Mediators, Metabolites and Atypical Immune Cells in Cardiovascular Disease

Cardiovascular disease (CVD) remains, despite intense research, the most common cause of death world-wide. The main underlying cause of CVD is atherosclerosis, which is characterised by chronic inflammation. CVD and atherosclerosis have a complex aetiology, which necessitates research into multiple areas in order to gain insight into the pathogenesis and find novel markers that could aid in identifying individuals at risk. In this thesis, I have investigated mediators, metabolites and atypical immune cells and how they affect atherosclerosis and risk of coronary events. To this end we have used both mouse models and a clinical cohort.In Paper I we investigated associations between the leukocyte guiding chemokines CCL21 and CCL19 and incident coronary events in the general population-based Malmö Diet and Cancer cohort. We found that high plasma levels of CCL21, but not CCL19, had an independent association to incident coronary events. High levels of CCL19 were on the other hand associated with both incident heart failure and mortality.In Paper II we investigated the effect of drinking water supplementation with α-ketoglutarate or glutamine on atherosclerosis development and plaque composition. Our main finding was that glutamine, an important fuel source for immune cells, caused increased development of atherosclerosis in male mice. These mice also had larger accumulation of cells, including neutrophils, in the adventitia surrounding the aorta.In Paper III we investigated CD21low age-associated B cells (ABCs), previously identified in atherosclerotic plaques. We evaluated their clonality, differentiation potential and effect on atherosclerosis development. In humans we investigated if CD21low ABCs were associated to incident coronary events. We found that CD21low ABCs were clonally expanded and could differentiate into plasma cells in vivo. CD21low ABCs also aggravated murine atherosclerosis and high numbers of circulating CD21low ABCs were associated with incident coronary events in humans.In Paper IV we investigated if, as suggested by animal studies, invariant natural killer T (iNKT) cells have an association to incident coronary events in humans. However, high numbers of these lipid-specific cells did not have an association to incident coronary events. Furthermore, we identified a subpopulation of iNKT cells that were CD4-CD8- which had an independent, inverse association to incident coronary events.In conclusion, this thesis illustrates the multifaceted contributions of inflammatory mediators and cells in CVD and atherosclerosis, while also providing novel insights into this important research field.