Inflammation in Atherosclerotic Cardiovascular Disease – From NR Supplementation to IL-8 as a Biomarker

Background and Aim Atherosclerosis and its clinical manifestations, collectively known as atherosclerotic cardiovascular disease (ASCVD), remain a leading cause of mortality worldwide. Despite the use of lipid-lowering drugs and advanced imaging techniques, a substantial residual inflammatory risk persists in patients. Previously, targeting inflammation has been shown to improve the outcome of ASCVD. This underscores the further need for the understanding of inflammatory pathways and the identification of new prognostic biomarkers. This dissertation investigates the role of inflammation in ASCVD by exploring both a metabolic intervention in a preclinical atherosclerosis model and the clinical significance of a key inflammatory cytokine in acute myocardial infarction (AMI) patients. Results The main body of this thesis is comprised of three studies that collectively address this issue. First, we investigated the effect of nicotinamide riboside (NR) supplementation on atherosclerosis in Apoe knockout mice. Challenging the prevailing view of NAD+ boosting as cardioprotective, our results showed that high-dose NR supplementation increased atherosclerotic plaque lesions and promoted systemic inflammation. Increased CD38 and pro-inflammatory NAD+ breakdown product indicated a potential pro-inflammatory effect of NAD+ boosting in this context. In a clinical study utilizing the SPUM-ACS cohort of AMI patients, we evaluated the prognostic value of interleukin-8 (IL-8), a neutrophil-related chemokine. Higher plasma IL-8 levels within 24 hours of AMI onset were observed in patients with one-year all-cause mortality or recurrent AMI. IL-8 is associated with risk for composite outcome after adjustment. In addition, IL-8 along with other neutrophil-related markers improved clinical GRACE 2.0 score in our selected patients. Finally, in a substudy of the PACMAN-AMI trial, we examined the association between IL-8 and plaque characteristics in AMI patients receiving intensive lipid-lowering therapy with alirocumab. Our findings demonstrate that higher plasma IL-8 levels at 52 weeks were associated with a smaller reduction in the plaque lipid core burden index (maxLCBI4mm), suggesting that IL-8 serves as a biomarker for residual inflammatory risk revealed with effective lipid management. Conclusions Our work further reveals the nature of inflammatory pathways in ASCVD. We provide mechanistic insights into a potential detrimental effect of NR supplementation on atherosclerosis, while establishing the clinical value of the key inflammatory biomarker, IL-8, for risk stratification and plaque phenotype changes in patients with AMI. These findings highlight the critical role of inflammation beyond traditional risk factors and emphasize the need for new therapeutic strategies targeting this pathway. $\textit{Full-text embargoed until: 2026-05-13}$