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Title: Vascular characterisation using multimodal imaging and relationship to functional lipid indices in blood
Author: Alkhalil, Mohammad
ISNI:       0000 0004 7959 9924
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Reduction in LDL cholesterol (LDL-c) has been shown to be effective in decreasing cardiovascular events. However, 1 in 5 patients return with a second event within 5 years despite achieving very low LDL-c. New lipid-lowering drugs have been shown to be efficacious in reducing LDL-c, however, in unselected populations the numbers needed to treat with these agents were unmanageably high. Therefore, attention should be sharply focused on developing stratification tools that not only identify high risk patients but also incorporate a mechanistic understanding when applying targeted therapies. Matching a prominent disease feature (inflammation, lipid accumulation etc.) with a drug mechanism of action may offer an opportunity to achieve more precise intervention. Remarkably, however, it is still unclear how reducing LDL-c translates into improved cardiovascular outcomes. One prevalent theory is that LDL-c reduction leads to evacuation of lipid from atherosclerotic plaque, rendering plaque less prone to rupture. Tools to measure plaque lipid content in humans in vivo have been fundamentally insensitive and incapable of systematically quantify lipid in every individual. Thus limiting the applicability of using plaque lipid quantification as an approach to select individuals for new lipid-lowering drugs. Recently, a new quantitative magnetic resonance imaging (MRI) T2 mapping technique has been shown to be capable of accurate, reproducible quantification of carotid plaque lipid on a voxel-by-voxel basis. Accordingly, this thesis hypothesized that using this newly validated technique, plaque lipid content and distribution can be systematically evaluated in all patients with clinical evidence of atherosclerosis. In addition, lipid content quantified on T2 mapping is reduced following intensive LDL-c reduction which can be assessed on subjects with no pre-defined carotid disease. Furthermore, blood lipid biomarkers are dissociated from plaque lipid content and its change on therapy. Finally, plaque lipid content is not influenced by perivascular adipose tissue, marker of inflammation, via paracrine local effect. T2 mapping MRI technique was able to identify patients with propensity to develop lipid-rich plaques at multi-sites vascular territories in patients scheduled for carotid endarterectomy (CEA) or presenting with acute coronary syndrome (ACS). Plaque lipid content and distribution quantified on T2 mapping MRI technique were related to the symptomatic status of plaques in patients scheduled for CEA. Intensive LDL-c reduction using high intensity statin treatment was associated with significant changes in plaque composition which was detected on T2 mapping as early as three months. There was no significant predictor of changes in carotid plaque lipid content using baseline, attained or change in blood lipid biomarkers following statin treatment. There was no spatial relationship between carotid plaque lipid content and adjacent perivascular adipose tissue. These findings support the use of plaque imaging as a potential tool to identify suitable patients for intensive lipid-lowering treatments and to track patients' response to these therapies.
Supervisor: Choudhury, Robin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available