201 General discussion levels and attenuate atherosclerotic development by inactivating the LDL-receptor and ApoE via estrogen receptor signaling.9 This results in a difference in observed atherosclerotic plaques between sexes. While women tend to have the same number of lesions as men, plaque morphology differs. Pre-menopausal women have more stable plaques, lower incidence of plaque rupture, and less calcification of the lesions, but experience more plaque erosion compared to men. In contrast, atherosclerotic plaques in men are typically thin-cap fibroatheromas, with a higher incidence of plaque rupture and more calcification of the lesion.10 However, one overlapping mechanism in obstructive CAD and ANOCA is the inflammatory role of the endothelium. One could hypothesize that the pathophysiological mechanisms in certain endotypes of ANOCA, especially CMD, are similar to those of obstructive CAD, but are at an earlier stage in the disease process, thereby resulting in different anginal symptoms. The interaction between CMD and obstructive CAD is described as close, however, to date the precise interaction remains unclear.11 Many of the studies performed in regards to ANOCA only included women, and lack to give insights into the sex-differences regarding ANOCA and the relationship between the various endotypes of CCS and sex. This thesis aimed to provide insights into the prevalence and cardiovascular outcome of the different endotypes of chronic coronary syndrome among sexes. Early identification of the pathophysiological mechanism causing the anginal complaints allows for stratified therapy, treating the patient accordingly and preventing the progression of inflammation and atherosclerotic disease. Part 2. Myocardial blood volume as driver of ANOCA In ANOCA, ischemic symptoms occur when oxygen delivery is insufficient to meet metabolic demand. Oxygen delivery is determined by two microvascular parameters, myocardial blood flow (MBF) and myocardial blood volume (MBV). However, current guidelines on ANOCA focus on reduced maximal coronary flow as a cause of myocardial hypoxia whereas the MICORDIS-study was the first to show a significant decrease in MBV in ANOCA patients at submaximal flow, compared to matched healthy controls. A reduced MBV is a known pathophysiological mechanism in comorbid diseases associated with ANOCA, such as diabetes type 1 and 2.12 Furthermore, ANOCA has a female predisposition. This female predisposition, and the involvement of MBV, could be related to the fact that MBV is higher in healthy women compared to healthy men.13 This might suggest that women are more sensitive to minor changes in MBV due to higher oxygen extraction, and therefore experience corresponding complaints at milder decreases in MBV and flow. Myocardial blood volume (MBV) can be assessed using myocardial contrast echocardiography (MCE)14, which exclusively images the coronary microcirculation. Unlike other imaging modalities, MCE uses microbubbles that remain in the microvasculature and respond to ultrasound by oscillating, producing detectable acoustic signals, which is detected by the echo-transducer.15, 16 By using different mechanical indices (MI), microbubble behavior can be used to generate time-intensity curves. In these curves 10
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