Emerging insights into early atherosclerosis in adolescents with chronic disease

Atherosclerosis is a life-long disease process. It remains subclinical for years and presents only after the first decades of life as peripheral artery disease, ischemic heart disease (heart attack), or stroke, together known as cardiovascular disease (CVD). Chronic disease may accelerate atherogenesis due to the presence of inflammatory, metabolic, or hemodynamic risk factors. In the first part of the thesis the “Cardiovascular Disease in Adolescents with Chronic Disease” (CDACD) study results were presented. The cross-sectional study enrolled 114 adolescents 12-18 years old with chronic disorders including juvenile idiopathic arthritis, cystic fibrosis, obesity, corrected coarctation of the aorta, and healthy controls with a corrected atrial septal defect. The study showed that early vascular changes such as an increased pulse wave velocity and wall thickness can be detected in the aorta using MRI in adolescents with chronic disease. In addition, early cardiac changes were detected that suggested that the heart meets greater vascular resistance. These cardiac changes include early signs of relative left ventricular wall thickening in obese adolescents, and significant lower left ventricular global longitudinal strain (LVGLS) in multiple adolescent chronic disease groups. These findings emphasize the need for cardiovascular follow-up of children with chronic disease, and the importance of the aorta for assessment of preclinical atherosclerosis. In the second part of the thesis, iNKT cells were introduced as immune players that couple metabolic derangement to an inflammatory immune response, and in that manner may contribute to atherogenesis. However, we don’t know yet how iNKT cells are activated exactly. The thesis describes our efforts to identify activating antigens and environmental factors. We explored the use of sortase-mediated transpeptidation to isolate CD1d, the antigen-presenting molecule for iNKT cells, and were able to suggest a potential CD1d endogenous ligand. We also explored lipoproteins as potential carriers of iNKT cell antigens and found that the ratio of unhealthy LDL-cholesterol versus HDL-cholesterol may play a role in iNKT cell activation. Ultimately, iNKT cells may be potential immune targets to prevent or decelerate atherosclerosis, but first we must learn a lot more about iNKT cell function in health and disease.