91 Rational and Design of the MICORDIS study Table 1. Entities of INOCA according to the COVADIS-criteria (continued) Ischemia with no obstructive coronary arteries (INOCA) 3. Inducible coronary artery spasm Spontaneously or during provocationtesting (with acetylcholine): a. Transient total or subtotal coronary artery occlusion (>90% vasoconstriction) b. Reproduction of angina symptoms c. Ischemic ECG-changes Definitive microvascular angina is diagnosed if all four criteria are present. If only criteria 1 and 2 are present, but only criteria 3 or 4 is present suspected microvascular angina is diagnosed. Definitive vasospastic angina is diagnosed if all three criteria are present. If only nitrate-responsive angina is evident during spontaneous episodes, but transient ischemic ECG changes are equivocal or unavailable and coronary artery spasm criteria are equivocal, suspected vasospastic angina is diagnosed. Abbreviations: CMD: coronary microvascular dysfunction; CAD; coronary artery disease, FFR; fractional flow reserve Reduced MBV, for example by rarefaction can reduce microvascular delivery of oxygen, and MBF and MBV are independently regulated. As such, MBV may play a role in CMD that is independent from the parameters identified using ICFT. Both MBF and MBV are linked to myocardial oxygen consumption (MVO2), and both independently increase when MVO2 increases.21 MBV can be studied in the clinical setting in resting conditions and by evaluating the MBV in response to different physiological stimuli, such as dobutamine, and hyperinsulinemia (Table 2). Dobutamine, a direct-acting synthetic catecholamine, increases heart rate and the contractile force of the myocardium, increasing stroke volume and cardiac output. Thereby, dobutamine significantly increases MVO2, and consequently MBF and MBV. As such, the ability of the microcirculation to increase MBV can be evaluated using dobutamine. Similarly, insulin, well known for its effects on glucose and fatty acid metabolism, also has quick and potent effects on MBV. Insulin receptors are present on endothelial cells, and direct binding of insulin to these receptors normally enhances nitric oxide (NO) release, causing microvascular dilatation. However, insulin also activates the mitogen-activated protein kinase pathway in endothelial cells, augmenting production of the vasoconstrictor peptide endothelin-1 (ET-1).22, 23 In healthy subjects, postprandial concentrations of insulin have a stronger effect on NO than on ET-1, leading to an overall enhancement of microvascular perfusion represented by an increase in MBV (ΔMBV) referred to as capillary recruitment.24 5
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