Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Afhandling--Copenhagen. / Summary in English and Danish. Includes bibliographical references.

Afhandling--Copenhagen. / Summary in English and Danish. Includes bibliographical references.

Around 170000 patients worldwide receive cardiac valve substitutes each year. Valve replacement with mechanical or bioprosthetic devices enhances patient survival and quality of life. Bioprosthetic valves have a significant advantage over mechanical valves: they do not necessarily require long-term anticoagulant therapy however, dystrophic calcification can lead to early failure. The actual mechanism of calcification is still poorly understood despite several established possible factors associated with it. Amongst these is the glutaraldehyde pre-treatment of the valves during their manufacture. Glutaraldehyde has been used for the treatment of bioprosthetic valves for the last thirty years, as a cross-linking agent and a sterilant. Whilst it is assumed to introduce stable inter- and intra-fibrillar collagen cross-links, which contribute to the durability of these valves, the specific chemistry of the fixation process is not fully understood. Additionally, glutaraldehyde is thought to be involved somehow in the process of dystrophic calcification of these same bioprosthetic valves. The primary aim of this study was to gain a greater understanding of the chemistry involved in the treatment of collagenous valve tissue with glutaraldehyde. Amino acids, peptides and proteins were thus used to mimic the effect of the glutaraldehyde treatment and to model potential reactions involved in such treatment. Techniques such as MALDI-TOF MS, ESI MS, NMR, FTIR-ATR and Raman spectroscopy were utilised to study the products of the glutaraldehyde reaction and their relationship with the calcification process. Data obtained from the products of the reactions between glutaraldehyde and model compounds showed the presence of: aldol and aldol/Michael condensation products of glutaraldehyde, Schiff base moieties (including cross-links) and various cyclisation products incorporating pyridinium and dihydropyridine ring structures. Some of these structures are in agreement with the literature, whilst others are essentially new structures that have never been proposed. Glutaric acid, used to mimic the oxidation of glutaraldehyde that can occur in-vivo, was shown to have the ability to form complexes with cations such as calcium in-vitro. A similar result was found with aqueous dilute solutions of glutaraldehyde (similar concentrations to the ones used in valve manufacture), thus leading to the hypothesis of its strong role in the initiation of calcification in-vivo. However, an extrapolation of these results to the role of the nucleophilic groups of amino acids or peptides, that could behave as the collagen macromolecule, was difficult to assess using FTIR because of the complex infrared spectra. However some findings corroborated the hypothesis that amino acids of the collagen tissue may also play a role in the initiation of calcification. Secondly, methodology was developed to allow successful analysis of tissue calcification using environmental scanning electron microscopy (ESEM). This is thought to be an important step in the analysis of tissues in their native state. Investigation of the calcification process with samples from clinical investigations (explanted human calcified valves), in-vivo screening (rat subcutaneous implantation model) and in-vitro screening (pericardial tissue incubated in metastable calcification solution) was thus undertaken using ESEM, along with other techniques such as FTIR-ATR, Raman, XRD spectroscopy and ICP-OES. The data revealed both similarities and differences between in-vivo and in-vitro calcification, although the process is unequivocally different. Late calcific deposits were assigned to poorly crystalline hydroxyapatite with high Ca/P ratios due to the probable presence of carbonate and possibly cations such as silicon and magnesium. A picture of the onset of mineralisation was hypothesised involving precursors, containing various amounts of calcium and phosphate, along with the incorporation of magnesium and silicon. These precursors phases evolved with time of implantation to the poorly crystalline form of hydroxyapatite found in the late stage of calcification. This work has provided an insight into how glutaraldehyde reacts with valve tissue and a possible explanation as to why valves fail by non-calcific or calcific mechanisms. A new approach to the study of calcified valve tissue has also been developed using ESEM methodology.

Pas de résumé en français / Pas de résumé en anglais

This dissertation describes an experimental study on the patterning of thin films and spin valve devices. Initially the change in the magnetisation reversal of ferromagnetic Ni80Fe15Mo5 thin films was investigated as the shape anisotropy was increased using optical lithography to pattern wire arrays. These structures show a progressive increase in coercivity and a transition between single and two-stage reversal with increasing milling depth. A similar patterning technique was applied to unpinned (Ni80Fe20/Cu/Ni80Fe20) pseudo spin valve (PSV) structures in order to enhance the coercivity of one of the ferromagnetic layers. The increased coercivity induced by micropatterning changed the natural similarity of the magnetic layers and the structure exhibited a small spin valve response. These initial measurements were carried out with separate milling and electrical characterisation steps. However, it was decided that it would be ideal to design a technique to do in-situ magnetoresistance measurements during milling. This meant that the samples could be milled and characterised in the same step, leading to a much cleaner and more efficient process. In-situ magnetoresistance measurements were carried out during micropatterning of PSV devices, and the measurements showed the evolution in the electrical response as wire structures were gradually milled through the thickness. Contrary to what was expected, the structures showed a maximum spin valve response when fully milled through. The effect of further increasing the shape anisotropy by reducing the wire width, and changing the material properties in the PSV structure has also been investigated. MR measurements were taken as the temperature was increased from 291K to 493K, and the results show that the patterned PSV structures have a better thermal stability than exchange biased spin valves with an IrMn pinning layer. The experiment was extended to the nanoscale, and the results show that a significant increase in MR is not observed despite the fact that the magnetic configuration tends more towards single domain. This is thought to be due to an increase in the initial resistance of the structures. A small increase in MR was observed as the wire width was decreased from 730 to 470 nm, although the spin valve response is heavily dependent on the gallium dosage density during patterning in the Focused Ion Beam (FIB). Micromagnetic simulations were carried out, which agree with the experimental results and showed the change in the magnetisation reversal from rotation to switching as the dimensions were reduced on the nanoscale.

No description available.

No description available.

The aortic valve (AV) functions in arguably the most demanding mechanical environment in the body. The AV experiences fluid shear stress, cyclic pressure and mechanical strain in vivo. Recent evidence has shown the progression of degenerative aortic valve disease (AVD) to be an active cellular mediated process, altering the conception of the AV as a passive tissue. AVD has shown a strong correlation with altered hemodynamics and tissue mechanics. Aortic valve endothelial cells (AVECs) line the fibrosa (aortic facing) and ventricularis (left ventricle facing) surfaces of the valve. AVECs sense and respond to circulating stimuli in the blood stream while maintaining a non-thrombogenic layer. AVEC activation has been implicated in the initiation and progression of AVD, but the role of cyclic strain has yet to be elucidated. The hypothesis of this dissertation is that altered mechanical forces have a causal relationship with aortic valvular endothelial cell activation. To test this hypothesis 1) the role of in vitro cyclic strain in regulating expression of pro-inflammatory adhesion molecule was elucidated 2) cyclic strain-dependent activation of side-specific aortic valve endothelial cells was investigated 3) a novel stretch bioreactor was developed to dramatically increase the ability to correlate valvular endothelium response to physiologically relevant applied planar biaxial loads. The results from this study further the field of heart valve mechanobiology by correlating AVEC physiological and pathophysiological function to cellular and tissue level strain. Elucidating the AVEC response to an altered mechanical environment may result in novel clinical diagnostic and therapeutic approaches to the initiation and progression of degenerative AVD. Furthermore, a cardiovascular health outreach program, Bulldogs for Heart Health, has been designed and implemented to combat the startling rise in childhood obesity in the state of Mississippi. It is the hope that these results, novel methods, and outreach initiatives developed will significantly impact the study of the mechanobiology of the aortic valve endothelial cell and potential treatment and prevention of cardiovascular disease.

INTRODUCTION: The ever-changing landscape of the US health care system is characterized by innovation and high-level care, yet it remains in a state of crisis. With the system seemingly locked in this dire state of rising costs, it becomes increasingly important to take costs into account when deciding between multiple treatments for a particular disease by undertaking cost-effectiveness analysis (CEA) studies. In the present study, a model for mitral regurgitation (MR)—a cardiac valvular disease for which multiple treatment options exist with varying degrees of effectiveness, making it a suitable candidate for CEA —was developed to determine the cost-effectiveness of the four main treatments of medical therapy (MT), mitral valve repair (MVR), mitral valve replacement with a mechanical valve (MVPm) and mitral valve replacement with a bioprosthetic valve (MVPb). The goal of the present undertaking was to determine the most cost-effective treatment option for a reference patient given patient-specific inputs to test the functionality of the developed model. METHODS: Input values for costs, probabilities of event’s occurrences and quality-adjusted life-year (QALY) estimates for each treatment option were first obtained from databases and relevant literature. These values were then standardized to account for source variability and input into a decision tree (DT) model created specifically for the present analysis that included branches for each of the four potential interventions, from each of which were three potential outcome arms representing the potential endpoints of each treatment: death, alive with complications and alive without complications. The costs, probabilities and QALY –values of each of the four complications of interest in the study—atrial fibrillation (AFib), stroke, congestive heart failure (CHF) and reoperation—were combined and averaged to create a unified endpoint for the alive with complications branches of the DT. Following the development of the model, the relevant cost, probability and utility values were used to run a simulation to test the functionality of the model using values associated with a fictional 65-year-old Medicare-covered patient with chronic MR to act as a representative of a sizable real-life population. The model results were then used to calculate the incremental cost-effectiveness ratio (ICER)—the standard comparison used in CEA—between treatment options to determine the most cost-effective among them. Following this simulation, one-way sensitivity analyses (SA) were conducted to determine the susceptibility of the result to variations in select input values. RESULTS: The probability-weighted costs of MT, MVR, MVPm and MVPb were found to be $40,387, $60,249, $76,293 and $74,320, respectively, with respective probability-weighted QALYs of 4.298, 4.740, 4.428 and 5.119. The calculation of ICERs from these values led to the conclusion that MVPb dominated all other treatments and had an ICER of $41,370/QALY gained over MT, which was treated as the baseline treatment option. The societal willingness-to-pay (WTP) threshold used in the present study ($62,000/QALY gained) was greater than the ICER, indicating that MVPb is a cost-effective solution to society. The results of the SA indicated that variations in mortality rate within the ranges in the relevant literature have significant effect on the cost-effectiveness of the interventions, with roughly a 4.74% increase in mortality for MVPb or a 5.09% decrease in the rate of MT leading MVPb to be considered cost-ineffective. CONCLUSIONS: The simulation study concluded that for the 65-year-old reference case, MVPb was the most cost-effective option and the additional cost to society was deemed less than society’s WTP for the additional health benefit. The successful simulation of the model indicates it may hold real-world potential and be applicable to numerous other situations with varying input values. Further research into more accurate input values for a larger number of variables need to be determined in order to increase the accuracy and maximize the applicability of the present model. In addition, the model will require further complication via the inclusion of an increasing number of variables to allow for a more accurate determination of cost-effectiveness in a wider range of health scenarios. Thus, the current model described here and a further evolved future model hold great potential for use all across health care in order to help contain rising costs plaguing the current health care system in the United States.