Inflammation and lipids in atherosclerosis From disease mechanisms to therapeutic targeting

This thesis explored novel strategies to improve cardiovascular risk management by investigating lipids, inflammation, and plasma proteomics in individuals at risk for atherosclerotic cardiovascular disease (ASCVD). Part I examined the role of triglyceride-rich lipoproteins and systemic inflammation in ASCVD and acute pancreatitis. One study showed that the association between remnant cholesterol and ASCVD events was largely independent of systemic inflammation, suggesting independent pathways. A randomized placebo-controlled trial with olezarsen showed that treatment reduced both fasting and postprandial triglyceride levels and altered monocyte phenotype and function. These findings indicate a potential for olezarsen to reduce the risk of both acute pancreatitis and ASCVD. Part II focused on inflammation as a driver of plaque vulnerability and cardiovascular events. LDL cholesterol, hsCRP, and Lp(a) were associated with increased long-term ASCVD risk in primary prevention patients within a large European cohort. Inflammatory markers IL-6 and hsCRP were associated with high-risk plaque features and progression. Moreover, 68Ga-DOTATATE PET/CT imaging showed promise in detecting vascular inflammation beyond systemic biomarkers. Part III investigated the utility of plasma proteomics in improving ASCVD risk prediction and informing treatment decisions. Proteomic analyses improved prediction of plaque progression and identified key inflammatory and apoptotic pathways. A study on PCSK9 inhibition and colchicine revealed differing proteomic effects, while another study on PCSK9 inhibition showed consistency between pharmacologic and genetically predicted effects. Together, these findings suggest that integrating biomarkers, imaging, and targeted therapies may support a more personalized approach to ASCVD prevention.