Ischaemic heart disease remains the single leading cause of death throughout the world. Rupture of an advanced atheromatous coronary plaque precipitates the majority of these clinical events, resulting in thrombosis and myocardial infarction. Post-mortem studies have identified thin-cap fibroatheroma (TCFA) as the plaque subtype most prone to rupture with prospective virtual-histology intravascular ultrasound (VH-IVUS) studies linking VH-TCFA to future adverse clinical events. VH-TCFA are however common along the coronary tree with the majority remaining clinically silent, suggesting that factors other than plaque phenotype play an important role in determining rupture and future plaque behaviour.

Rupture is thought to occur when the structural stress within the plaque exceeds the material strength of the overlying fibrous cap. Previous histological work has demonstrated that ruptured plaques are associated with higher stress compared to non-ruptured controls, with in vivo VH-IVUS studies linking higher plaque structural stress (PSS) with the presentation of acute coronary syndrome. Wall shear stress (WSS) on the other hand has been implicated in early plaque development and plaque growth suggesting that both PSS and WSS can influence future plaque behaviour.

The work presented in this thesis is associated with a number of novel findings. First, it is the only work to demonstrate that in vivo PSS is higher in coronary atherosclerotic plaques with rupture vs. no rupture across a range of plaque subtypes and irrespective of whether analysis of the entire plaque or of regions close to the minimal luminal area is performed. Second, it shows that the pattern and extent of plaque progression and regression defined as an increase and decrease in plaque area, respectively, are associated with specific biomechanical environments at baseline, in the only study that examines the role of both PSS and WSS in this process. More specifically, high PSS is associated with changes consistent with increased vulnerability both in areas of progression and regression. On the other hand, lower WSS at baseline is associated with greater increases in plaque area and burden in areas that progress and with smaller decreases in areas that regress largely due to changes in fibrous tissue. Although the role of WSS in determining future plaque behaviour has been previously examined, this is the first time that this is assessed specifically in areas of progression and regression, particularly important in view of the dynamic nature of atherosclerotic plaques. More importantly, the work presented in this thesis demonstrates that the interplay of these biomechanical forces is associated with specific patterns of plaque progression and regression despite the fact that PSS and WSS are independent of each other. This has never been previously demonstrated and further suggests that incorporation of biomechanical analysis can play role in the identification of plaques that lead to future clinical events. Finally, the ability of PSS to identify plaques that lead to adverse clinical events was assessed through a propensity core matched analysis of the PROSPECT (A Prospective Natural-History Study of Coronary Atherosclerosis) study. The analysis presented here is the largest, most extensive and thus most significant work to ever examine this with results suggesting that incorporation of PSS and associated parameters can improve the capability of VH-IVUS to identify plaques that lead to such events.

In summary, the results of this thesis suggest that coronary PSS plays an important role in the pathophysiology of plaque rupture, and that its incorporation in routine plaque assessment may improve our current ability to identifying coronary plaques that lead to future adverse clinical events. The interplay between PSS and WSS may also affect future plaque behaviour and in particular progression and regression. Prospective studies are now required to fully evaluate the role of these biomechanical forces in plaque development, and whether their incorporation in plaque evaluation can be of clinical significance.