No description available.

No description available.

No description available.

Stroke is caused by atherosclerosis (furring up) of the carotid artery in up to 40% of cases. This area of narrowing'can be treated to reduce future stroke risk. Traditionally the narrowing has been treated by vascular surgeons performing an open operation on the artery - termed carotid endarterectomy (CEA) - which involves working on the artery under direct vision. The artery needs to have the flow of blood stopped within it for a variable period of time in order to completely remove the lesion. More recently a less invasive approach has gathered support. In carotid artery angioplasty and stenting (CAS - performed by vascular surgeons, radiologists and cardiologists) a wire is passed via the femoral artery across the narrowed segment of artery. A balloon is then used to stretch the artery and plaque, followed by the insertion of a stent - a sort of wire scaffold to support diseased area of the vessel and overcome the elastic recoil of the artery. Clinical outcome and complication rates for both procedures have been declining, prompting the search for more subtle and sensitive measures. This thesis describes what is known so far about the sub-clinical outcomes of each procedure, and analyses the results of each technique as performed at St Mary's Hospital, London. A multimodal approach has been used to achieve this aim. Trans-cranial Doppler has been performed to record the number of presumed emboli impacting on the brain, as well as measuring intra-operative changes in blood flow to the brain. Biomarkers of brain injury that are well recognised have been used, as have newer tests that are still under development by biomedical research companies. ELISA has formed the mainstay of this component of the comparison of CEA and CAS. Changes in the functional ability of the patient's brain have been assessed using a robust battery of . neuropsychometric tests performed before and after the surgical intervention. This has been studied previously, but never according to the consensus guidelines produced by cardiac surgeons investigating similar changes after various forms of coronary artery bypass grafting. Little is known about the effect of CEA versus CAS on the intra-cerebral blood flow. The imaging component of this study used specialist Computed Tomography Perfusion scans to take measurements, and note changes, in brain blood flow in the short and mid term post-operatively. In the various chapters each of these outcome measures have been correlated to the other. For example, determining whether a rise in biomarkers of brain injury can predict which patient may develop a post-operative neuropsychometric deficit, or whether those with enhanced neuropsychometric performance have improved brain perfusion. The later experimental chapters involve radiological and histopathological analysis of carotid plaques to try and help determine which ones pose a greater risk to the patient in terms of clinical and subclinical neurological deficit. Radiological appearances of carotid plaques are also correlated with electron microscopic findings of the filters used to catch debris dislodged during the CAS procedure, thereby preventing peri-operative stroke. The final chapter summarises some of the thesis' key findings and highlights some potential areas for exploitation by future research.

During the last four decades, there has been a significant improvement in the management of coronary artery disease (CAD). These improvements have been achieved through the following advances: use of angioplasty with a stent; and, the development of drug eluting stents (DES). However, the occurrence of in-stent stenosis (ISS) following these procedures results in failure rates of 5-25% depending on the procedure. DES inhibit the proliferation and migration of vascular smooth muscle cells (VSMCs), the main culprit of restenosis and ISS. Fully functional endothelial cells inhibit potential side effects of angioplasty such as thrombus formation and VSMC proliferation and migration. Many studies have suggested that damage to the EC layer and inflammation are important factors that underlie ISS. Inflating the balloon and deploying the stent injures the vessel wall and induces an acute inflammatory response. Thus, anti-inflammatory agents might offer a novel approach for overcoming ISS. Previous studies in our laboratory have shown that non-steroidal anti- inflammatory drugs (NSAIDs) inhibit the proliferation ofVSMCs when used in non-toxic concentrations. In this project, we have investigated the effects of specific NSAIDs on EC proliferation and migration as well as on VSMC migration and phenotype and we try to address the possible mechanisms of actions involved. Our in vitro data indicate that the concentrations of ibuprofen required to inhibit EC migration are higher than those required to inhibit VSMC migration. The effects of aspirin and ibuprofen on proliferation and migration ofVSMCs may be partially mediated via PPARy through the regulation of integrin expressions, as the pretreatment with synthetic antagonist for PP ARy (GW9662 (1 ~M)), or natural antagonist for PPARy (PGF2a(100nM)) partially rescue the inhibitory effects of aspirin and ibuprofen; whilst, COX may mediate the effects of ibuprofen on VSMC proliferation and migration, but not of aspirin, as the exogenous PGF2a (10nM) could rescue the inhibitory effect of ibuprofen. Aspirin and ibuprofen switch VSMC phenotype from a synthetic (pathological) one into a contractile (healthy) phenotype. An IV ibuprofen drug-eluting stent may provide a novel therapeutic strategy for inhibiting an inflammatory response that promotes VSMC differentiation and leads to inhibition of proliferation and migration ofVSMCs without limiting healing of the EC layer.

Current drug-eluting stents used in the treatment of myocardial ischaemia are unsuitable for all lesion types, and have been associated with endothelial The aim of this work was to develop a novel prostacyclin analogue eluting stent, which would represent a significant advance on existing devices by virtue of a superior biological profile, and optimal release kinetics. The functional effects of leading prostacyclin analogues were assessed on isolated pig coronary and rabbit iliac arteries. AFP07 produced relaxation and contraction in both arteries, whilst cicaprost produced relaxation with no evidence of contraction. Antagonists were used to demonstrate the presence of prostanoid IP receptors mediating relaxation, and contractile EP] and EP3 receptors in each artery bed. Differences in functional responses between analogues were found to be due to differences in activity at E type receptors, with cicaprost being the most selective IP receptor agonist studied.

No description available.

Computer modelling provides powerful and flexible methodology for the predictive simulation of complex flow systems. However, despite the versatility of this methodology quantitative modelling of blood flow through human heart presents a difficult and challenging problem. Although derivation of appropriate governing equations representing combined blood flow and soft solid deformation of the tissues of heart valves does not pose any particular theoretical problems. Accurate solution of such equations is not a trivial matter. Another source of complexity in the modelling of a biological system such as blood flow/heart valve deformation is the uncertainties associated with the available physical and rheological data that are required to obtain quantitative simulations. Variations between individual situations is usually considerable which precludes broad generalizations. In this research project an attempt has been made to identify the most important aspects of the blood flow through human heart valves. This has led to making rational approximations which render the development of a model for the described system both possible and meaningful. The main focus have been on the best use of available software and mathematical schemes. In cases where existing computational or mathematical tools were considered to be incapable of tackling realistic situations new techniques have been developed. It has been shown that using the modelling methodology which is developed in this research study a number of important and reliable conclusions about the operation of heart valves can be drawn. This information can in turn be used to design artificial heart valves.

Austenitic stainless steel designed for implant applications is used to fabricate balloon expandable coronary stents. The alloy was not designed for this purpose but has been found to work well except for relatively low radiopacity in the energy range used for stent deployment, typically 80kV to 100kV. Stents made of more dense elements such as tantalum exhibit high radiopacity in this energy range. Low radiopacity is due to a combination of tubular stents having a thin wall (strut) thickness (less than 0.13mm) and the alloy being comprised of low-density elements, approximately 2/3 iron and 1/3 chromium and nickel. To retain the desired thickness and increase radiopacity, alloy density may be increased by partial substitution with dense element(s). The new alloy must maintain the biocompatibility, corrosion resistance, non-ferromagnetic structure, strength, ductility, and fatigue- and fracture-resistant characteristics that made the original alloy attractive to stent designers. Coronary stents are subject to intensive review by regulatory authorities prior to being approved for human use, thus stent designers are hesitant to depart from accepted standards in selecting new alloys. Revising an existing alloy is the preferred approach to achieve subtle feature changes. A set of criteria was set that maintained chromium, nickel, and molybdenum within prescribed compositional ranges and diminished iron to its minimum level, allowing platinum to be substituted for approximately 1/3 the total elemental weight (wt%). Above 20wt% platinum, undesirable precipitates were found. An alloy containing 20wt% platinum, in the form of foil and at a thickness of 0.127mm, was found to be free of precipitates not found in the base or original alloy and to provide approximately 20% radiopacity increase at 80kV and 15% radiopacity increase at 100kV, exceeding minimum programme goals at 80kV and equaling those at 100kV.

No description available.