15 General introduction microvascular dysfunction in both symptomatic men and women. Additionally, this chapter delineates the differences in cardiovascular outcomes among men and women across different endotypes of chronic coronary syndrome. Chapter 3 delves further into the relationship between sexes and invasive coronary function assessment, assessing the vasodilatory capacity of the coronary circulation via the microvascular resistance reserve (MRR). The MRR corrects the vasodilator reserve capacity for the presence of epicardial disease, providing a tool to assess microvascular vasodilator function in the presence of obstructed CAD. Chapter 4 provides a comprehensive review of coronary vasospasm in ANOCA, elaborating on both epicardial and microvascular spasm, as well as its prevalence, clinical characterization, and prognosis in men and women worldwide. Part 2. Myocardial blood volume as driver of ANOCA The second part of this thesis focuses on the role of a reduced MBV as a pathophysiological contributor to the cause of ANOCA. Chapter 5 outlines the background and rationale of the MICORDIS (reduced MIcrovascular blood volume as a driver of CORonary microvascular DISease in ANOCA) study, a prospective randomized clinical study in ANOCA patients compared to healthy controls, investigating this possible pathophysiological phenomenon. In Chapter 6, we demonstrate the results of the MICORDIS-study, evaluating myocardial blood volume through myocardial contrast echocardiography under various physiological stimuli, such as dobutamine-induced stress and hyperinsulinemia induced by the hyperinsulinemic-euglycemic clamp method. Part 3. Quantitative perfusion CMR in ANOCA The last part of this thesis looks into the use of cardiac CMR in ANOCA patients. Chapter 7 presents the validation of an improved and ready-to-implement workflow for quantitative perfusion CMR. This protocol incorporates simplified dual-bolus usage and fully-automated image post-processing, making implementation into clinical practice more accessible. In Chapter 8, this protocol is applied to validate the quantitative perfusion, including visual assessment and absolute quantification of myocardial blood flow (MBF), and deriving myocardial perfusion reserve (MPR), in ANOCA patients from the MICORDIS study, compared to healthy controls. In this thesis, the pathophysiology of ANOCA is explored through a multimodal approach, with a particular focus on sex differences. ANOCA, a condition where ischemic symptoms occur in the absence of obstructive coronary artery disease, is often associated with microvascular abnormalities. Despite its clinical significance, ANOCA is underdiagnosed and poorly understood, particularly in women. This research combines both invasive and non-invasive imaging modalities to enhance the understanding of ANOCA, aiming to improve diagnostic strategies and tailor treatments based on individual pathophysiology. 1
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