WOMEN’S SYMPTOMS: TYPICAL OR ATYPICAL?
Whether the presenting symptoms of acute coronary syndromes differ between men and women has been much debated.
More women than men seem to present with atypical symptoms.25–27 (The term “atypical” refers to symptoms that do not include the three classic components of angina: substernal chest pain or discomfort, provoked by exertion or emotional stress, and relieved by rest or nitroglycerin, or both.28)
However, most women still present with chest pain. In a study by Dey et al,26 92% of the 7,638 women with presumed acute coronary syndrome presented with chest pain. In women who had atypical symptoms, dyspnea, nausea, vomiting, and diaphoresis were the most common symptoms. Women were significantly more likely than men to present with nausea and vomiting (32% vs 23%, P = .001).
Women in the study were also more likely to have angiographically normal coronary arteries (12% vs 6%, P < .001).26 This difference may be largely due to noncardiac chest pain, but it may also represent conditions such as vasospasm, microvascular disease, or stress cardiomyopathy, all of which disproportionately affect women.
An earlier review of 10 major studies found a higher percentage of women presenting with atypical symptoms (37.5% of women vs 27.4% of men).25 However, symptoms were not a focus of these studies, and the findings may therefore be skewed by inaccurate documentation.
Atypical warning signs. Although most women with acute coronary syndrome present acutely with chest pain, women may have different warning signs than men. Only about one-third of women experience angina before presentation.29 Compared with men, women are more likely to complain of shortness of breath, fatigue, and weakness leading up to a diagnosis of a myocardial infarction.29 Therefore, the prodromal symptoms of cardiovascular disease may in fact be significantly more atypical in women than in men, suggesting the need for heightened vigilance in the cardiovascular evaluation of women who have nonanginal symptoms.
THE ROLE OF STRESS TESTING IN WOMEN
Stress testing in various forms continues to be widely used in the diagnosis of heart disease in women, although data are scarce regarding its utility in women.
The ACC/AHA guidelines continue to recommend exercise stress electrocardiography (ECG) for women who have symptoms, are at intermediate risk, and have a normal result on resting ECG.30
Exercise ECG has a higher false-positive rate in women than in men,31 and there appears to be no relationship between exercise-induced ST-segment depression and the rate of cardiovascular mortality or all-cause mortality in women.32,33 On the other hand, exercise ECG yields valuable additional information such as exercise capacity, chronotropic response, heart-rate recovery, and blood pressure response, all of which have important diagnostic and prognostic implications in women.34
For those who have an abnormal resting ECG, the addition of an imaging test, ie, echocardiography or single-photon emission computed tomography (SPECT), is indicated. Both have limitations: SPECT can give false-positive results because of breast attenuation, and echocardiography varies in accuracy depending on the quality of acoustic windows obtained. Both exercise stress SPECT and exercise stress ECG have higher sensitivity and specificity than electrocardiographic exercise stress testing alone,34 and there is evidence that the two imaging tests are comparable in women.35
In those women who have baseline left bundle branch block or who cannot exercise, a pharmacologic stress test should be performed. Of course, this is a less desirable testing method, given the loss of valuable information obtained from exercising the patient.
UNDERLYING CONDITIONS THAT DISPROPORTIONATELY AFFECT WOMEN
Perimenopausal and postmenopausal women account for 70% of patients presenting with chest pain and elevated cardiac enzymes but no significant angiographic evidence of coronary artery disease.36 This condition, commonly called syndrome X, is often characterized by lingering, dull chest pain after exertion and is seen more frequently in women younger than those presenting with classic cardiovascular disease.
Because at least some of these patients show evidence of ST-segment depression and reversible perfusion defects on imaging, the condition is thought to be caused by ischemia of the microvascular bed leading to microvascular angina.37
Although this is still an area of research, microvascular dysfunction has recently been proposed as an explanation for these findings. Abnormal vasoconstriction and impaired vasodilation of the microvascular bed, insulin resistance, increased systemic inflammation, and abnormal pain response have all been cited as potentially contributing to microvascular dysfunction.36
Estrogen deficiency is thought to play a central role in the significantly increased burden of microvascular dysfunction seen in women, with some studies suggesting that hormone therapy can relieve symptoms. However, given the concerns about adverse cardiovascular outcomes in women on hormone therapy, there has been little investigation of this treatment for this disorder.
Studies have shown worse cardiovascular outcomes and higher rates of angina-related hospitalization and repeat heart catheterizations in women with microvascular dysfunction.38
Diagnosing microvascular angina must be done indirectly, as there is no safe and minimally invasive technique by which to directly observe the microvasculature. Current coronary angiographic techniques cannot image vessels smaller than 0.5 mm in diameter, and endomyocardial biopsy cannot access the larger periarterioles thought to play a major role in regulating coronary blood flow.39
Because the coronary microvasculature controls total coronary resistance and therefore regulates myocardial blood flow, measuring myocardial blood flow at maximum vasodilation, termed coronary flow reserve, can indirectly evaluate the degree of microvascular dysfunction.40 In the absence of obstructive epicardial coronary disease, noninvasive imaging techniques or provocative testing in the coronary catheterization lab can be used for this purpose. In terms of noninvasive imaging, perfusion magnetic resonance imaging (Figure 2) or positron emission tomography is often performed.40
Coronary flow reserve can also be measured by invasive means in the catheterization laboratory after maximum hyperemia is induced by adenosine or other such vasodilatory agents.41 However, measurements obtained in this invasive manner are greatly affected by hemodynamic changes and can have poor reproducibility.40
Proposed therapy for microvascular angina. Once a diagnosis has been made, lifestyle modification, antianginal agents, angiotensin-converting enzyme inhibitors, and statins have been suggested for therapy.39 Pain management techniques are also used, given the increased pain sensitivity observed in women with this condition. However, no therapy to date has proven overwhelmingly effective in these patients, and a disproportionate number of women suffer from chronic symptoms despite these treatments. Currently, researchers are looking for new agents to treat microvascular disease.
Stress cardiomyopathy, also called takotsubo cardiomyopathy or “broken heart syndrome,” is another condition that disproportionately affects postmenopausal women. It is often associated with sudden emotional or physical stress. Patients present with signs and symptoms of myocardial infarction without demonstrable epicardial coronary artery disease. The hallmark of stress cardiomyopathy is left ventricular dysfunction, often severe, with classic apical ballooning that resembles a Japanese fishing pot (takotsubo) used to trap octopuses, hence the name (Figure 3).
According to a review by Akashi et al42 based on previously reported Mayo Clinic criteria, the diagnosis of stress cardiomyopathy includes each of the following:
- Transient hypokinesis, akinesis, or dyskinesis in the left ventricular midsegments with or without apical involvement; regional wall-motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger
- Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
- New abnormality on ECG (eg, ST-segment elevation, T-wave inversion) or modest elevation in cardiac troponin
- Absence of pheochromocytoma or myocarditis.
From 80% to 100% of reported cases are in women, with an average age range of 61 to 76.42 It is unclear why there is such an overwhelming postmenopausal female preponderance of the disease. Studies have implicated estrogen deficiency, as it appears to attenuate the levels of cardioprotective substances in the body that in part regulate catecholamine surges and may also increase the level of oxidative stress.42
Several mechanisms for this condition have been proposed. The condition may be caused by multivessel epicardial coronary spasm or spontaneously resolved plaque rupture, resulting in stunned myocardium. However, the regional distribution of wall-motion abnormality is often out of proportion to the level of cardiac enzyme elevation, and in the case of plaque rupture, is frequently not consistent with a single coronary vessel.42 A catecholamine surge causing myocardial and neurogenic stunning has also been proposed, although many of these patients have normal catecholamine levels.42 Finally, microvascular dysfunction has been found in a number of patients with this condition. However, it is difficult to establish a causal relationship, since apical ballooning could result in microvascular dysfunction.42
Treatment of stress cardiomyopathy has not been standardized, in part because the left ventricular dysfunction often resolves spontaneously within several weeks.43,44 Given the proposed catecholaminergic mechanism, some experts believe that beta-blockers are contraindicated because of the resulting unopposed activation of alpha-adrenoreceptors. However, this continues to be a matter of debate. There is also no clear indication for other standard therapies for acute coronary syndrome such as aspirin and heparin, and their use appears to vary in clinical practice.
Although most patients improve with time and recurrence is exceedingly rare, it should be emphasized that they may present acutely with severe hemodynamic instability and cardiogenic shock. Therefore, advanced means of support, such as an intra-aortic balloon pump, may be indicated until the patient recovers from the acute phase of the disease.