115 The MICORDIS study Figure 1. Myocardial contrast echocardiography regions of interest (ROIs) on end-systolic frames of apical 4-chamber, 2-chamber and 3-chamber views derived with myocardial echocardiography. ROI’s were placed mid-ventricular and apical on each wall segment (inferoseptal, lateral, inferior, anterior, inferolateral and anteroseptal). Adjacent ROI’s were placed in the left ventricular cavity Abbreviations: ROI: region of Interest; LV: left ventricular cavity. Hyperinsulinemia induced by hyperinsulinemic-euglycemic clamp After measuring baseline MCE under resting conditions, measurements were repeated during HE-clamp- induced hyperinsulinemia.18 HE-clamping elevates insulin plasma concentration to a postprandial level while preserving normoglycemia. This method assesses insulin sensitivity, as during steady state euglycemia the glucose infusion rate equals the body’s glucose uptake. Participants fasted for 12 h prior to the HEclamp. Prior to the HE-clamp, baseline blood glucose was assessed. A steady state of hyperinsulinemia, with glucose infusion rate matching whole-body uptake, was achieved in the final 30 min. In this condition, MCE was repeated to measure MBV during hyperinsulinemia. Hyperinsulinemia-induced microvascular recruitment (MVR) was calculated as MBVhyperinsulinemia/MBVbaseline.19 Insulin sensitivity, represented by the M-value (μmol/kg/min), was calculated from the average glucose infusion rate during the HE-clamp period divided by body weight. Dobutamine-induced stress Infusion of incremental doses of dobutamine was performed to allow measurement of the MBV response to increased myocardial oxygen demand (Supplemental Table 2). MCE was performed at a target dose of 40 μg/kg/min, or upon occurrence of undesired (side) effects. If the diagnostic endpoint (detailed in Supplemental Table 2) was not reached at the target dose, an additional three minutes of 40 μg/kg/min dobutamine was given and followed by atropine if needed (totaling 0.50 mg atropine in two boluses of 0.25 mg each). Dobutamine stress-induced microvascular recruitment (contraction-induced MVR) was calculated as MBVstress/MBVbaseline Heart rate and blood pressure were measured at baseline and during each incremental dose of dobutamine to calculate heart rate reserve, defined as the difference between peak heart rate and resting heart rate.20 Heart rate reserve was adjusted for age using the formula (maximum heart rate-resting heart rate/ age predicted maximum heart rate-resting heart rate) x100. 6
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