The persistence of high global mortality rates directly attributable to cardiovascular disease drives ongoing research into novel approaches for improved diagnosis and treatment of its primary underlying cause, atherosclerosis. Combined intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging is one such modality, actively being developed as a tool for improved characterization of high-risk atherosclerotic plaques. The pathophysiology associated with progression and destabilization of atherosclerotic plaques leads to characteristic changes in arterial morphology and composition. IVUS/IVPA imaging seeks to expand upon the ability of clinically utilized intravascular ultrasound (IVUS) imaging to assess vessel anatomy by adding improved sensitivity to image the underlying cellular and molecular composition through intravascular photoacoustic (IVPA) imaging of either endogenous chromophores (e.g. lipid) or exogenously delivered contrast agents. This dissertation focuses on the expansion of IVUS/IVPA imaging using exogenous contrast agents to enable the detection and subsequent optically-triggered therapy of atherosclerotic plaques. The passive extravasation and aggregation of systemically injected plasmonic gold nanorods absorbing within the near infrared tissue optical window within plaques of atherosclerotic rabbit models is first demonstrated, along with the ability to localize the contrast agents using ex vivo IVUS/IVPA imaging. The motivation for nanoparticle labeling of atherosclerosis is then expanded from that of purely image contrast agents to vehicles for image-guided, dual-modality phototherapy. The integrated IVUS/IVPA imaging catheter is utilized for photothermal delivery with simultaneous IVPA temperature monitoring using the high optical absorption of gold nanorod contrast agents to enable localized heating. Subsequently, the potential role for IVUS/IVPA-guided phototherapy is further expanded through the characterization and in vitro assessment of novel multifunctional theranostic nanoparticles comprised of a gold nanorod core with a degradable, photosensitizer-doped silica shell. Together, the results presented within this dissertation provide a framework for ongoing research into the expansion of IVUS/IVPA imaging as a platform for complimentary diagnosis and local treatment of atherosclerotic plaques using multifunctional theranostic nanoparticle contrast agents. / text

This thesis presents the first work, to our knowledge, to evaluate the potential of Optical Coherence Tomography (OCT) as an intravascular imaging modality to characterize and guide interventions on chronic total occlusions (CTOs) in arteries. An ex vivo imaging study using OCT is presented that characterizes various pathologies associated with peripheral CTOs and illustrates the ability to differentiate between the vessel wall and the occluded lumen. We also found that, while OCT could image approximately 1mm through tissue, it was effective for imaging deeper through clarified microchannels seen within the occluded lumen. While others had reported observing such microchannels within the lumen before, little was known about the global architecture of these channels. This motivated a study of the global morphology of microchannels in occlusions using micro computed tomography (microCT). In this microCT study, we found that microchannels within the occluded lumen of the artery appeared to be continuous over several millimeters. However, these channels also exited the artery frequently, suggesting the need for some form of imaging guidance. As a potential intravascular imaging set-up, a forward-viewing OCT catheter was built. This catheter uses a novel scanning mechanism that combines high voltage and a dissipative polymer to achieve fast compact actuation. Doppler OCT results are presented using this catheter to image flow in the forward direction. Doppler OCT imaging of microchannels in vivo is also shown in a surgically exposed occluded artery in situ.

This thesis presents the first work, to our knowledge, to evaluate the potential of Optical Coherence Tomography (OCT) as an intravascular imaging modality to characterize and guide interventions on chronic total occlusions (CTOs) in arteries. An ex vivo imaging study using OCT is presented that characterizes various pathologies associated with peripheral CTOs and illustrates the ability to differentiate between the vessel wall and the occluded lumen. We also found that, while OCT could image approximately 1mm through tissue, it was effective for imaging deeper through clarified microchannels seen within the occluded lumen. While others had reported observing such microchannels within the lumen before, little was known about the global architecture of these channels. This motivated a study of the global morphology of microchannels in occlusions using micro computed tomography (microCT). In this microCT study, we found that microchannels within the occluded lumen of the artery appeared to be continuous over several millimeters. However, these channels also exited the artery frequently, suggesting the need for some form of imaging guidance. As a potential intravascular imaging set-up, a forward-viewing OCT catheter was built. This catheter uses a novel scanning mechanism that combines high voltage and a dissipative polymer to achieve fast compact actuation. Doppler OCT results are presented using this catheter to image flow in the forward direction. Doppler OCT imaging of microchannels in vivo is also shown in a surgically exposed occluded artery in situ.

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.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal