Fenton, Matthew James; (2022) Inflammatory cytokines, endothelial function and cardiac allograft vasculopathy in children: an investigation of the donor and recipient vasculature after heart transplantation. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Cardiac allograft vasculopathy (CAV) limits the life span of paediatric heart transplant recipients. I investigated blood markers of inflammation, endothelial dysfunction and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from paediatric heart transplant recipients for markers of inflammation and endothelial activation. The presence of systemic inflammation was assessed using serum markers including interleukin (IL) 1beta, IL 6, IL 8, c reactive protein (CRP), serum amyloid A (SAA) and tumour necrosis factor (TNF) alpha, an increase signifying the presence of a general inflammatory state. In order to assess endothelial activation measurements of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, P selectin and E selectin were taken. Each of these molecules belongs to a family of cell adhesion molecules present on the surface of endothelial cells. They are responsible for the adhesion of white blood cells and platelets to the endothelial surface and are markers of increased endothelial activation. Investigation into thrombotic mechanisms was determined by measuring Tissue Factor (TF), an important component of the coagulation cascade, von Willebrand Factor(vWF), an important protein involved in binding platelets to the site of endothelial injury and Thrombomodulin (TM), a protein involved in controlling excessive coagulation through natural anticoagulant properties and preventing inflammation. IL 10 is a cytokine with many effects on regulating the immune system and inflammation, acting to down regulate inflammation and moderating the immune response. Monocyte chemoattractant protein (MCP-1) regulates the migration and adhesion of monocytes and macrophages to atherosclerotic plaques and is present as part of a proinflammatory response. Vascular endothelial growth factor (VEGF) is involved in regulating angiogenesis, vascular permeability and inflammation and is a candidate protein involved in the development of atherosclerosis amongst other vascualar disorders. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5mm was used to define significant CAV. 48 children (25 male) aged 8 to 18 years were enrolled in the study. Patients were a median (IQR) 4.1 (2.2 to 8.7) years after transplant. Patients had increased levels of circulating IL 6 (3.86 (2.84-4.95) vs 1.66 (1.22-2.63), p < 0.0001*), VCAM1 (539(451-621) vs 402(342-487), p<0.001*), ICAM1 305(247-346) vs 256(224- 294), p=0.002* and TM (7.1(5.5-8.1) vs 3.57(3.03-4.71,) p<0.0001*) and decreased levels of TNF alpha, E selectin and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum TM. Post-transplant TM levels are elevated after transplant but significantly lower in those with mIMT > 0.5mm. TM is a protein bound to the endothelium that moderates the deleterious effects of inflammation, coagulopathy and fibrosis. vWF supports platelet to platelet adhesion and is involved in the stabilisation of clots in response to injury. This suggests that subclinical inflammation is present and natural anticoagulant/TM activity is an important area for future transplant research into CAV. This is the first time that the protective role of TM has been identified in a clinical cohort of children after heart transplantation.

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