Thesis (Ph. D.)--Worcester Polytechnic Institute. / Keywords: vulnerable plaque; optical spectroscopy; atherosclerosis; tissue lactate; tissue pH. Includes bibliographical references (p. 109-115).

Thesis (M. Sc.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (leaves 118-130). Also available via the World Wide Web.

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Tannenbaum, Allen; Committee Member: Skrinjar, Oskar; Committee Member: Yezzi, Anthony. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (M. Sc.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (leaves 74-83). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / "December 2006" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

The high density lipoprotein (HDL) receptor Scavenger Receptor, Class B, Type I (SRBI) is a 509 amino acid integral membrane protein which has been shown to have an important role in HDL-mediated reverse cholesterol transport. SR-BI has been shown to mediate selective uptake of cholesterol, and also mediates efflux of cholesterol to HDL as seen in in vitro cell culture studies. SR-BI is abundant in the liver and steroidogenic tissues, and is also present in macrophages, which play an important role in the initial stages of atherosclerotic development. SR-BI has been shown to be protective against atherosclerosis by way of overexpression and knockout (KO) studies in murine atherosclerosis models, including low density lipoprotein receptor (LDLR) knockout mice, apolipoprotein E (ApoE) knockout mice, and human apolipoprotein B (ApoB) transgenic mice. SR-BI/LDLR double knockout (dKO) mice show a 6-fold increase in diet-induced atherosclerosis compared to LDLR single KO controls, and SR-BI/ApoE dKO mice show severe coronary occlusion, myocardial infarction, and premature death on a normal chow diet. In both, plasma total cholesterol levels are significantly elevated, and associated with abnormally large HDL particles. The majority ofSR-BI's atheroprotective effect has been shown to result from plasma cholesterol clearance by way of selective uptake in the liver. Recently, Covey et al showed that elimination of SRBI expression in macrophages of LDLR KO mice resulted in increased diet-induced atherosclerosis. To see if SR-BI in macrophages contributes to the overall atheroprotective effect of SR-BI in ApoE KO mice, presumably by mediating cellular cholesterol efflux to HDL, selective deletion ofSR-BI was induced in bone marrow derived cells of ApoE KO mice using bone marrow transplantation. Female ApoE -/recipient mice were transplanted with either SR-BI +/+ ApoE -/-or SR-BI -/- ApoE -/bone marrow from male donor mice, and fed a high fat diet for 12 weeks. This resulted in significantly increased atherosclerosis in mice transplanted with SR-BI -/- ApoE -/-bone marrow, with a concomitant decrease in cholesterol associated with HDL-sized lipoproteins. No significant differences were seen in plasma total cholesterol levels or levels of cholesterol associated with non-HDL lipoproteins. These data suggest that SRBI in macrophages contributes to SR-BI's overall protective effect against atherosclerosis, and also plays a role in the regulation ofHDL cholesterol, in ApoE deficient mice. / Thesis / Master of Science (MSc)

Five atherosclerotic carotid and femoral plaques were sliced longitudinally. Each section was analysed for the concentrations of neopterin, α-tocopherol, TBARS, DOPA, dityrosine, protein carbonyl, protein and cholesterol. The spatial concentrations of the oxidative and inflammatory markers were diverse across and between the individual plaques suggested by the lack of consistent correlations and trends. The only correlation that occurred twice within the individual plaques was a positive correlation between α-tocopherol and cholesterol levels. In the combined plaque analysis which included data from eight previously studied plaques, neopterin, protein carbonyl and protein concentrations all had significant positive correlations and α-tocopherol concentrations positively correlated to cholesterol and negatively to TBARS. Thus overall the level of protein may influence protein carbonyl concentration and α-tocopherol may provide an antioxidant effect towards lipid peroxidation. Furthermore, the plaques were divided into three zones, pre-bifurcation, bifurcation and post-bifurcation, associated with shear stress levels. The neopterin concentrations were significantly high within the pre- and post-bifurcation region and the opposite trend occurred with the to peroxyl radical driven TBARS levels. The protein and cholesterol content in the postbifurcation was high, possibly due to the low and/or oscillatory shear stress occurring at these sites. The overall composition of the plaque, either thrombosed, heavily calcified or neither, also identified significant trends in marker concentrations between the plaques. The calcified plaques had significantly low levels of protein, cholesterol, α-tocopherol, DOPA and dityrosine whereas the thrombosed plaques had significantly high protein, α-tocopherol and dityrosine concentrations. The medication and symptoms presented by the patient had no major influence of the overall concentration of the markers within the plaques. Therefore even though individually the plaques have varied biochemical compositions, common influences were dictate the spatial and overall concentration of the markers within and across the plaques. Further potential markers were investigated for detection within plaque. AAS and GGS for replacement of the protein carbonyl assay as a more specific marker for protein oxidation, as well as the oxysterol 7-ketocholesterol detected simultaneously during α-tocopherol analysis. The 7-ketocholesterol would increase the information on lipid oxidation occurring in the plaque without increasing the volume of the limited homogenate required for the analysis. Investigation was also carried out on the mechanism of protein oxidation in human plasma that may provide mechanisms and interactions to protein oxidation within plaques.

Abstract not available

Atherosclerotic plaque disruption leading to thrombosis has traditionally been studied as a rupture of a thin fibrous cap over a lipid-laden necrotic core. However, two noteworthy categories of plaques that do not rupture have presented themselves: 1) in mice, plaque rupture is rare if not absent, and 2) in humans, some plaques erode and form a thrombus without rupturing. Current understanding of the biomechanical differences between plaques that rupture and those that do not is incomplete. In this research, we used patient-specific computational biomechanics tools to study differences among these groups. Lesion-specific solid mechanical modeling of murine plaques revealed that the relative distribution of stresses differs considerably between mice and man. In human vulnerable plaques, peak stresses are on the thin fibrous cap over a necrotic core, but in mice the highest stresses are in the media and adventitia, away from the plaque. Whereas atherosclerotic human arteries usually experience neointima formation around the entire circumference of the vessel, mouse plaques tend to be punctate and adjacent lesion-free regions. The difference in mechanical environment suggests that plaque rupture, if possible in mice, is likely not driven by mechanics in the same manner as humans. Similar mechanical modeling of human ruptured and eroded plaques and comparison to histological staining revealed that ruptured plaques exhibit increased levels of inflammatory markers in response to strain in ruptured plaques, but no such response was observed in plaque erosion. This suggests that treatment of inflammation, a current paradigm for care of atherosclerotic patients, may not be an effective approach to mediate plaque erosion. Computational fluid dynamics modeling of patients with plaque erosion revealed no relation between wall shear stress magnitude or direction, further suggesting that the mechanism of plaque erosion differs considerably from that of plaque rupture. Together, these findings suggest that biomechanics can help explain why not all plaques rupture and that different clinical approaches are necessary to address different phenotypes of lesions.

Cardiovascular Disease (CVD) continues to be the leading cause of death in western countries according to the statistics update by the American Heart Association. Atherosclerosis is estimated to be responsible for a large portion of CVD and affects 60 million people in the United States. Accurate diagnosis is crucial for proper treatment planning. Currently, the clinical standard screening technique for diagnosing atherosclerosis is x-ray angiography, which reveals the residual lumen size. X-ray angiographic images possess good resolution and contrast, however, lumen size is not always a proper criterion given the positive remodeling nature of atherosclerotic plaques. In the past decade, it has been shown that most plaques responsible for a fatal or nonfatal myocardial infarction are less than 70% stenosed. Clinical data support the idea that plaques producing non-flow-limiting stenoses account for more cases of plaque rupture and thrombosis than plaques producing a more severe stenosis. Due to this fact, plaque itself must be imaged in order to assess its vulnerability. A wealth of literature suggests that multicontrast MRI has the potential of characterizing plaque constituents, and thus is a promising technique for plaque imaging. Because of the technical difficulties associated with in-vivo plaque imaging and the fact that our research was aimed at developing new methodologies, our approaches was to image excised coronary arteries under simulated in-vivo conditions in a tissue culture chamber. It is shown by this research that automatic plaque characterization techniques developed under ex-vivo conditions still apply for in-vivo studies. Based on this finding, an automatic plaque characterization technique using multicontrast MRI was developed. Furthermore, "shared k-space" reconstruction techniques were interrogated to assess their feasibility in accelerating multicontrast MRI acquisition. Results show that these techniques are promising in accelerating multicontrast MRI acquisitions.