The advances in interventional cardiology over the past decades have literally visualized important sex differences in the extent of coronary atherosclerosis and mechanisms that are involved in ACS. Considering all ages, plaque rupture (type 1 ACS) is the cause of fatal MI in 76% of men and 55% of women [38]. Below 65 years of age women have less obstructive CAD than men and more often an ACS with ‘open’ coronary arteries with spasm and vascular dysfunction as etiologic factors [38–41]. This has been referred to as a type II ACS in the most recent ESC/AHA 2012 definition of ACS [42]. Despite the associated adverse mortality, there is currently an ongoing discussion whether type II ACS should be more considered as myocardial injury rather than as a distinct infarction. With the introductions of high sensitive (hs) troponin measurements, type II ACS are currently twice as often recognized in women than before [43]. The ‘negative’ findings at coronary angiography (CAG) during ACS are now called ‘myocardial infarction with no obstructive coronary arteries’ (MINOCA), which has recently been discussed in an ESC position paper on MINOCA [44–46]. This occurs in 40% of predominantly younger female patients and their coronary arteries are often misinterpreted as being ‘clean’, while intracoronary non-obstructive plaques are frequently present and can be identified with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) [41, 47–50]. These plaques contain cytokines (vasoactive proteins) that may induce vascular dysfunction and/or spasm in the larger and smaller coronary arteries, presenting in patients as a type II STEMI or NSTEMI [51, 52]. The wrong labeling of these ACS as being ‘false positive’ may lead to under-treatment of cardiac symptoms and risk factors in women. From pathology studies it is known that younger patients and especially women more often have erosive plaques compared to the classical atherosclerotic plaques that are present in type I ACS [38, 53, 54]. A dysfunctional intima of erosive plaques can induce distal embolization of small thrombi leading to obstruction and necrosis in focal myocardial areas [38]. This can cause elevation of hs-troponins without visible abnormalities at coronary angiography. At older age (>65 years) type I ACS is also the predominant manifestation of ACS in women. Coronary plaque ruptures are more often associated with thrombus formation in women than in men [55]. Age- and sex-related differences in the thrombotic system interfere with the clotting cascade and thrombocyte function within the various manifestations of ACS [56].

Differences in underlying pathophysiology importantly contribute to another clinical presentation of ACS in women compared to men. When vascular dysfunction/spasm is an important component of ACS, as is often the case in younger women (<65 years), symptoms can vary over time in a crescendo-decrescendo pattern (patient A). This can be very misleading in the interpretation of symptoms by the patient herself and her doctor. This ‘atypical’ ACS presentation can delay adequate referral to a hospital for several hours or even days [57, 58]. Another barrier for timely referral to the hospital is de lack of awareness in women themselves [59]. The more direct way of symptom expression in men is more accurate and helpful in emergency medical situations. Women tend to ‘interpret’ their symptoms, while men ‘report’. In elderly (>65 years) women with multi-vessel disease, the concomitant presence of diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), can lead to an ACS presentation with acute decompensated heart failure as the predominant clinical symptom. The most common symptoms when having an ACS in women and men are listed in Table 3.2, with women having more atypical symptoms than men. It is noteworthy to realize that there are often overlapping symptoms among both genders and that ACS diagnosis always includes a rapid evaluation of lifestyle and risk factors [60]. Women more often than men report no chest pain at all (37% versus 27%) during ACS, most frequently in patients at older age (>75 years) and in diabetics [61, 62]. This is an important reason why there is still a longer patient-delay in the elderly in seeking medical care after onset of ACS-associated symptoms [63]. Women may experience a period of extreme tiredness, even exhaustion, prior to their ACS [64]. In the ARIC study it was found that silent myocardial infarctions occur in 45% of all ACS, more often in men than women, but with a poorer prognosis in women [65].

Most important determinants for a failure to diagnose ACS at the emergency department (ED) are female gender <55 years, the absence of chest pain, a (near) normal ECG and ethnic diversity [66, 67]. In NSTEMI-ACS it is established that an early invasive strategy results in better survival in men but not in women [68–71]. However, data from different ACS registries such as CRUSADE and the Get With the Guidelines (GWTG) initiatives in the USA and MINAP in the UK suggest that the early mortality in women is not sex-dependent but predominantly related to less frequent use of evidence-based care, such as lower CAG use [72, 73]. In women with NSTEMI, cardiac hs-troponins are less likely to be elevated and the ECG is more often non-diagnostic than in men. These facts may lead to a preferential referral of women with suspected NSTEMI to hospitals without cardiac catheterization facilities, adding further delay to diagnosis and treatment. Recent studies have shown that there is still a less aggressive (invasive) management approach in women with ACS compared to men, also after correction for the severity of underlying CAD [17, 37, 74]. At discharge and by the end of 1 year post ACS fewer women than men receive standard medication, especially when they are young and had MINOCA [75, 76].

Women have a more than two times higher bleeding risk after (acute) coronary interventions [77, 78]. This is closely related to their higher in-hospital and one-year mortality. The risk of bleeding following PCI is higher among elderly women, in patients with a low body weight, impaired renal function, and with the administration of multiple antithrombotic drugs [79]. Women also have more bleeding complications after thrombolytic therapy [80]. Using the transradial access for coronary interventions reduces the incidence of peri-procedural bleeding complications and improves clinical outcomes [81]. However, because of the smaller size of the radial/brachial artery with a higher risk of spasm and bleeding, this approach may have more difficulties in women [82, 83].

With the increase in ACS at middle-age, pre- and perimenopausal women are treated with (dual) platelet therapy (DAPT) including acetylsalicylic acid and clopidogrel (or ticagrelor) for a longer period of time. This can induce excessive uterine bleeding and even anemia, which is especially harmful when the coronary circulation is compromised [84]. Heavy menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Clinical symptoms of dyspnea and tiredness are often not recognized as being caused by excessive uterine bleeding. Moreover, the majority of cardiologist and other vascular specialists do not ask questions about menstrual status or disorders. See the case of patient B. Importantly, the use of combined oral contraceptives to reduce menstrual bleeding is relatively contraindicated in patients with established CAD (unstable angina, ACS, NSTEMI, STEMI, PCI, CABG) because of the increased risk of myocardial infarction and thrombosis [85, 86]. The use of levonorgestrel releasing intra uterine system (LNG-IUS), endometrial ablation or hysterectomy are alternative options, depending on the gynecology advise. Post ACS antithrombotic therapy may also induce bleeding in postmenopausal women, which is always an indication for consultation of a gynecologist.

Spontaneous coronary artery dissection (SCAD) is a relative rare manifestation of ACS (1.2–2%), of which more than 90% occur in women between 45 and 65 of age [87–89]. In young women its prevalence is estimated at >10% in women <50 years, up to 25% in all women <65 years with ACS (see patient C) [87, 90–92]. A SCAD may also (rarely) occur during pregnancy or in the postpartum period, with a prevalence estimated at 1.8 in 100,000 pregnancies [93–95]. Provoking stressors for a SCAD may be emotional, extreme physical exercise, but also coughing, vomiting and heavy lifting. In the majority of SCAD patients a sudden coronary tear is found in the intima of the LAD (60%), followed by the RCA (26%), RCX (19%) and rarely in the LM (9%) (Figs. 3.1 and 3.2) [96]. A SCAD can also be caused by an intramural hematoma in the media of the vessel wall, with or without an intimal flap [94, 97]. Compression of the coronary artery by the false lumen or by a dissecting flap causes obstruction or restriction of flow within the true lumen, resulting in myocardial ischemia or an ACS. The clinical presentation may vary between STEMI, NSTEMI, unstable angina or sudden cardiac death. The diagnosis of SCAD can easily be missed, even in experienced interventional centers, as there are different angiographic features of SCAD that are often interpreted as caused by atherosclerosis [87, 98]. With intracoronary imaging with IVUS or OCT, the true and false lumen can be distinguished from each other, but these manipulations in vulnerable and hemodynamically instable young coronary arteries can be harmful and may lead to secondary iatrogenic dissections.

In several large registries of SCAD patients, an underlying fibromuscular dysplasia (FMD) can be the causative factor, with prevalence estimates in case-series varying from 20 to 72% (Fig. 3.3) [87, 89]. Fibromuscular dysplasia has several angiographic features of coronary artery lesions (smooth stenosis, segmental ectasia and tortuosity) that are often not recognized as such (Fig. 3.4) [99, 100]. In one third of SCAD patients, pre-existent hypertension is present and in 15% signs of atherosclerosis may be involved. In a low percentage of patients (2–8%) mixed connective tissue disorders, such as Ehlers-Danlos and other inflammatory diseases are reported. Only a minority of SCAD patients undergo genetic testing and when performed pathogenic mutations are not frequently found [101]. Given the heterogeneity of this disorder and the relative low prevalence, there are no evidence-based management guidelines yet. When the flow in the dissected artery is higher than TIMI II, a conservative approach is preferred [90]. Coronary stenting may further enlarge the dissection and often leads to more residual symptoms afterwards [102]. It is assumed that most SCAD lesions resolve within 3 months. It is still unclear for how long antithrombotic treatment should be administered and there is no evidence that the use of statins is beneficial in SCAD patients when having normal lipid values. Despite, many young women are sent home with the identical ‘big five’ medication as a 85 year old man with severe three-vessel disease. This often leads to frustration in younger women who already have a low adherence to long-term medical therapy [76]. The use of beta-blockade reduces arterial shear stress and is (temporarily) advised after SCAD and for prolonged time when hypertension is present [103]. In patients with residual symptoms long-acting diltiazem is often more effective than a beta-blocker.

There is no standardized work-up in patients after SCAD although it is recommended to perform genetic testing for the most common types of mixed connective tissue diseases. Given the relatively high prevalence of FMD in SCAD patients it is advised to perform a CT angiography or MRI of the renal arteries [99, 104]. The recurrence rate of SCAD varies between 10 and 17% [102]. It has been suggested that the degree of tortuosity in the coronary arteries may be a prognostic indicator of SCAD recurrence, but this has not been confirmed by others yet [105].

Takotsubo cardiomyopathy (TTC), first described in 1990, is a unique predominant female type of ACS characterized by the presence of transient LV wall dysfunction without any significant culprit lesion in the epicardial coronary arteries (Fig. 3.5) [106, 107]. In the majority of cases (>70%) severe emotional-stress acts as a triggering event, resulting is a high-dose catecholamine exposure that induces acute apical LV dysfunction [108, 109]. TTC is nowadays more often recognized than before and occurs in 2–3% of all ACS patients, with a predominance (>90%) in postmenopausal women above 60 years of age [110]. Women have an increased response to adrenergic stress after menopause which may contribute to their increased risk of TTC [111]. Lower estrogen status in postmenopausal women may lead to an impairment in vasodilating and vasoconstrictive reactivity in the microvascular coronary system, resulting in an increased responsiveness to sympathetic activity [112]. In IVUS studies in classical TTC patients no signs of obstructive CAD are seen [113]. In the International Takotsubo Registry it was found in 1750 patients (90% women) that emotional triggers were not as common as physical triggers (27.7% vs. 36.0%) and that 28.5% of patients had no evident trigger at all prior to their ACS [114]. Rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) compared to patients with standard ACS. In 4% of patients a ‘happy’ emotional event served as a trigger for TTC-ACS, in these cases named as the ‘happy heart syndrome’ [115]. In 20% of patients in this cohort more atypical presentations of TTC were noticed, characterized by a younger age of onset, more frequent presence of ST-segment depression, a higher prevalence of neurologic diseases, less pronounced reduction in left ventricular ejection fraction, and lower brain natriuretic peptide values on admission [116]. In general, ECG changes in TTC are comparable with other causes of ACS with a relatively smaller increase in creatinine kinase and hs troponin in proportion to the degree of LV dysfunction. A low serum N-terminal brain natriuretic peptide (NT-proBNP) at admission is a reliable indicator of a favorable prognosis [107]. Cardiac catheterization is still necessary for definitive differentiation between TTC and other causes of ACS and echocardiography or MRI plays a key role in diagnostic and follow-up assessment. A remarkable recovery of systolic LV function is mostly seen within days/weeks after acute onset. In clinical practice it may be difficult to differentiate between a TTC and standard ACS, as is showed in patient D. The use of ACE inhibitors or ARBs after TTC significantly reduces 1-year mortality rates, while this has not been established for the use of beta-blockers [114]. It is unknown yet whether prolonged use of platelet inhibitors and statins may prevent recurrence (0–11.4%) of TTC. Complication rates and mortality in general are comparable between TTC and standard ACS.