In patients with microvascular angina, chest pain is frequently provoked by exercise, resembling ‘classical’ stable angina caused by severe epicardial vessel narrowing. However, the presence of CMD is more likely if there is a variable threshold of physical activity that provokes angina, if the chest pain persists for several minutes after effort is interrupted and/or whether there is slow or poor response to nitroglycerin [19, 20]. In addition to exercise induced angina, (prolonged) chest pain at rest and or at night/early morning is often reported, which may be provoked by vasospasm [21, 22]. Also, low heart rate activities such as mental arousal, or palpitation are more common triggers of angina than in patients with obstructive atherosclerosis [23]. In many patients, dyspnea at exertion is also reported an equivalent of a disturbed oxygen demand, with a general feeling of tiredness and loss of energy (see patient example) (Table 4.2). Microvascular angina has now been incorporated in the 2013 European Society of Cardiology (ESC) guidelines on management of stable CAD [20].

Common cardiovascular risk factors such as hypertension, dyslipidemia, diabetes mellitus, and smoking are also known to be involved in CMD [18]. Most CMD type 1 patients have multiple ACSVD risk factors, despite data suggesting that a poor relation exists between these risk factors and CMD severity [24]. Female-specific cardiovascular risk factors (e.g. gestational diabetes and hypertension, pre-eclampsia, HELLP syndrome) and non-traditional risk factors, such as migraine and chronic inflammatory rheumatoid diseases are more commonly seen in women than in men. It is assumed that CMD may be the key mechanism involved in accelerated atherosclerosis in chronic inflammatory diseases [25, 26].

The diagnosis of CMD requires the exclusion of obstructive CAD by coronary computed tomography angiography (CTA) or coronary angiography (CAG). Since women often express a more diffuse pattern of atherosclerosis instead of stenotic disease, It is important to not merely focus on significant anatomical stenoses (commonly defined as >50% luminal narrowing) [1]. Excluding the hemodynamic relevance of evident coronary plaque—yet without the appearance of stenosis—by fractional reserve measurement (FFR) may be helpful in selected patients before making a diagnosis of microvascular disease as the most probable cause of the patient’s symptoms [27].

Apart from exclusion of hemodynamic relevant epicardial CAD, attempts should be made to obtain objective evidence of CMD. The diagnosis can be established if a symptomatic patient has normal or non-obstructed coronary arteries by arteriography (coronary CTA or CAG), but with objective signs of cardiac ischemia (e.g. ST segment depression on exercise ECG, ischemic changes by myocardial perfusion imaging). It is of note that in CMD patients wall motion abnormalities usually cannot be induced during dobutamine stress echocardiography [28].

Since ischemia cannot always be detected by commonly used methods in cardiology practice, diagnostic tests for CMD are focused on the evaluation of coronary vascular function. Invasive coronary reactivity testing (CRT) using vaso-active agents to evaluate macrovascular and microvascular responses is still considered the reference standard for a definitive diagnosis of CMD [29]. During invasive coronary angiography non-endothelial mediated vasoreactivity is tested by measurement of coronary flow reserve (CFR). This is defined as the ratio of hyperemic myocardial blood flow, as induced by administration of adenosine or dipirydamole, divided by resting flow. A CFR ≤ 2.5 is indicative of coronary microvascular dysfunction. In both symptomatic men and women, a CFR < 2.0 has been shown to be an important predictor of adverse outcomes [13]. Endothelial dependent microvascular function is tested by injection of acetylcholine. A reduction of coronary blood flow >50% in response to high dose acetylcholine is regarded as abnormal endothelial microvascular function. In extent, acetylcholine, in different dosages, is used to assess macrovascular endothelial function and micro- and macrovascular vasospasm. Furthermore, non-endothelial macrovascular function is tested using nitroglycerin [29]. Invasive coronary reactivity testing is a very complete and thorough study of macro- and microvascular coronary (dys)function, and an invasive established diagnosis of CMD has been associated with a worse outcome [13, 30, 31]. Despite, this test is not routinely performed for a variety of reasons, including a lack of standardized protocols and concerns over catheterization laboratory time and safety. Several studies, however, have shown this method to have acceptably low complication rates and recently guidelines have been published for vasoreactivity testing [29, 32, 33].

In recent years, technological advances have led to the development of several non-invasive imaging techniques that allow sufficiently reliable measures of CMD. Using transthoracic Doppler echocardiography (TTDE), CFR can be assessed by measuring diastolic coronary blood flow in the left anterior descending (LAD) coronary at peak vasodilatation and at rest. Although this technique needs practice, reproducibility studies have shown acceptable intra-observer and inter-observer variability of TTDE–CFR performed by skilled operators [34]. Validation studies have shown that TTDE is feasible in the majority of patients and show a high agreement with CFR obtained with invasive coronary reactivity testing [35]. Positron emission tomography (PET) can also measure CFR and detect coronary vasomotor abnormalities caused by microvascular disease. PET has been shown to be a reliable tool to quantify myocardial blood flow (MBF) and CFR. Unfortunately, availability of PET scanning for diagnosis of CMD is limited. The nuclear tracers that can measure MBF and CFR most reliably are oxygen-15 labeled water and nitrogen-13 labeled ammonia [36]. However, an on-site cyclotron is mandatory for usage of these tracers. There is no consensus yet on whether contrast stress echocardiography or cardiac magnetic resonance (CMR) can reliably quantify perfusion abnormalities caused by CMD [35].

First of all, it is of note that therapy studies for CMD are limited and often suffer from small sample sizes and a heterogeneous patient selection. Current ESC guidelines recommend that in all patients with microvascular angina optimal coronary risk factor control should be achieved and all patients should receive secondary cardiovascular prevention medications including aspirin and statins [20]. However, the benefits of long-term aspirin use in CMD patients is uncertain. Risk factor control should also include non-pharmacological therapy including weight loss, healthy diet and exercise [37]. For some patients, stress reduction therapy, like mindfulness based cognitive therapy, can be beneficial in reducing symptoms [SE, unpublished data].

Anti-anginal treatment is empirical while underlying mechanisms of CMD are often diverse and overlapping with macrovascular coronary disease. Treatment approaches should be tailored to the underlying mechanism whenever possible. In patients with exercise induced angina beta-blockers are first choice. Research has shown more favorable results from nebivolol compared to metoprolol [38]. Calcium antagonists and long-acting nitrates have shown variable results in clinical trials and are more helpful when used in addition to beta-blockers in the case of insufficient control of symptoms. However, in patients with predominant angina at rest, indicating an underlying vasospastic component, calcium antagonists are recommended as first line of therapy [37]. Short acting nitrates are recommended to relieve spontaneous attacks of angina. However, patients often report a limited effect of this treatment. In patients with angina refractory to various combinations of traditional anti-anginal medication, non-traditional forms of anti-anginal treatment can be added. Options include xanthine derivatives (aminophylline, bamiphylline), ivabradine, ranolazine, and nicorandil [20]. In patients in who enhanced pain perception is suspected drugs which modulate pain perception, like tricyclic antidepressants, are indicated [23]. Unfortunately, in patients with microvascular angina, the susceptibility of symptoms to medical treatment is extremely variable. Trialing of different drug combinations is often needed before establishing satisfactory symptom control and about 30% patients have refractory angina despite optimization of pharmacotherapy [39]. In those patients, additional interventions for pain relief like spinal cord stimulation or enhanced external counterpulsation may be discussed [see Fig. 4.1. Schematic overview therapy ESC guideline].

While most cardiologists still focus on obstructive CAD, the diagnosis CMD is often overlooked leading to preventable visits to the emergency room, repeat coronary angiograms, high treatment costs, diminished quality of life and even a worse cardiovascular prognosis [5].