Interleukin-8 plasma levels correlate with changes in coronary atherosclerosis in patients with acute myocardial infarction treated with alirocumab

Introduction Inflammation plays a critical role in the progression of coronary artery disease. In high-risk patients after acute myocardial infarction (AMI) with high-intensity lipid-lowering intervention, residual inflammatory risk is a particular concern. In patients with AMI, interleukin-8 (IL-8) is a key chemokine in the early inflammatory response to injury and is associated with 1-year mortality. Yet, the relationship between IL-8 and progression of coronary artery atherosclerosis in AMI patients remains unknown. Purpose We aimed to explore the association between IL-8 plasma levels and changes in atherosclerosis in non-infarct-related coronary arteries of AMI patients. Methods This is a substudy of PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients with Acute Myocardial Infarction) trial. 261 AMI patients were randomized to alirocumab (127) or placebo (134) and underwent serial 2-vessel intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near-infrared spectroscopy (NIRS) in non-infarct-related coronary arteries at baseline (BL) and after 52 weeks. The main end points were percent atheroma volume (PAV) by IVUS, minimum fibrous cap thickness (FCTmin) by OCT and maximum lipid core burden index within 4 mm (maxLCBI4mm) by NIRS. All patients received high-intensity statin and the designated study treatment (150 mg alirocumab vs placebo) biweekly. Plasma samples were collected at BL, 4 weeks, and 52 weeks for OLINK proteomic analyses including IL-8. Two-way ANOVA was used for comparing IL-8 levels at different timepoints. Changes in intracoronary imaging were analyzed using linear regression models. Age, sex, treatment arm, diabetes status, and BL LDL-c levels were included for adjustment. Absolute image outcomes were analyzed with mixed-effects models. Results Plasma IL-8 levels decreased 4 and 52 weeks after BL (both p<0.001); alirocumab did not affect IL-8 levels at any timepoints. (Fig. 1) IL-8 levels were not associated with changes in PAV or FCTmin. Yet, IL-8 levels at 52 weeks positively correlated with changes in maxLCBI4mm (β=25.68, R2adj=0.017, p=0.020) and remained correlated after adjustment (β=24.39, R2adj=0.06, p=0.024). In the mixed-effects models, which included timepoint, IL-8 level, treatment arm, and their interaction as fixed effects, the impact of IL-8 at 52 weeks on maxLCBI4mm at different timepoints were significantly higher in the alirocumab group (difference in slopes=58.47, p=0.015) compared to the placebo group (difference in slopes=-2.32, NS) (Fig.2). Conclusions With alirocumab added to high-intensity statin therapy, IL-8 plasma levels at 52 weeks correlated with changes of maxLCBI4mm in non-infarct-related coronary arteries of AMI patients. These findings suggest the presence of IL-8-related residual inflammatory risk in AMI patients after very intensive lipid-lowering therapy, and that residual inflammation affects the magnitude of plaque lipid changes.