Coronary atherosclerotic plaque rupture is a critical event during atherosclerosis disease progression. Clinical consequences of atherosclerotic plaque rupture vary from asymptomatic to acute arterial thrombosis, yet the mechanisms underpinning such divergent biological response remain poorly understood. Novel biological signatures of plaque rupture will confer further insights into the dynamic responses triggered by plaque rupture event(s), and may provide alternative strategies for modulation of this prevalent disease. This thesis aims to investigate the events that accompany coronary plaque rupture and their relations to subsequent, downstream systemic effects. In a prospective clinical study of patients undergoing non-emergency percutaneous coronary intervention (PCI), stenting induced plaque disruption was used as a model of plaque rupture in vivo. Optical coherence tomography (OCT) imaging of the plaque lesion was performed prior to stenting, followed by serial blood sampling from targeted anatomical sites in reference to the plaque disruption event. Coronary plaque debris were also retrieved in a controlled manner. Analysis of candidate markers demonstrated a role of matrix metalloproteinase 9 (MMP9) in the systemic response to plaque disruption. Local and systemic elevations of MMP9 were observed promptly after plaque disruption. The systemic release of MMP9 was independent to the myocardial injury and systemic inflammation as a result of PCI. OCT analysis further suggested that plaque morphology may be a determining factor in the subsequent MMP9 release, as the disruption of lipid rich plaque(s) resulted in more acute elevation 'of ~1'MP9 when compared to disruption of non-lipid lesions. Changes of systemic MMP9 served as an index of response to the stent induced plaque disruption. Subjects with divergent MMP9 responses to the plaque disruption event were put forward for further comprehensive investigation during the discovery phase, using mass spectrometry techniques to investigate the lipidomic, metabolomics, and proteomic signatures of plaque disruption. Coronary atherosclerotic plaque disruption was associated with immediate changes in the plasma lipidomics and metabolomics profiles, which had distinct relations to the subsequent systemic MMP9 release. Coronary plaque debris provided a "catalogue" of proteins which could be acutely liberated into systemic circulation. Several such novel proteins were detected in circulation after plaque disruption, which triggered disparate responses in known canonical pathways. Evidence from this thesis implicates the role of liver X receptor / retinoic acid receptor pathway (LXR/RXR) as a key mediator to the divergent systemic responses after plaque disruption, and pinpoints a direction for future investigations.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:618468 |
| Date | January 2014 |
| Creators | Lee, Regent |
| Contributors | Channon, Keith; Kessler, Benedikt |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:7f0136bf-ad55-4dc8-bcc3-1d55cb269ef8 |
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