89 Rational and Design of the MICORDIS study BACKGROUND Chronic ischemic heart disease (IHD) has a complex multifactorial origin and may present with a variety of symptoms related to chest discomfort, referred to as angina pectoris or angina-like symptoms. The current diagnostic process for angina is dominated by the evaluation of atherosclerotic obstructive coronary artery disease (CAD) as its potential cause. However, a substantial proportion of patients with angina do not have relevant obstructive CAD on computed tomography or invasive coronary angiography (CAG).1, 2 This condition is referred to as Ischemia with Non-Obstructed Coronary Arteries (INOCA).3, 4 Recent studies have demonstrated that INOCA is associated with an increased risk of major adverse cardiac events (MACE), reduced quality of life, repeated hospitalizations and high healthcare costs.5–7 In addition, INOCA seems to be sex-related with a strong female preponderance. The Women’s Ischemia Syndrome Evaluation (WISE)-study was the first study to document that a high percentage of women with angina and normal coronary arteries on angiography have evidence of myocardial ischemia.8, 9 The pathophysiology underlying INOCA is complex and frequently multifactorial, but commonly starts with abnormal vasomotor responses of the coronary circulation, typically involving an abnormal vasoconstrictor response, abnormal vasodilator response, or a combination of these entities. Abnormal vasoconstriction refers to a variety of vasospastic patterns, including focal or diffuse epicardial vasospasm, microvascular vasospasm, or a combination of these. These disease patterns are, amongst others, associated with endothelial dysfunction and vasomotor smooth muscle cell hyperreactivity. Abnormal vasodilatation in INOCA, frequently referred to as coronary microvascular dysfunction (CMD), refers to the presence of impaired vasodilator reserve of the coronary microcirculation, due to abnormally high microvascular resistance at maximal vasodilatation (structural CMD, including arteriolar obliteration and capillary rarefraction), or exaggerated vasodilatation already in resting conditions (functional CMD, related to metabolic dysregulation), or a combination of both.10–12 These different vasomotor disorders are not mutually exclusive and frequently occur in combination, complicating the diagnosis and treatment of INOCA in patients.13 Comprehensive invasive testing for these disease endotypes, termed intracoronary function testing (ICFT), encompasses invasive measurement of coronary flow reserve (CFR) and minimal microvascular resistance (MR) using adenosine, as well as spasm provocation testing typically using acetylcholine as the provocative agent.14, 15 The Coronary Vasomotor Disorders International Studygroup (COVADIS) formulated diagnostic criteria for coronary vasospasm and CMD which currently support diagnosis and treatment of INOCA (Table 1),16, 17 which follow from ICFT. The recent CorMicA-trial showed the importance of identifying the underlying mechanisms in INOCA-patients to enable tailored treatment, reduce angina-burden and improve quality of life.18 This underscores the importance of a refined diagnostic algorithm for this group of patients and emphasizes the importance of identifying the individual pathophysiology in INOCA. 5
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