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5.2.2.2 Epicardial vasospastic angina

Vasospastic angina is the clinical manifestation of myocardial ischaemia caused by abnormal vasoconstriction of one or more epicardial coronary arteries leading to a dynamic coronary obstruction. Standardized diagnostic criteria for VSA have been defined.73 Microvascular angina and epicardial VSA can co-exist, which is associated with a worse prognosis.947 Concomitant endothelial dysfunction is prevalent in most patients with INOCA with inducible coronary artery spasm and/or impaired adenosine-mediated vasodilation.38,948 The Japanese population has a higher prevalence of coronary vasospasm than Western populations. In addition, the frequencies of multiple coronary spasms (≥2 spastic arteries) by provocative testing in Japanese (24.3%) and Taiwanese populations (19.3%) are markedly higher than those in Caucasians (7.5%).949–951

5.2.3 Clinical presentations

Angina/ischaemia with non-obstructive coronary arteries is associated with a wide variation in its clinical presentation, and symptom burden may vary over time. Failure to diagnose epicardial obstructive CAD in a patient with documented ischaemia should stimulate a subsequent search pathway to elucidate ANOCA/INOCA endotypes.

5.2.4 Short- and long-term prognosis

Symptoms of angina/ischaemia with non-obstructive coronary arteries are associated with adverse physical, mental, and social health.952 Angina/ischaemia with non-obstructive coronary arteries is associated with poor QoL, higher risk of disability, and a higher incidence of adverse events, including mortality, morbidity, healthcare costs, recurrent hospital readmissions and repeat coronary angiograms.300,953–958 The incidence of all-cause death and non-fatal MI in patients with nonobstructive atherosclerosis was higher than in those with angiographically normal epicardial vessels.298,959–961 Proven myocardial ischaemia by stress echocardiography or nuclear imaging was associated with a higher incidence of events compared with ischaemia detected by exercise electrocardiographic stress testing.958 There is a two- to four-fold higher risk of adverse cardiovascular outcomes in patients with MVA diagnosed by PET or transthoracic echocardiography and a two-fold higher risk in patients with epicardial endothelial-dependent dysfunction.300,962 Microvascular angina due to impaired CFR was associated with increased major adverse cardiac events and target-vessel failure rates over a 5-year follow-up period.931 Vasospastic angina is associated with major adverse events, including sudden cardiac death, acute MI, and syncope.963 In a group of ANOCA/INOCA patients, abnormal non-invasive testing did not allow the identification of patients with a higher risk of long-term cardiovascular events. However, adding intracoronary physiological assessment to non-invasive information allowed the identification of patient subgroups with up to a four-fold difference in long-term cardiovascular events.357

5.2.5 Diagnosis

The presence of myocardial ischaemia on functional imaging without obstructive CAD on CCTA or ICA should always raise the clinical suspicion of ANOCA/INOCA. The diagnosis of ANOCA/INOCA is exclusively based on invasive functional evaluation of the coronary microcirculation, given that no technique allows direct visualization of the coronary microcirculation in vivo in humans. Several non-invasive and invasive tests have been established to assess the coronary microvascular function (Figure 13).6,41,964,965 5.2.5.1 Non-invasive diagnosis

Non-invasive tests (stress echocardiography, PET, perfusion CCTA, and CMR) allow diagnosing ANOCA/INOCA by measuring the CFR.41 These techniques have an excellent negative predictive value, but the positive predictive value is an issue for most, as obstructive CAD needs to be ruled out before the diagnosis of CMD can be made. Only hybrid techniques such as CCTA with perfusion and PET-CT offer combined imaging of the epicardial coronary arteries and functional testing of the coronary microcirculation in a single test.6,964

5.2.5.2 Invasive coronary functional testing

Invasive coronary functional testing consists of a comprehensive evaluation of the coronary circulation in a single procedure by combining angiography, direct invasive assessment of the coronary haemodynamics by intracoronary pressure and flow measurement either by thermodilution (bolus/continuous) or Doppler techniques, and pharmacological vasomotor testing. Recently, a standardized protocol has been proposed.36

5.2.5.2.1 Basic coronary functional testing. Intracoronary pressure

and flow measurements allow assessment of the haemodynamic significance of focal or diffuse coronary lesions by measuring FFR or iFR (see Section 3.3.3.2) and of microcirculatory function by measuring CFR and IMR, HMR, or MRR361,961 (see Section 3.3.3.3). Coronary microvascular dysfunction is characterized by decreased CFR and increased microvascular vascular resistance (IMR, HMR, MRR). Decreased CFR can be due to structural or functional microvascular dysfunction.926,966 Functional CMD is characterized by increased resting flow linked to enhanced nitric oxide synthase (NOS) activity, whereas patients with structural CMD have endothelial dysfunction, leading to a reduced increase of coronary blood flow during exercise.926,966 A Doppler-derived CFR of <2.5 in non-obstructive CAD indicates an abnormal microcirculatory response corresponding to a thermodilution-derived CFR of <2.5.361,926,937,961 Of note, in assessing coronary microvascular function, continuous thermodilution showed significantly less variability than bolus thermodilution on repeated measurements.382 An increased IMR (≥25) indicates microvascular dysfunction.380,381 For the Doppler-derived HMR, a value of >2.5 mmHg/cm/s indicates augmented microvascular resistance.42 Recently, MRR has been considered abnormal for values <2.7.364,967 Doppler flow analysis allows assessment of the flow-recovery time after Ach administration as a sign of myocardial ischaemia, which is helpful in the diagnosis of patients with equivocal test results.968

5.2.5.2.2 Coronary vasomotor testing. Epicardial and microvascular

endothelium-dependent vasodilation and vasospasm are tested by intracoronary bolus administration or graded infusion of Ach, first at a low dose/grade to assess endothelial dysfunction at the microvascular or epicardial level, and after that at a higher dose/grade to eventually induce microvascular or/and epicardial coronary vasospasm. The LAD artery is usually preferred as the pre-specified target vessel reflecting its subtended myocardial mass and coronary dominance. The left circumflex coronary artery is also tested if Ach is administered in the LMCA. Additional studies in the right coronary artery may be appropriate if the initial tests are negative and clinical suspicion is high. As Ach exerts a cholinergic effect on the atrioventricular node, significant bradycardia may ensue if infused especially in the right coronary artery or a dominant left circumflex coronary artery. Bradycardia can be prevented by selective infusion in the LAD, prophylactic ventricular pacing, or reduction of the concentration infused or of the injected dose. If necessary, the

ESC Guidelines                                                                                                                                                                                          3481

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