123 The MICORDIS study Conversely, these systemic responses do not acutely alter microvascular recruitment induced by hyperinsulinemia or dobutamine stress. Myocardial blood volume The coronary circulation contains about 12 mL of blood per 100 g of myocardium volume during diastole. Within the myocardium, the microcirculation contains approximately 90% of the blood volume, where MBV is mostly contained within the capillaries.21 During resting conditions, around half of the capillaries in the myocardium are simultaneously filled with blood.22 Upon increased myocardial oxygen demand, such as in response to dobutamine stress, the fraction of perfused capillaries in the myocardium can increase, referred to as ‘microvascular recruitment’ (MVR). This microvascular regulatory process involves the relaxation of precapillary arterioles, leading to the redistribution of blood to capillary beds that supply larger areas of the myocardium. Consequently, tissue oxygenation becomes more efficient.23, 24 Insulin also regulates vasomotor tone, as hyperinsulinemia induces vasodilatation and reduces coronary microvascular resistance via nitric oxide (NO) activity.11 In type 2 diabetes, hyperinsulinemia enhances the release of the vasoconstrictor endothelin-1 (ET-1), increasing vascular tone and counteracting the NO-mediated vasodilation.25 In insulin-sensitive individuals NO-mediated vasodilatation is dominant, leading to microvascular recruitment.26 Until today, these aspects of microvascular integrity remain understudied as a potential pathophysiological mechanism in ANOCA. We hypothesized that comprehensive assessment of MBV and MBF in response to insulin and dobutamine could provide novel insights the pathophysiology of ANOCA. Our study documents the presence of lower myocardial blood volume in ANOCA patients compared with healthy age-matched controls. MBV was lower in ANOCA patients in resting conditions, as well as during hyperinsulinemia and dobutamine-induced stress. This finding suggests the presence of microvascular rarefaction in ANOCA patients, since MBV measured using MCE at rest is a marker of vascular density. In contrast, there was no difference between ANOCA patients and matched controls with respect to microvascular recruitment in response to hyperinsulinemia or dobutamine stress, since the change in MBV in response to these triggers was equivalent between groups. It is important to note the discrepancy between the presence of an abnormal HMR in the ANOCA population (9.5%) and a decreased MBV. Both HMR and MBV indicate structural microvascular alterations but are regulated differently. HMR is regulated by arterioles, while MBV is regulated by capillaries. Additionally, HMR is typically measured in a single coronary territory, whereas MBV is calculated across multiple coronary territories and represents a generalized measurement of myocardial perfusion. Structural changes such as rarefaction may affect microvascular regions non-uniformly, potentially resulting in normal HMR readings in some areas despite decreased MBV. This is in line with our findings, as we did not observe a correlation between MBV and HMR. In combination, these data suggest that ANOCA is associated with a loss of structural integrity of the microcirculation, whereas its functional integrity with respect to acute microvascular recruitment in response to an 6
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