Nous avons observé dans une cohorte de 259 patients atteints d’hypercholestérolémie familiale (HF) hétérozygote et de 208 témoins normolipidémiques que le type de mutation causant l’HF était associé à des changements significatifs dans la taille de la principale sous-population de particules LDL. Les patients porteurs d’une mutation récepteur-négatif présentaient un profil lipidique plus défavorable que les patients porteurs d’une mutation récepteur-défectif et que les témoins. Dans la même cohorte, nous avons associé l’HF avec la présence de plus petites particules HDL, qui sont plus rapidement éliminées de la circulation et qui ne peuvent alors plus assurer correctement leur rôle dans le transport inverse du cholestérol. Finalement, nous avons associé l’HF avec des niveaux élevés de résidus de chylomicrons. Les résidus de chylomicrons participent au développement de l’athérosclérose, tout comme les LDL. De plus, ces résultats soulignent le rôle du récepteur des LDL dans la clairance de ces résidus de la circulation chez l’humain. Dans un second volet, nous avons examiné le métabolisme de l’apoprotéine (apo) B-48 dans le diabète de type 2 (DM2). Nous avons observé que les patients atteints de DM2 présentaient des niveaux élevés d’apoB-48 en circulation, dus à une production intestinale élevée et à un catabolisme ralenti. Nous avons par la suite examiné l’effet d’un traitement au fénofibrate ou à l’atorvastatine sur la cinétique de l’apoB-100 et de l’apoB-48 et sur l’inflammation, le stress oxydatif et l’adhésion monocytaire dans le DM2. L’atorvastatine et le fénofibrate ont été également efficaces pour réduire les triglycérides plasmatiques. L’atorvastatine a principalement augmenté le catabolisme des VLDL et des IDL en augmentant le catabolisme via les récepteurs cellulaires, alors que le fénofibrate a principalement augmenté le catabolisme des VLDL, des IDL et des chylomicrons en augmentant la lipolyse. L’atorvastatine a réduit les niveaux d’apoB-48 en diminuant la production intestinale. L’atorvastatine a été efficace pour réduire l’inflammation, le stress oxydatif et l’adhésion monocytaire dans le DM2, alors que le fénofibrate n’a été efficace que pour réduire un seul marqueur d’adhésion monocytaire. Par contre, le fénofibrate a été associé à une augmentation de cholestérol-LDL et de la phospholipase A2-IIA. / We observed in a group of 259 patients with heterozygous familial hypercholesterolemia (FH) and 208 normolipidemic controls that the type of mutation causing FH was associated with changes in the LDL peak particle diameter. Patients carrying a negative-receptor mutation displayed a more deteriorated profile than patients carrying a defective-receptor mutation and than controls. In the same group, we observed that FH was associated to smaller HDL particles, which are more rapidly cleared from circulation and can no longer correctly participate to the reverse cholesterol transport pathway. Finally, we observed that FH is associated to increased fasting levels of chylomicron remnants, which participate to atherosclerosis development, in the same way as LDL do. Moreover, these results underline the role of the LDL receptor in these remnants catabolism. In the second part of the work presented, we examined the metabolism of apoprotein (apo) B-48 in type 2 diabetes mellitus (DM2). We observed that patients with DM2 had increased apoB-48 levels, due to marked increased intestinal production and decreased catabolism. We also observed the effects of a treatment with fenofibrate or atorvastatine on apoB-48 and apoB-100 kinetics and on inflammation, oxidative stress and monocytes adhesion in DM2. Atorvastatin and fenofibrate were equally effective to lower plasma triglyceride levels. Atorvastatin increased VLDL and IDL catabolism by increasing receptor-mediated catabolism while fenofibrate increased VLDL, IDL and chylomicrons catabolism by increasing lipolysis. Atorvastatin decreased apoB-48 levels by decreasing production. Atorvastatin was potent to reduce inflammation, oxidative stress and monocyte adhesion while fenofibrate was potent to reduce only one monocytes adhesion marker. However, fenofibrate increased LDL-C and phospholipase A2-IIA levels.

Akademisk avhandling--Lund. / Extra t.p., with thesis statement, inserted. Bibliography: p. 11-14.

Akademisk avhandling--Lund. / Extra t.p., with thesis statement, inserted. Bibliography: p. 11-14.

Plaque rupture with superimposed thrombosis is the primary cause of acute coronary syndromes of unstable angina, myocardial infarction and sudden death. Although intensive studies in the past decade have shed light on the mechanism that causes unstable atheroma, none has directly addressed the clinical observation that most myocardial infarction (MI) patients have moderate stenoses (less than 50%). Considering the important role the arterial wall compliance and pulsitile blood flow play in atheroma rupture, fluid-structure interaction (FSI) phenomenon has been of interest in recent studies. In this thesis, the impact is investigated numerically of coupled blood flow and structural dynamics on coronary plaque rupture. The objective is to determine a unique index that can be used to characterize plaque rupture potential. The FSI index, developed in this study for the first time derives from the theory of buckling of thin-walled cylinder subjected to radial pressure. Several FSI indices are first defined by normalizing the predicted hemodynamic endothelial shear stress by the structural stresses, specifically, by the maximum principal stress (giving the ratio ), and the Von Mises stress (giving the ratio ). The predicted at the location of maximum (i.e { }) denoted , is then chosen to characterize plaque rupture through systematic investigation of a variety of plaque characteristics and simulated patient conditions. The conditions investigated include varying stenosis levels ranging from 20% to 70%, blood pressure drop ranging from 3125 Pa/m to 9375 Pa/m, fibrous cap thickness ranging from to , lipid pool location ranging from the leading to the trailing edge of plaque, lipid pool volume relative to stenosis volume ranging from 24% to 80%, Calcium volume relative to stenosis volume ranging from 24% to 80% and arterial remodeling. The predicted varies with the stenosis severity and indicates that the plaques investigated are prone to rupture at approximately 40-45% stenosis levels. It predicts that high pressure significantly lowers the threshold stenosis rate for plaque rupture. In addition, the plaque potential to rupture increases for relatively thin fibrous cap, lipid core located near the leading plaque shoulder, and dramatically for relative lipid pool volume above 60%. However, calcium deposit has marginal effect on plaque rupture. Overall, the predicted results are consistent with clinical observations, indicating that the has the potential to characterize plaque rupture when properly established. In the appendix, the unsteady flow in a collapsible tube model of a diseased artery is solved analytically. The novelty of our approach is that the set of governing equations is reduced to a single integro-differential equation in the transient state. The equation was solved using the finite difference method to obtain the pressure and compliant wall behavior. The analytical approach is less computer-intensive than solving the full set of governing equations. The predicted membrane deflection is quite large at low inlet velocity, suggesting possible approach to breakdown in equilibrium. As the transmural pressure increases with wall deflection, bulges appear at the ends of the membrane indicating critical stage of stability, consistent with previous studies. An increase in wall thickness reduces the wall deflection and ultimately results in its collapse. The collapse is due to breakdown in the balance of wall governing equation. An increase in internal pressure is required to maintain membrane stability.

No description available.

published_or_final_version / Dentistry / Master / Master of Philosophy

No description available.

Atherosclerosis is a complex inflammatory disease in which oxidative stress is a major protagonist in the development and progression of the atherosclerotic plaque. All biochemical analysis studies of plaque over the past fifteen years have been carried out on whole plaque with no attempt to localise sites of differing biochemical conditions. This study set out to identify in oxidation levels and inflammatory markers in relation to spatial localisation within the plaque. Advanced plaque samples removed during endarectomy were obtained from the Christchurch Hospital Department of surgery and were dissected into 3-5 mm sections along the longitudinal axis prior to analysis. Samples were analysed for vitamin E, neopterin, total cholesterol and markers of oxidative damage to protein and lipids. Neopterin is a marker of inflammation as it is released by activated macrophages yet it has never been measured in plaques. Initial analysis showed that the acid precipitation method for removing protein from samples prior to HPLC neopterin analysis was causing a significant loss in neopterin. A new acetonitrile based protein removal procedure was developed. Markers of oxidative stress and inflammation where shown to vary across the length of an atherosclerotic plaque. This variation allows for localized incidences of high and low radical flux and microenvironments of depleted antioxidants or areas in which the prooxidative actions of molecular components are favoured. Significant correlations were rarely seen in more then one plaque and trends found in the combined data set generally did not hold true in individual plaques. This reflects upon the complexity of the disease, especially at this advanced stage in which the biochemical morphology of individual plaques is extremely diverse. Separation of the plaques into pre-, post-, and bifurcation areas did produce some trends. These can be related to shear stress variations in the blood flow; further investigations into the biochemical differences between these areas may provide a better understanding of the growth and development of the atherosclerotic plaque.

No description available.

No description available.