A delay in the referral for coronary angiography and subsequent diagnosis of CAD may lead to a higher morbidity and mortality. As women more often present with atypical symptoms, misinterpretation of symptoms and underdiagnosis cannot be ruled out.

There is conflicting evidence as to whether there is a bias against women in the referral for cardiac catheterization and likelihood for revascularization. Rates of coronary angiography and PCI increased among both women and men over time. Although there seems equal access to cardiac invasive procedures in Europe, there are still sex-related differences in the use of these procedures and subsequent revascularizations (Fig. 1.2) [20].

Several studies have examined the gender-related difference in the referral rate for coronary angiography with or without prior noninvasive testing. Tobin et al. documented the highest estimated male–female odds ratios for relative risks of referral, reporting that women were much less likely than men to be referred for coronary angiography after an abnormal nuclear exercise test, even when important covariates that could influence the referral decision had been considered [21]. However, more recent studies concluded that lower crude referral rates for coronary angiography in women no longer persisted after adjustment for confounding variables or appropriateness of its use. Nguyen et al. reported similar referral rates for revascularization procedures, once significant CAD was elucidated [22]. Interestingly, since women appear to have more nonobstructive CAD, sex differences in referral and revascularization can also be interpreted as overuse of angiography in women or under-referral in men. In a German registry study of Heer et al., women with NSTEMI and stable CAD had even higher rates of PCI as compared to men and similar rates in case of STEMI [23].

Clinical guidelines do not differentiate between women and men regarding revascularization recommendations. If despite medical treatment, flow-limiting coronary stenoses are present, revascularization, by either PCI or coronary artery bypass graft (CABG) surgery, may be indicated to reduce myocardial ischemia and its adverse clinical manifestations and to relieve symptoms. Revascularization of nonischemic lesions not only increases the treatment costs but also poses an increased risk for the CAD patient rather than offering any benefit. Since women have less severe CAD with less obstruction, revascularization strategies will be applied less frequently. At present, 15–38 % of patients treated with revascularization techniques are women [17]. Modern stent implantation with new generation drug eluting stents (DES) have shown to be effective and safe in women and are recommended as the standard of care for PCI in women [24].

The Women’s Ischemia Syndrome Evaluation (WISE) studies have demonstrated that up to 50 % of women undergoing coronary angiography do not have obstructive CAD [25]. While women compared to men have a higher incidence of angina-like symptoms of IHD, these women are often reassured and frequently not treated or further investigated although this finding is not benign and is associated with an adverse cardiovascular outcome compared to asymptomatic women. This syndrome of angina-like symptoms and evidence of ischemia but without obstructive epicardial CAD is attributed to functional disorders of the larger and smaller coronary arteries, spasm and microvascular disease (MVD), and is associated with 3.5 times greater risk of MACE (hospitalization for heart failure, MI, and stroke rate or all-cause mortality) and worse quality of life compared to women with no CAD (hazard ratio [HR] 3.58; 95 % CI 1.87–6.86), whereas for men with nonobstructive CAD, there was no difference in MACE compared to men with no CAD (HR, 0.82; 95 % CI, 0.35–1.93) [26].

Although the prevalence of nonobstructive CAD is higher in women, it is not only a women’s disease. A recent publication by Murthy et al. demonstrated no difference in the prevalence of MVD (documented by PET) and showed that the severity of MVD was associated with older age and cardiovascular RF [27]. Furthermore, they found that the presence of MVD increased adverse cardiovascular outcomes irrespective of gender. It can be concluded that these findings establish the importance to consider the diagnosis of MVD in both sexes. Further studies are needed to establish the role of the particular higher prevalence of MVD in women compared to men.

Therefore, after obstructive CAD has been ruled out by invasive coronary angiography, other etiologic mechanisms for angina-like complaints should be investigated by noninvasive (Doppler echocardiography, MRI, or PET) or invasive tests as demonstrated in Table 1.4 [28]. The golden standard for the diagnosis of spasm and MVD is invasive coronary reactivity testing by using adenosine, acetylcholine, ergonovine, or nitroglycerine. Measurement such as coronary flow reserve (CFR), fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and index myocardial resistance (IMR) will help to understand the pathophysiology in patients presenting with angina without obstructive CAD. However, there is still concern about the safety of using acetylcholine, like the occurrence of arrhythmias reported with acetylcholine (9.3 %), and also transient atrioventricular blocks have been reported. Chapter 2 will provide more details with respect to these invasive measurements.