The term “ischemic heart disease” (IHD) is preferable over CAD when describing heart disease in women [25]. With IHD the importance of myocardial ischemia is implied without requiring involvement of significant obstructive narrowing of the epicardial coronary arteries [26]. This is consistent with the relatively higher prevalence of non-obstructive CAD (NOCAD) in women combined with the comparable levels of myocardial ischemia [25]. Moreover, approximately half of the women with chest pain do not have significant CAD as measured by coronary angiography (i.e., <50% luminal narrowing of a coronary artery), whereas chest pain in the absence of significant CAD has been found to be less prevalent in men (10–20%) [27–29]. It is therefore remarkable that premenopausal women who have had an acute coronary syndrome (ACS) have a greater incidence of adverse outcomes compared to men, despite having less obstructive CAD [25].

Ischemic heart disease can include microvascular ischemia, which is characterized by abnormal vascular function in “resistance vessels” of the heart, i.e., the microvasculature [30, 31]. This condition can co-exist with endothelial dysfunction in the epicardial coronary arteries. Endothelial dysfunction involves poor function of the lining cells of the coronary vessels (i.e., the endothelium) and is common at all stages of CAD. Endothelial dysfunction can result in transient vasoconstriction and subsequent myocardial ischemia, and can be present in vessels without luminal narrowing. Endothelial dysfunction may therefore explain why significant obstructive CAD (i.e., luminal narrowing >50%) is often not detected in women with cardiac symptoms and why non-obstructive CAD (NOCAD) is not necessarily benign. In this context it is relevant to consider coronary microvascular dysfunction (CMD). This is discussed extensively in Chap. 4 and in short CMD is characterized by: (1) inducible myocardial ischemia as documented by ECG changes, transient wall motion abnormalities, or perfusion defects on cardiac imaging following exercise or pharmacological provocation tests; (2) a history of chest pain or other cardiac symptoms; and (3) normal or minimally narrowed coronary arteries (<50% luminal stenosis) at angiography [30, 32–34]. It is possible that CMD involves both epicardial coronary dysfunction as well as microvasculature dysfunction. Both pathophysiological processes may lead to reduced blood flow and cause myocardial ischemia and symptoms that can be qualitatively different from obstructive CAD [35, 36]. These conditions require further investigation as the differential diagnosis is complicated and treatment options are not well defined.

Women diagnosed with IHD report poorer health status when compared to men [37, 38]. A poor health status has been found to be a predictor for adverse prognosis [39, 40]. However, sex differences related to health status, depression, or anxiety-associated risk of IHD remain under-investigated [41]. The increased prevalence of depression in women is observed in patients with IHD, with a higher frequency in women (19%) compared to men (12%) [42]. Some evidence suggests that depression is only associated with future IHD-related mortality in men but not in women, whereas depression predicts IHD incidence in both men and women [43]. However, sex differences are not consistently found across studies. In the INTERHEART study significant sex differences for ACS risk were present for work stress; non-significant for women, but significant for men, and locus of control with more protective effects in women, but no sex differences in risk were observed for stress at home, financial stress, stressful life events, or feeling depressed [44]. The Women’s Ischemia Syndrome Evaluation (WISE) study showed that in women with suspected IHD depression predicted hospitalization as well as mortality [45]. Similar findings were observed in other large epidemiological cohorts in women, such as The Stockholm Female Coronary Angiography Study, showing that women with high stress levels related to work or family challenges develop narrowing of the coronary arteries [46]. Smolderen and colleagues showed that women below 60 years of age with a history of depression were more likely to be admitted for an ACS compared to men [47]. Moreover, recovery after an ACS is worse in young and middle-aged patients who report higher stress at baseline. Higher stress levels were present in women, which partially explained their worse recovery [48]. In patients with IHD, after adjustment for potential confounding factors, depressive symptoms predicted presence of obstructive CAD, as well as follow-up major adverse cardiac events (MACE), and death in women below 55 years, but not in men or women over the age of 55 years [49]. In relatively young women after an ACS, vital exhaustion (an episode of extreme tiredness, demoralization and increased irritability) was associated to accelerated coronary atherosclerosis progression [50]. Low and colleagues reviewed 67 reports on sex differences in psychosocial risk factors for CAD incidence or recurrence. Results indicated that depression, anxiety disorders, and stress related to family issues are associated with an elevated IHD risk among women, whereas the associations of general anxiety, work-related stress and hostility are less clearly associated with IHD in women compared to men [14].

Doyle and colleagues performed a systematic review and individual patient data meta-analysis of sex differences in depression and subsequent prognosis of people with an ACS [51]. The prevalence of depression was higher in women compared to men, and depression was associated with all-cause mortality and cardiac events. Interestingly, the association of depression with all-cause mortality was higher in men (HR 1.38, 95%CI 1.30–1.47), compared to women (HR 1.22, 95%CI 1.14–1.31), which was confirmed by a significant interaction between sex and depression [51]. Similar findings were observed for the presence of depression in people reporting angina pectoris in both Western and non-Western populations; depression was more prevalent in both men and women who reported angina pectoris, but this association was stronger in men [52]. Still, these findings represent IHD conditions which are more prevalent in men. More attention is needed for IHD conditions including non-obstructive CAD, which is more present in women, and age stratified findings.

In summary, psychosocial risk factors are more prevalent among women compared to men both in the general population as well as in individuals with IHD. Psychosocial risk factors are associated with adverse cardiac outcomes in both men and women. Risk for psychosocial distress and cardiac outcomes appear to be stronger for men, and for younger women with depression or anxiety. This trajectory of elevated psychosocial across the life cycle is in contrast with the relatively low risk of obstructive CAD in women during this time period. This discrepancy may be explained in part by difference in the clinical phenotypes of IHD in women versus men (with predominance of CMD in younger and middle-aged women) and/or the unique presentation of cardiac symptoms in women with IHD.

A number of biological mechanisms have been suggested and are considered to be associated with psychosocial factors on the one hand, and adverse cardiac outcomes on the other, including neuroendocrine dysfunction, autonomic control, endothelial dysfunction, and inflammation [10, 53, 54], for a detailed review see reference [55]. In addition, the prevalence of depressive symptoms and anxiety across the lifecycle in women may suggest an effect of sex hormones on mood. During reproductive years depressive symptoms have been related to cyclic changes in sex-steroid hormones during the menstrual cycle, infertility treatment, during pregnancy or after delivery (e.g. post-partum depression) [56–58]. In the perimenopausal phase estrogen levels decline and fluctuate substantially and after menopause estrogen is no longer produced by the ovaries but in smaller amounts by the adrenal glands and in fat tissue. The fluctuating levels of estrogens over the lifecycle suggests a ‘window of vulnerability’ for depression and mood states. Moreover, the fluctuating and declining estrogen levels in perimenopause and thereafter makes estrogen a plausible contributing factor to ageing in the development of atherosclerosis.

Psychosocial factors have consistently been related to inflammation in IHD [13, 59–61], and sex differences have been observed in levels of biomarkers, such as high sensitive C-reactive protein (CRP) and other inflammatory cytokines [62, 63]. This is supported by clinical-observational and epidemiological investigations [64–66]. The predictive value of inflammatory markers such as CRP, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) for IHD development and prognosis are well established [62, 67–69]. Estrogens inhibit local production of pro-inflammatory markers such as CRP by decreasing IL-6 secretion [69]. Consistent with these immune system-related effects of estrogens, postmenopausal women have increased circulating levels of pro-inflammatory cytokines IL-6 and TNF-α, and an increased response of the body to these cytokines [70]. Although estrogens levels can affect endothelial function [71], inflammation plays a key role in endothelial dysfunction. Endothelial dysfunction has been related to depressive symptoms [72].

Symptoms of chest pain are associated with IHD in men with relatively good sensitivity and specificity, but in women these symptoms are less sensitive/specific [35, 73]. The most common ACS symptoms in women are shortness of breath, weakness, and fatigue in addition to chest pain [35, 73]. Other reported symptoms which are more prevalent in women compared to men include, nausea, vomiting, numbness in hands, back, neck or jaw pain, dizziness, palpitations, chest discomfort, sense of dread, anxiety, or cold sweat [74]. One of the consequences of these different symptom profiles in women is that the patient as well as physicians and other health care providers have to differentiate their interpretations of these symptoms from other conditions such as anxiety, psychological distress, and acute panic disorder. These “competing interpretations” may result in delayed and often missed diagnosis of IHD and lack of initiation of necessary clinical interventions [25, 35, 75–77]. One of the major challenges is to be able to differentiate between cardiac symptoms and complaints that accompany anxiety or a panic attack. Another major challenge is the correct diagnosis of symptoms of IHD that are not characterized by chest discomfort (e.g., dyspnea, fatigue, pain in regions other than the chest and/or radiation to arms or jaw).

A panic attack by definition is a period of intense fear, which develops suddenly. Symptoms of a panic attack largely resemble symptoms of angina pectoris or even a myocardial infarction. Figure 13.2 shows a Venn-diagram for symptoms of a panic attack and angina, and the overlap between both entities. The majority of symptoms overlap, which makes it challenging to distinguish angina from a panic attack in the emergency department and other clinical settings. The meta-analysis by Huffman and Pollack showed that five factors were predictive of panic disorder among persons who present with chest pain: the absence of obstructive CAD, atypical quality of chest pain, female sex, younger age (mean age 45 years), and a high level of self-reported anxiety [78].

Irrespective of ‘hard’ cardiac outcomes, the presence of chest pain and other cardiac symptoms are important, since patients with NOCAD continue to report chest pain [79], limiting their physical activity, and they continue to have hospital readmissions [80]. From a health perspective, the increased health care utilization, follow-up visits and laboratory testing are costly and demanding to patients and their families. Recurrent chest pain does not necessarily lead to mental health care referral [80]. Still, the presence of panic disorder is not harmless; patients with panic disorder have a 47% increased risk of developing IHD, a 36% increased ACS risk, and a 40% increased risk for MACE [81] compared to individuals without panic disorder. Moreover, both anxiety, mental stress, and a panic attack are associated with coronary vasoconstriction and reversible myocardial perfusion defects indicative of myocardial ischemia [82–86], which have found to be more prevalent in women compared to men [87]. Thus, a bidirectional relationship can be assumed; both stress and panic can cause ischemia, and vice versa ischemia can cause a panic attack. The possibility of an ACS, or coronary ischemia causing a panic attack, is suggested via increased catecholamine levels (noradrenaline and adrenaline), a decreased heart rate variability (HRV), or cerebral CO₂ levels secondary to an increase in lactate as a consequence of ischemia [80].

These findings indicate that although chest pain is prevalent in both angina and panic disorder, the latter can occur with typical angina. Even if a panic disorder is recognized, this does not exclude the possibility of co-occurring CAD [80]. Screening tools to date are not adequate for the differential diagnosis of cardiac chest pain versus chest pain that is part of a panic attack. It is possible that clinical benefits will result from the validation study of a 4-item Panic Screening Score instrument for use in the emergency department [88].

An autonomic nervous system imbalance can be a vital part of the missing link in the association between sex differences in cardiac symptoms, psychosocial distress, and pathophysiological functioning in IHD. Heart rate is regulated by the autonomic nervous system, the parasympathetic branch acting as a brake, via the neurotransmitter acetylcholine, while activation of the sympathetic nerves, releasing noradrenaline, accelerates heart rate. The vagus nerve transmits signals from the brain to the heart to regulate heart rate, but at the same time 80% of the vagus nerve comprises sensory (afferent) nerves, informing the brain about the heart and other peripheral organs [89]. Via the vagus nerve autonomic functioning is balanced in a dynamic way to respond to internal and environmental demands, which can be examined noninvasively by heart rate variability (HRV). HRV is the irregularity of consecutive heart beat intervals [90–92]. High HRV represents more variation in interbeat intervals, indicating a more variable and healthy heart rate regulation. A disturbance in autonomic balance, reflected in a reduced HRV suggests a decreased parasympathetic inhibition.

Examining HRV is intriguing for several reasons. There are many studies confirming the relevance of examining HRV in relation to chest pain [93–98], sex differences [90, 99], CAD [90, 91, 100], inflammation [61, 101–103], microvascular and endothelial functioning [104–107], and psychosocial factors [95, 108–112], though inconsistent findings have been reported [113, 114]. Few studies have combined these elements: more chest pain and lower HRV was observed in women who report panic attacks [97], and a reduced parasympathetic tone was observed in patients with cardiac symptoms and inducible ischemia but without clinically significant CAD [115, 116]. Differences in vagal nerve activation between men and women suggest sex-related variations in sensory properties of this pathway and/or central perception and interpretation of internal and external signals, resulting in increased perceived chest pain and subsequent feelings of anxiety. It remains to be investigated if and how autonomic dysregulation plays a role in cardiac symptom perception, and sex differences in mood associated with IHD.

Interventions for patients with IHD typically take place in the context of cardiac rehabilitation (CR) following ACS or revascularization with either PCI or CABG. Cardiac rehabilitation involves modules to enhance physical exercise, medical management of blood pressure and lipids, and lifestyle counseling on diet and smoking cessation (see Chap. 10). Evidence suggests that CR reduces cardiac mortality, hospitalization and improves quality of life [118]. Moreover, exercise-based cardiac rehabilitation interventions results in reduced risk for cardiovascular mortality, hospitalization and improved health related quality of life, but not in improvements in the risk of ACS or coronary intervention or total mortality [119].

Stress reduction, e.g. a stress management training, is not routinely incorporated in the CR program [118], but psychological interventions are often added to a subset of patients with psychosocial problems. Cardiac rehabilitation is not offered yet to IHD patients with CMD who do not have clinical significant CAD. However, CR provides a very useful existing framework that can be adapted to better meet the needs of IHD patients with CMD, particularly those with high levels of psychosocial burden. A recent randomized controlled trial that integrated a stress-management training as an additional part of CR showed significant reductions in stress immediately after treatment, and showed improvement in clinical outcomes [118]. Considering treatment options aimed at reducing psychosocial stress, a recent Cochrane systematic review showed that psychological and pharmacological interventions have small to moderate effects on reducing depression and anxiety, but not on reduction in mortality or cardiac events. However, the number of studies is still relatively small and design characteristics have been heterogeneous [120, 121]. A recent review showed that behavioral change interventions reduced the risk of mortality, but not IHD events [122]. A meta-analysis of collaborative care interventions showed that there are small effects for a reduction in depression, depression remission, anxiety and mental quality of life, but no long-term reduction in MACE [123]. The Cochrane review by Kisely and colleagues concluded that there is a modest to moderate benefit for psychological interventions in reducing non-specific chest pain in patients with normal coronary anatomy [124]. However, there was strong heterogeneity between the findings. More studies on psychological interventions exceeding a period of 12 months are warranted [124].

There is also a need to consider the usefulness of sex-specific CR strategies. Psychological intervention trials in IHD patients indicate that women benefit less than men. Orth-Gomer and colleagues propose to compose same-sex intervention groups on stress management training [125], and for scientists to report more sex-specified outcomes in studies [126]. Screening for high-risk patients may be an important first step to optimize long-term clinical outcomes in IHD. The risk for adverse outcomes stratified for gender or other diversity groups can be observed and reported, e.g. by using the ESC screener for psychosocial factors [23]. Another route that needs to be taken is to incorporate a panic screening instrument in the emergency department to investigate unexplained panic attacks and chest pain, which may improve more appropriate referral [88]. Practical suggestions on how to proceed to study female-specific cardiovascular health and disease are provided by Ouyang and colleagues [127]. The Society for Women’s Health Research compiled an inventory for the study of women and CV health across the lifespan, and provides practical recommendations for clinical scientists, including a significant role for the study of psychosocial variables [127].