Atherosclerosis is a focal inflammatory disease, non-uniformly distributed in regions of disturbed flow within the arterial system. The local accumulation of lipids and inflammatory cells in these regions drives lesion initiation and progression into advanced plaques. Along with systemic risk factors, local haemodynamic metrics, such as wall shear stress (WSS), have been shown to be good correlates to plaque development. Few studies have investigated the relationship between mechanics and biology longitudinally over plaque development. However, conflicting views on the role of low and high wall shear stress in the development of the disease remain. Using high-resolution imaging and novel techniques like 3-D histology, we seek to provide more conclusive evidence of the correlation between perturbed haemodynamics and markers of atherosclerosis in two longitudinal studies in different animal models. The first study comprised of the development of a computational workflow to analyse co-localisations of selected disease markers with perturbed shear regions, induced in carotid arteries of ApoE-/- mice. Serial, in vivo mouse-specific haemodynamics were computed in micro-CT based geometries and coupled with plaque distribution spatially mapped on the in vivo lumen at each time point. Two novel haemodynamic metrics and other established metrics were assessed to find the best predictor of local areas of plaque formation. A quantitative analysis revealed plaque lipids and macrophages in the initial stage of the disease best overlapped with our custom metric, the low shear index (LSI), suggesting the importance of low shear in the initiation of atherosclerosis. In the second study, the developed workflow was applied to correlate plaque biology and mechanical metrics in transgenic hypercholesterolemic Yucatan minipigs. Lesions were induced by implanting a stenotic stent in one of the coronaries, and in vivo haemodynamics were computed in OCT based coronary reconstructions serially from healthy to advanced disease stages. Animals developed advanced human-like atherosclerotic lesions in regions of sustained low and oscillatory shear, induced by the stent. Histology based macrophage distribution showed good correlations with the newly developed metric, LSI, further emphasising the importance of low shear in atherogenesis. In conclusion, we have developed an integrated platform for high-resolution studies of plaque mechanobiology. Low shear was the best correlate to markers of atherosclerosis in two animal models, quantified by our novel metric-LSI, which might be a good predictor of disease development. Additionally, this thesis shows the importance of longitudinal in vivo studies of atherosclerosis and contributes to further understanding of this disease, while also providing tools that can be further extended in future studies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:682070 |
| Date | January 2014 |
| Creators | Mehta, Vikram |
| Contributors | Krams, Rob ; Pedrigi, Ryan |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/30724 |
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