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Endothelial dysfunction in atherosclerosis

Kharbanda, Rajesh Kumar; (2003) Endothelial dysfunction in atherosclerosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Endothelial dysfunction may serve as a mechanism to explain the vasoconstriction, inflammation, thrombosis and abnormal flow regulation in atherosclerosis, and play a role in the development of atheroma, and pathophysiology of its complications. This thesis describes experiments to characterise the mechanisms of endothelial dysfunction that could contribute to the pathogenesis of human atherosclerosis and its complications, in three main areas; 1. Mechanisms of flow-mediated dilatation The role of endothelial nitric oxide (NO) in flow-mediated dilatation (FMD) was investigated in healthy volunteers and hypercholesterolaemic patients. FMD to transient-flow stimuli was found to be NO-dependent and reduced in hypercholesterolaemia. In contrast, FMD to sustained-flow stimuli was largely NO- independent and preserved in these patients. These data suggest a second mechanism of FMD exists in humans, which is preserved in certain atherosclerosis risk groups. 2. The effect of acute inflammation on endothelial function Vascular inflammation has been implicated as a precipitant of endothelial dysfunction and consequent cardiovascular events in humans. The effect of a mild inflammatory stimulus (typhoid vaccination) on conduit and resistance vessel endothelial function was determined. Vaccination caused endothelial dysfunction, which was prevented by prior treatment with an anti-inflammatory dose of aspirin. These data implicate acute inflammation as a possible mechanism of endothelial dysfunction in humans and a link between inflammation and acute cardiovascular risk. 3. The effect of ischaemia-reperfusion on endothelial function Arterial thrombosis leading to ischaemia and infarction is a complication of atherosclerosis. Reperfusion strategies are complicated by ischaemia-reperfusion injury. A novel model for assessing the effect of ischaemia-reperfusion on endothelial function was developed. This indicated that 20 minutes of forearm ischaemia caused endothelial dysfunction and activated circulating neutrophils. Local and remote ischaemic preconditioning abolished endothelial dysfunction during experimental ischaemia-reperfiision and reduced myocardial infarction in a porcine model. Limiting endothelial dysfunction in ischaemia-reperfusion could improve the outcome of reperfusion strategies.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Endothelial dysfunction in atherosclerosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Endothelial dysfunction
URI: https://discovery.ucl.ac.uk/id/eprint/10105404
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