FMD will be measured using using a high-resolution ultrasound scanner with a 10 MHz linear-array transducer (MyLab25 Gold Ultrasound Machine, Esaote, Italy), with the volunteer resting in the supine position for at least 5 min. The brachial artery in the right arm will be identified 5–10 cm above the antecubital fossa using ultrasound. FMD will be measured as described previously, using Cardiovascular Suite software (Quipu srl, Pisa, Italy).34

GTN-mediated dilation will be measured using the same equipment, in the same artery. GTN (25 mcg) will be administered sublingually, with the brachial artery diameter measured at baseline and 5 min after GTN, as described.34

Central haemodynamics as well as arterial stiffness, assessed by determination of the AIx and the carotid-to-femoral PWV, will be determined using a commercially available SphygmoCor system (AtCor Medical, Sydney, Australia), as previously described.35

Carotid IMT will be measured by using a high-resolution ultrasound scanner with a 10 MHz linear-array transducer (MyLab25 Gold Ultrasound Machine, Esaote, Italy), with the volunteer resting in the supine position for at least 5 minutes. The common carotid artery will be identified and scanned, 2 cm below its bifurcation. Measurements will be repeated three times, and the average of the values will be recorded.

The primary outcome will be the change in vascular inflammation on FDG-PET /CT using derivatives of standard uptake value and tissue to background ratio (TBR) in the aorta and carotid arteries of patients following approximately 8 weeks of treatment.

A variety of secondary outcome measures include comparison of the effects of adding alirocumab or ezetimibe on top of high-dose statin treatment on FMD and sublingual GTN response, as surrogate measures of endothelial-dependent and endothelial-independent vasodilation, respectively, changes in Aix, PWV, cIMT, lipid profile, hsCRP and other markers of systemic inflammation. An assessment of safety and tolerability will be undertaken as part of standard clinical practice, including physical examination, blood pressure, heart rate, 12-lead ECGs, clinical laboratory tests and adverse event reporting.

FDG-PET/CT imaging of the aorta and carotid arteries will be performed at V2 and V7. The images will be analysed using OsiriX imaging software (Pixmeo, Bernex, Switzerland). The maximum standardised uptake value of FDG within each axial PET/CT fused image of artery, containing wall and lumen, will be divided by the average blood FDG concentration in the superior vena cava (for aorta) or jugular vein (for carotids) to yield an arterial maximum TBR, as a quantitative measure of arterial tracer uptake corrected for systemic uptake. Average TBR for ascending, descending and abdominal aorta, as well as average TBR for the right and left carotid arteries combined, will be calculated. Additional analysis will examine the proportion of aortic slices with a TBR of > 1.6, which is used as a threshold to define highly inflamed areas of aorta. Imaging data will be analysed blinded to the allocated study treatment and visit number.

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