In patients with non-obstructive CAD at coronary angiography, lesions up to 20% can be present, without being noticed [18]. However, with coronary intravascular ultrasound techniques (IVUS) it has been shown that in most patients with suspected IHD without signs of obstructive CAD coronary plaques are already present [25]. Non-obstructive CAD has been found to be associated with a significantly greater 1-year risk of ACS and all-cause mortality, compared with no apparent CAD [26]. Symptoms of IHD are often caused by a combination of atherosclerosis, endothelial dysfunction and spasm in the macro- and microvascular coronary arteries together with activated inflammation and platelet function (Fig. 2.3) [27]. Within all these causative components of IHD important sex differences exist throughout all various stages of life [4]. In clinical practice, an important dilemma is that the agreement between anatomical CAD and functional IHD is rather poor [28, 29]. This is especially disadvantageous for younger women (45–65 years) in whom functional and more diffuse CAD often predominates over focal obstructive CAD (Fig. 2.4). The over-emphasis of obstructive CAD over NOCAD in the current US and ESC guidelines stable CAD is one of the major reasons that symptoms and risk factors in women are still less well treated than in men [30, 31]. Women with recurrent chest pain syndromes and NOCAD need to be diagnosed and treated since they have a twofold increased risk to develop obstructive CAD events in the next 5–8 years and have a four times higher risk for re-hospitalizations and recurrent angiograms than women without these symptoms [32, 33].

The clinical evaluation of symptoms of angina pectoris in women is still considered along the male standard. However, the various sex differences in underlying pathophysiological mechanisms involved in IHD often translate into other symptoms than the classical angina pectoris, which is more associated with obstructive CAD (Table 2.1). The combination of NOCAD with endothelial dysfunction frequently occurs in young and middle-aged women with a combined typical and atypical symptom presentation, that may be misinterpreted as being of non-cardiac origin [34]. The classification of symptoms in typical or atypical alone has been shown to be unreliable for the detection of obstructive CAD in women under 55 years of age [35]. Black women have an even more atypical symptom presentation than white women, which may be an extra barrier to appropriate and timely treatment [36]. It is therefore mandatory to simultaneously consider lifestyle behavior and CVD risk factors when evaluating symptoms. In general, women have more symptoms of chest pain than men, leading to recurrent presentations at the emergency department and repeated coronary angiograms (CAG) [4, 32, 37]. The diffuse pattern of CAD can easily be missed at angiography in young high risk women and mistakenly being interpreted as ‘small female coronary arteries’. In Patient example A this has mistakenly led to the conclusion that she had a ‘false-positive’ X-test. After 65 years of age the mode of CAD in women gradually changes into more obstructive stenoses, also depending on the individual CV risk profile. The higher the chance of having focal obstructive CAD, the more classical (male) symptoms of angina pectoris women will have (Patient B). When the underlying degree of obstructive CAD is similar as in men, there is no apparent gender difference any longer in symptom presentation [38]. However, this selection bias in coronary stenoses is not reflecting daily clinical practice. In addition, the increasing prevalence of vascular stiffness and diastolic dysfunction in women at older age leads to additional symptoms of dyspnea, tiredness and loss of condition that can make it more difficult to establish the diagnosis of IHD (Patient C) [39]. At older age (> 70 years) and in diabetic patients symptoms of angina may become more atypical in both women and men. Also, the occurrence of paroxysmal atrial fibrillation (AF) and diastolic heart failure (HFpEF) is a common manifestation of IHD in the elderly and predominates in women over men [40].

Gender differences in communication may hamper the early recognition of angina pectoris in women. Men usually report their symptoms in a direct way, while female patients ask more questions, present more and diverse symptoms and give more detailed histories of their activities [41]. Women’s communication is more likely to be emotional, subjective, polite, and self-revealing with more concern and awareness for the feelings of others. This can be misleading to both female patients and their doctors in the correct interpretation of symptoms of IHD.

The classic Diamond & Forrester prediction risk model overestimates the chance of having obstructive (≥ 50%) CAD in women and has been updated in 2011 and incorporated in the 2013 ESC guidelines treatment of stable CAD (Fig. 2.5) [31, 42, 43]. Especially in the age-group below 60 years non-invasive imaging techniques should be used more often than invasive angiography. There is still no consensus however for the optimal diagnostic pathway for IHD among the various guidelines in women [31, 44–46]. The 2013 ESC guideline advises stress imaging techniques (SPECT, stress echocardiography) when available as first test of choice, with a preference of non-radiation diagnostics in younger women [31]. The optimal classification criteria of patients into low- intermediate- and high risk categories is also still a matter of debate. The algorithm to classify symptomatic women in IHD risk categories is depicted in Table 2.2 [47–49]. The ESC has recently released the 2016 EU guideline CVD prevention, containing four categories of risk patients (Fig. 2.6) [50].

In 2014 a consensus document for women with suspected IHD was published by the AHA, providing sex- and gender-specific evidence-based guidance to the clinician in the use of diagnostic procedures [51]. In Table 2.3 the most important guidance advice is summarized [52] and in Table 2.4 factors are described that may hamper the sensitivity of non-invasive testing in women. In the large PROMISE trial, performed in predominantly middle-aged patients (m/f) at intermediate IHD risk, initial anatomical testing with computed tomographic angiography (CTA) or functional (exercise or pharmacological) testing with electrocardiography, nuclear stress imaging or stress echocardiography, did not show any differences in clinical outcomes over a median follow-up duration of 2 years [53]. However, at a closer sex-specific analysis women had a higher prevalence of traditional CVD risk factors, but were estimated to be at lower risk by their doctors [54]. Women were more often referred for nuclear imaging stress testing than men, but had fewer positive tests. Women seem to derive more prognostic information from a CTA, whereas men tend to derive similar prognostic value from both test types [55]. It is noteworthy that with the use of the current available diagnostic testing the full spectrum of manifestations of IHD is still underestimated in women [56].

In the initial clinical work-up of women at intermediate risk cardiologist should choose for imaging testing that is available and which they are accustomed with. Coronary angiography is indicated in women at intermediate or high risk with functional disability and an abnormal rest-ECG or X-test. New developing non-invasive imaging modalities such as combined fractional flow reserve (FFR)-CT scans are promising for women by the combination of anatomical and functional testing [44, 57]. This also accounts for upcoming combined CTA-PET imaging.

Invasive coronary angiography has more limited value in women, since they have more outward remodeling, NOCAD and functional IHD that is not well recognized at angiography. However, its diagnostic value increases with age and with a more classical symptom presentation of exercise-induced angina, mimicking the typical ‘male’ pattern of symptoms. Comparable data from registries show that nearly two thirds of women with stable angina pectoris have (nearly) no abnormalities at angiography [13, 33, 58]. An important limitation of diagnostic angiography is the inability to assess the hemodynamic relevance of a coronary stenosis whereas the functional severity of a lesion can be easily over- or underestimated [28, 29, 59]. As a consequence, an incorrect indication for coronary angiography may also lead to an inappropriate percutaneous coronary intervention (PCI) or even coronary artery bypass graft (CABG). This is especially harmful for women, as they have more residual symptoms after coronary interventions than men [60–62]. The use of fractional flow reserve-guided PCI for stable IHD has improved outcomes in both genders [63, 64]. Fractional flow reserve (FFR) values are found to be higher in women after correction for visually assessed coronary anatomic severity. This may be (partly) caused by the more frequent presence of coronary vascular dysfunction in women [65]. It is currently discussed whether gender-specific guidelines in interpreting fractional flow reserve measurements are indicated [65, 66]. The use of IVUS and or optical coherence tomography (OCT) should be more applied in symptomatic women with NOCAD to characterize coronary plaques as strong arguments for adequate prevention and treatment [25, 46]. Outcomes after coronary stenting have improved in women with the new generations drug eluting stents (DES), which are more safe and effective on the long-term than bare-metal stents (BMS) [67].

Most common peri-procedural complication of coronary angiography or PCI is bleeding at the puncture site. This occurs more frequently in women, but less often with the transradial access [68, 69]. The latter may be more difficult to perform in women, due to spasm-related complications in the radial/brachial artery [70]. Besides the need to adapt dosages of anti-thrombotic agents to body surface are, there are also important sex differences in the thrombotic system that may account for the higher bleeding risk in women [71–73].

The presence of impaired (endothelial) vascular function without occlusive epicardial disease presents as global dysfunction of the macro- and micro vascular coronary circulation. Flow-mediated vasodilatation (FMD) of the brachial artery is perhaps the most known technique to measure endothelial function, and involves measuring response of brachial artery diameter to secondary to hyperemia due to occlusion of the brachial artery [74]. It is associated with coronary artery endothelial function [75]. This test is of limited use however in the clinical setting for IHD detection.

Invasive measurement of vascular dysfunction involves imaging of vasomotor responses of epicardial coronary arteries and functional testing with acetylcholine infusion and measuring coronary flow reserve (CFR) during cardiac catheterization [74]. The main limitation of these techniques however is the invasive nature and potential harmful test in inexperienced hands, making it less applicable for widespread use in cardiology practice. The Coronary Vasomotion Disorders International Study Group (COVADIS) has released a consensus statement as a guidance for coronary vasomotor disorders [76, 77]. The focus of this expert paper was vasospastic angina, which occurs more often in (middle-aged) women than in men. In Tables 2.5 and 2.6 the diagnostic criteria and interpretation of invasive coronary vascular testing are described. In many female patients at intermediate risk, with normal or near normal coronary arteries, having recurrent angina symptoms of presumably vasospastic origin, pragmatic treatment options may be chosen without additional invasive testing, see Patient D.

In the 2013 ESC guidelines treatment stable CAD, no gender-specific advice is provided for the treatment of stable symptoms of angina [31]. Despite, from several surveys it is known that women are still undertreated for their symptoms and risk factors [78–80]. This is especially important as the traditional risk factors may serve as triggers for concomitant vascular dysfunction and insufficient treatment of these risk factors worsens future outcomes [17]. Women have more often side-effects of a variety of cardiovascular medications [81]. On the other hand, they tend to use more often (unproven) vitamin and herbal preparations, which is discouraged in the 2011 AHA prevention guidelines in women [49]. When women present with chest pain at the general practitioner or emergency department, they are often directly treated with aspirin, even before the diagnosis IHD has been established. Primary prevention with anti-platelet therapy in low risk women <65 years of age, does not protect against a first cardiac event and has not proven yet to be beneficial in predominantly functional driven IHD [49, 82]. In contrast, inappropriate anti-platelet therapy increases the risk for major bleeding. Most women benefit best from a tailored medical approach for their cardiac symptoms and risk factors that are present. In younger symptomatic women, the threshold for systolic blood pressure should be preferable in the optimal range <120/80 mmHg [50]. With a low blood pressure, there is less oxidative stress as a trigger for (coronary) vascular dysfunction. Caution should be taken in the years after menopause, as total cholesterol and LDL levels rise with 10–15% [83]. The use of calcium antagonists like diltiazem are often very helpful in treatment of persistent angina symptoms in women at middle-age (patient D). It may even be advantageous to combine this with a low-dose selective b-blocker to address autonomic dysfunction that is induced by menopausal hormonal changes [84, 85]. Other women with symptoms of fluid retention due to the enhanced postmenopausal salt sensitivity may profit more from a combination of diltiazem and/or selective b-blocker with an ACE inhibitor or ARB antagonist.