Locally disturbed blood flow is a major determinant of coronary atherosclerotic plaque initiation and progression, identification of which remains a major unmet clinical challenge. Addition of wall shear stress (WSS) assessment to intracoronary imaging-derived evaluation of plaque morphology, improves identification of plaques likely to develop high risk features. In this thesis, the causal relationship between altered local WSS, endothelial cell (EC) pathobiology and coronary atherogenesis was investigated for the first time in vivo, in human-like D347Y-PCSK9 hyperlipidaemic minipigs instrumented with a stenotic shear stress modifying stent. The research reports: (i) There are detectable local concentration gradients within coronary arteries of the acutely released flow-sensitive EC mediator prostacyclin using the novel Liquid Biopsy System catheter. This demonstrates the potential utility of this device for future longitudinal studies of locally released biomarkers associated with atherogenesis.
(ii) RNA sequencing from locally sampled ECs coupled with computational fluid dynamics (CFD) revealed that altered WSS (low TAWSS and high OSI and tSS) is implicated in influencing coronary artery EC biology and resulting in advanced plaque formation, through transcriptional mechanisms leading to distinct gene expression profiles associated with thick-cap fibroatheroma development. This included upregulation of genes TLR1, TXN, ITGB3, MYD88 and ANGPT1. Notable enriched pathways discovered were toll-like receptor signalling and fibrosis-specific processes such as TGF-β signalling. (iii) Future adoption of rapid WSS assessment in clinical practice could be feasible from angiography based-CFD, due to calculation of similar WSS magnitudes and distributions compared with the gold standard optical coherence tomography-methodology. This work provides a model system for studying the mechanisms linking altered WSS, EC biology and coronary atherogenesis in vivo and supports the use of WSS as a biologically plausible biomarker of advanced coronary plaque formation. These data can be used in future translational studies for development of specific diagnostics and therapeutics for advanced coronary atherosclerosis.