Lipid particles and 3D models in cardiovascular inflammation A scientific quest from bench to bedside and back

This thesis investigates the role of lipid-driven inflammation in cardiovascular disease and explores both mechanistic insights and innovative experimental models.
Part I focuses on lipoprotein(a) [Lp(a)] as a key driver of cardiovascular inflammation. Elevated Lp(a) was associated with increased labelled glucose uptake in aortic valves and triggered inflammatory activation in valvular interstitial cells (VICs) via NF-κB signaling. Sustained inflammation was linked to a metabolic shift toward glycolysis, mediated by PFKFB3, highlighting a connection between metabolism and inflammation. Moving from bench to bedside, we investigated a pediatric cohort of children with familial hypercholesterolemia. Long-term clinical data revealed how elevated levels of Lp(a) accelerate early atherosclerosis progression, emphasizing the importance of early Lp(a) screening.
Part II examines triglyceride-rich lipoproteins and the therapeutic potential of apoC-III inhibition using olezarsen in hypertriglyceridemic patients. Olezarsen significantly reduced both fasting and postprandial triglyceride levels, markedly lowering pancreatitis risk. Importantly, triglyceride reduction also attenuated monocyte activation, decreasing lipid accumulation, inflammatory markers, and adhesion capacity. These findings suggest that targeting triglycerides not only improves lipid profiles but also reduces inflammatory responses that might contribute to ASCVD progression.
Part III shifts to methodological innovation. First, the current status of three-dimensional (3D) multicellular models to study ischemia-reperfusion injury is reviewed. Secondly, we present a practical guide to investigate cardiovascular inflammation. Here, we use Emulate organ-on-chip technology to study complex interactions between cardiomyocytes and the vasculature.