98 Chapter 5 The re-challenge is used for clinical indication, re-administration of acetylcholine after NTG provides insight on the response to nitrate and enables further tailored treatment. Acetylcholine-induced coronary spasm is defined as transient, total or subtotal occlusion (>90%) of an epicardial coronary artery, according to the more recent developed COVADIS-criteria and prior guidelines.16, 17, 38 After repeated nitroglycerin administration, and weaning of its initial effects, ICFT is completed by invasive coronary pressure and flow measurements during resting conditions and during maximal vasodilatation to calculate fractional flow reserve (FFR), coronary flow reserve (CFR), and microvascular resistance (MR). Hyperemia is induced by an intracoronary bolus of 150 μg adenosine applied manually and reflects maximal, endothelium-independent vasodilation of the coronary arterioles.39 FFR is calculated as the ratio of hyperemic average peak flow velocity to basal average peak flow velocity and is considered abnormal if <0.80. CFR is calculated as the ratio of hyperemic average peak flow velocity to basal averaged peak flow velocity. A CFR <2 is considered abnormal.36 Doppler flow velocity derived CFR has high concordance to CFR derived from [150]H2O positron emission tomography (PET) which is considered the gold standard for absolute quantification of myocardial perfusion.40 Minimal MR is calculated as the ratio of distal coronary pressure to distal coronary flow and during maximal coronary vasodilatation and reflects the intrinsic resistance of the coronary microvasculature blood flow as a marker of structural microvascular alterations.41 Minimal MR is expressed by the hyperemic microvascular resistance (HMR), where HMR >1.9 is considered abnormal and used for diagnosing CMD.42 Myocardial Contrast Echocardiography (MCE) Myocardial contrast echocardiography is performed in all study subjects. MCE enables visualization of the microcirculation by mixing echogenic microbubbles as contrast agent with blood, providing specific measurements of MBV and microvascular flow velocity (MFV). The product of these parameters is MBF, using the equation MBF = MBV*MFV.43 Microbubbles (1.5 ml Luminity, diluted in 50 ml NaCl; Lantheus Medical Imaging, Newbury, United Kingdom) are infused with a constant infusion rate until a steady state is achieved in the coronary microcirculation. Once the steady state is reached, the microbubbles are locally destroyed using a high Mechanical Index (MI) ultrasound pulse (MI-flash 1.3) and during this process the video intensity is measured until the microbubble concentration in the coronary microcirculation returns to its steady-state level (i.e., myocardial replenishment) (Figure 3).
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