1.53–6.90) for IHD; 2.85 (95% CI 1.59–5.09) for hypertensive heart disease; 2.06 (95% CI 1.19–3.56) for congestive heart failure; 2.8 (95% CI 1.42–5.52) for peripheral vascular disease; 1.83 (95% CI 1.09–3.08) for atrial fibrillation; and 2.23 (95% CI 1.21–4.09) for lacunar infarction. Cox multivariate analysis, considering also the classical CVRFs, has shown a significant and independent association of BAC with both cardiovascular-event-free and specific survivals (1.94 − 95% CI 1.38–2.73).
Another study has assessed 292 women by use of digital mammography and CCTA, and BAC and CAC were quantitatively assessed (0 to 12), correlated with each other and with the Framingham risk score. The sensitivity, specificity, positive and negative predictive values, and accuracy of BAC > 0 for CAC > 0 were 63%, 76%, 70%, 69%, and 70%, respectively. BAC > 0 had an area under the curve of 0.73 for the identification of women with CAC > 0. There was a strong quantitative association between BAC and CAC, and BAC was superior to the traditional CVRFs regarding CAC accuracy. The incorporation of BAC for the CVR assessment of peri- and postmenopausal women is premature, but BAC is an opportunity to identify women at high risk by using routine mammography analysis in breast cancer screening.