195 English Summary MRR and an increased risk of major adverse cardiac events (MACE), independent of sex. Chapter 4 of this thesis presents a comprehensive overview of coronary vasospasm in ANOCA. Our study reveals a high prevalence of coronary artery spasm, encompassing both epicardial and microvascular spasm, in ANOCA patients. Of note, the occurrence of coronary vasospasm observed in Asian populations is significantly higher than that in the Western population. Our results also indicate a sex-difference in regard to presentation of vasospasm, with men being more likely to be diagnosed with epicardial spasm while women are more likely to have microvascular spasm. Furthermore, a large variation in definitions regarding epicardial and microvascular spasm are used by different centers, alongside differences in diagnostic protocols., highlighting the importance of an unambiguous protocol. Part 2. Reduced myocardial blood volume as driver of ANOCA The second part of this thesis describes the role of myocardial blood volume (MBV) as a possible driver of angina complaints in ANOCA. MBV encompasses the total blood volume in the myocardium, including arterioles, capillaries and venules, and changes in response to elevated myocardial oxygen consumption. In skeletal muscle, responses of MBV to stimulation is diminished due to e.g. insulin resistance. Insulin resistance, which is primarily characterized by impaired insulin-stimulated glucose uptake in cells, is a key mechanism in type 2 diabetes mellitus, a disease frequently associated with ANOCA. However, MBV and its regulation had not been studied before in ANOCA. Therefore, the MICORDIS (reduced MIcrovascular blood volume as a driver of CORonary microvascular DISease in ANOCA) study was conducted. Chapter 5 describes the rationale and design of the MICORDIS study, in which we hypothesized that a reduced MBV is part of the pathophysiology of ANOCA, and that various stressors, such as insulin or dobutamineinduced stress, influence the regulation of MBV. MBV was compared between 28 ANOCA patients and 28 sex- and age matched healthy controls, using myocardial contrast echocardiography (MCE) at baseline, during hyperinsulinemia induced by the hyperinsulinemic-euglycemic (HE) clamp and during dobutamine-induced stress. MCE allows real-time, non-invasive quantitative assessment of myocardial perfusion. The main results of the MICORDIS-study are presented in Chapter 6 of this thesis. MBV measurements were performed at baseline, during hyperinsulinemia and during dobutamine stress in 28 ANOCA patients and 28 healthy controls. In ANOCA patients, MBV was reduced under all physiological conditions. ANOCA patients also experienced a diminished metabolic insulin sensitivity. However, this did not result into an observed difference in microvascular recruitment, calculated as the difference of MBV (as fold) between different conditions, between ANOCA patients and healthy controls. It seems that capillary rarefaction, as a pathophysiological phenomenon, is involved in ANOCA. Part 3. Quantitative perfusion CMR in ANOCA In the third and final part of this thesis, we evaluated the use of quantitative perfusion cardiac magnetic resonance (CMR) to diagnose patients with ANOCA. Currently, 9
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