No description available.

No description available.

Background Superparamagnetic particles of iron oxide (SPIO) are part of a novel and exciting class of ‘smart’ magnetic resonance imaging (MRI) contrast agents that are taken up by inflammatory cells. Ultrasmall SPIO (USPIO; ~30 nm diameter) can be used to assess cellular tissue inflammation and SPIO (80-150 nm) have the potential to be used to label cells ex vivo for in vivo cell tracking studies. Objectives The aims of the thesis were therefore (i) to develop and validate quantitative MRI methodology for assessing SPIO uptake within tissues, (ii) to demonstrate USPIO accumulation within the aortic wall and its implications in patients with abdominal aortic aneurysms (AAA), and (iii) to develop and apply a Good Manufacturing Practice (GMP) compliant method of SPIO cell labelling in healthy volunteers. Methods Patients with asymptomatic AAA >4.0 cm in diameter were recruited. Imaging sequences were optimised in eight patients using a 3 tesla MRI scanner. Data were analysed using the decay constant for multi echo T2* weighted (T2*W) sequences (T2*) or its inverse (R2*) and the repeatability of these measurements was established. A further twenty-nine patients underwent MRI scanning before and 24- 36 hours after administration of USPIO. T2 and multi echo T2*W sequences were performed and ultrasound-based growth rate data were collected. Operative aortic wall tissue samples were obtained from patients undergoing open surgical aneurysm repair. A GMP compliant protocol was developed for labelling cells with SPIO for clinical cell tracking studies. The effects of SPIO-labelling on cell viability and function were assessed in vitro. A phased-dosing protocol was used to establish the safety of intravenous administration of SPIO-labelled cells in healthy volunteers. The feasibility of imaging cells at a target site in vivo following local or systemic administration was assessed. Tracking of SPIO-labelled cells to a target site was investigated by inducing an iatrogenic inflammatory focus in the skin of the anterior thigh of healthy volunteers, following which autologous SPIO-labelled cells were administered and their accumulation was assessed using MRI scanning and histology of skin biopsies. Results Robust and semi-quantitative data acquisition and image analysis methodology was developed for the assessment of SPIO accumulation in tissues. In patients with AAA, histological analysis of aortic wall tissue samples confirmed USPIO accumulation in areas of cellular inflammation. USPIO-enhanced MRI detected aortic wall inflammation and mural USPIO uptake was associated with a 3-fold higher aneurysm expansion rate. Human mononuclear cells were labelled with SPIO under GMP compliant conditions without affecting cell viability or function. Both local and intravenous administration of SPIO-labelled cells was safe and cells were detectable in vitro and in vivo using a clinical MRI scanner. SPIO-labelled cells tracked to a focal iatrogenic inflammatory focus following intravenous administration in humans and were detectable on MRI scanning and histological examination of skin biopsies. Conclusions SPIO contrast agents have an extensive range of potential clinical applications. USPIO uptake in the wall of AAA appears to identify cellular inflammation and predict accelerated aneurysm expansion. This is therefore a promising investigative tool for stratifying the risk of disease progression in patients with AAA, and may also be considered as a biomarker for response to novel pharmacological agents. The ability to label cells for non-invasive cell tracking studies would facilitate the further development of novel cell-based therapies and would enable assessment of dynamic inflammatory processes through inflammatory cell tracking.

No description available.

The management of the asymptomatic patients with severe aortic stenosis (AS) is challenging; clinicians have to balance the risks of early surgery against the risk that irreversible myocardial damage may occur with a conservative management strategy. It has become increasingly apparent that prognosis in asymptomatic AS depends not only on the degree of valvular stenosis, but also on the myocardial response to pressure overload and understanding the mechanisms of myocardial decompensation may help to guide management in the future. The degree of myocardial fibrosis, microvascular dysfunction, hypertrophy and left ventricular (LV) geometry may all play important roles. However, current guidelines for management of asymptomatic AS limit assessment of the myocardium to the measurement of ejection fraction with echocardiography. More advanced techniques may provide greater information that could be clinically useful. This thesis seeks to further our understanding of the mechanisms of the myocardial response to AS, using Cardiac Magnetic Resonance (CMR) in patients with moderate and severe AS. Myocardial perfusion in AS is examined in chapter 3. The results show that CMR first pass perfusion can be carried out safely and is well tolerated by AS patients. Microvascular dysfunction in these patients was associated with age, exercise time and markers of diastolic dysfunction. Myocardial strain is examined in chapter 4, utilizing a new software tool to look at strain throughout the left ventricle, and also to explore the relationship between strain and myocardial fibrosis. The results show that there are significant variations in circumferential strain measurements, depending on slice position in the LV, and also that there was no relationship found between strain and the degree of LV fibrosis. In chapter 5, the potential of CMR T1 mapping to identify fibrosis is examined using a new shortened non-contrast sequence (ShMOLLI - Shortened Modified Look-Locker Inversion) developed in our unit. CMR T1 values were validated against histological quantification of myocardial fibrosis in a large group of moderate and asymptomatic AS. A good correlation was found between ShMOLLI derived T1 values, with T1 values increasing with the severity of AS. The clinical value of measuring myocardial perfusion and LV global strain is examined in chapter 6 by linking these to prognosis. Measurement of circumferential strain could predict prognosis in asymptomatic AS, but myocardial perfusion showed poor ability to predict events. In conclusion, this thesis offers further insights into the changes that occur in the myocardium of patients with asymptomatic moderate and severe AS, using established and new CMR techniques. The clinical value of measuring these CMR parameters to aid risk stratification is shown, and the future potential for monitoring new therapies in these patients is discussed in the final chapter.

M.Cur. / The natural progress of an abdominal aortic aneurysm is enlargement and rupture. The incidence of abdominal aortic aneurysms has increased in the past 30 years and up to 50% of the patients with untreated aneurysms will die due to rupture within 5 years. Open surgery is effective in the prevention of rupture and can be performed with a mortality of 2 -5% in most cases. However, patients with aneurysms are generally older and have associated medical co-morbidities, which increase the risk in surgical intervention. In view of these associated risks with open surgery for abdominal aorta aneurysm repair, a less invasive option such as endoluminal stent-grafts, are often preferred. This new, less invasive technique with Parodi as pioneer has several advantages for patients, the greatest being the reduction in peri-operative risks of aneurysm repair. As in all new procedures, this new intervention sets specific requirements for quality peri-operative nursing. Within the legal-ethical framework of nursing there is no room for random nursing, and we as nurses must turn to protocols and standards applicable to quality nursing, and in effect the quality assurance process. Quality nursing care delivery to the patient remains the ideal of each nurse. The endovascular repair of abdominal aortic aneurysms, although less invasive, is still associated with major morbidity and mortality. The potential for complications is a reality. Complications are mainly systemic and/or procedure related. The reality of these complications affects the quality of nursing. Finally, the need to accommodate this problem requires that protocol/standards are established for the nursing of the patient with an endoluminal repair of an abdominal aortic aneurysm by means of an endovascular stent-graft. The following question can be asked in view of the above arguments and problem statement: How must these patients be nursed peri-operatively to ensure quality nursing care? The aim of this study is to compile protocol/standards for quality nursing of patients with an erldovascular stent-graft repair of an abdominal aortic aneurysm in a Coronary Intensive Care Unit in a private hospital in Cape Town.

Le principal objectif de cette thèse est de caractériser l'écoulement dans un anévrisme abdominal aortique (AAA) sous différentes conditions physiologiques et à différents stades de son développement. Cette étude est consacrée aux AAA axisymétriques, modélisés comme une dilatation de profil gaussien et de section circulaire. Ainsi, les résultats s'appliquent surtout aux étapes précoces du développement d'un AAA. Le modèle d'AAA est caractérisé par une hauteur maximale H et une largeur W, l'unité de mesure étant le diamètre d'entrée de l'artère. Pour commencer, la dynamique est étudiée pour les écoulements stationnaires. La stabilité globale de ces écoulements de base est analysée en calculant les valeurs propres et les fonctions propres pour des perturbations de faible amplitude. Pour comprendre les mécanismes d'instabilité, le transfer d'énergie entre l'écoulement de base et les perturbations est calculé. L'écoulement pour des AAA peu profonds (ou de grande longueur) se déstabilise par un mécanisme de ‘lift-up' et les perturbations amplifiées sont stationnaires. Des anévrismes plus localisés (ou plus profonds) deviennent instables pour des nombres de Reynolds plus élevés, sans doute par instabilité elliptique ; dans cette situation, les perturbations sont des modes oscillants. Dans le cas des écoulements pulsés, deux types de profil de débit physiologique ont été considérés dans cette étude, correspondant à une situation de repos ou d'exercice physique. Ces écoulements restent collés aux parois pendant la phase de systole et un écoulement décollé est généralement observé pendant la décélération après le maximum de systole. Dans cette phase, un vortex se forme à l'extrémité aval. Ce vortex s'agrandit au cours du temps et impacte l'extrémité aval de l'AAA, ce qui conduit à de forts gradients de contrainte pariétale, qui ne sont pas observés dans les cas sains. Il a été observé que les conditions d'écoulement varient significativement avec les nombre de Womersley (Wo) et de Reynolds (Re); l'écoulement reste attaché aux parois plus longtemps pour des nombres de Womersley croissants. Le principal effet d'une augmentation de Re est un renforcement du vortex primaire qui se forme après le maximum de systole. Les décollements de l'écoulement, l'impact de vortex au bord aval de l'AAA ou encore de faibles contraintes pariétales oscillantes (des caractéristiques importantes dans les cas d'anévrismes pathologiques) sont observés même pour des anévrismes de faible profondeur. Pour des anévrismes plus développés, des vortex multiples sont observés tout au long du cycle dans la cavité de l'AAA. Une analyse de stabilité de ces écoulements de base pulsés a montré que le maximum des perturbations se développe vers l'extérmité aval des AAA. Cependant, les perturbations ne sont pas complètement confinées dans la cavité de l'AAA et se développent aussi au-delà en aval. On en déduit qu'une fois qu'un AAA s'est développé, les perturbations affectent aussi les artères saines en aval de l'AAA. Enfin, en considérant deux profils équivalents d'AAA, de formes sinusoïdale et gaussienne, la sensibilité des résultats aux détails de la géométrie a pu être établie / The main objective of this thesis is to characterise the flow fields observed in an abdominal aortic aneurysm (AAA) under different physiological conditions during its progressive enlargement. An axisymmetric AAA, modeled as an inflation of Gaussian shape on a vessel of circular cross-section, is considered in the present study. This means that the results are more significant for the early stages of growth of an AAA. The model AAA is characterized by a maximum height H and width W, made dimensionless by the upstream vessel diameter. To begin with, the flow characteristics in AAAs are investigated using steady flows. The global linear stability of the base flows is analysed by determining the eigenfrequencies and eigenfunctions of small-amplitude perturbations. In order to understand the instability mechanisms, the energy transfer between the base flow and the perturbations is computed. The flow in relatively shallow aneurysms (of relatively large width) become unstable by the lift-up mechanism and have a perturbation flow which is characterized by stationary, growing modes. More localized aneurysms (with relatively small width) become unstable at larger Reynolds numbers, presumably by an elliptic instability mechanism; in this case the perturbation flow is characterized by oscillatory modes. For the case of pulsatile flows, two types of physiological flowrate waveforms are considered in our study, corresponding to rest and exercise conditions. The flows are observed to remain attached to the walls during the systolic phase, with flow separation generally observed during the deceleration after the peak systole. During this phase, the vorticity is found to roll-up into a vortex at the proximal end. This vortex enlarges with time and impinges at the downstream end of the AAA, resulting in large spatial gradients of wall shear stress (WSS) along the wall, which are not found in the healthy case. The flow conditions are observed to vary significantly with Womersley (Wo) and Reynolds (Re) numbers, with the flow remaining attached to the walls for longer times, as the Womersley number Wo increases. The principal effect of increasing Re is that the primary vortex formed after peak systole is stronger. Clinically relevant flow characteristics of aneurysmal flow, i.e. detachement of flow and impingement on the distal end, the presence of low oscillatory WSS within the AAA, are observed even for very shallow aneurysms. For deep aneurysms, multiple vortices are observed throughout the cycle within the AAA cavity. Stability analysis of pulsatile base flows reveals that the maximum values of the perturbations are observed near the distal end of the AAA. However, they are not entirely confined to the AAA cavity and extend downstream, implying that once an AAA is formed, the disturbed flow conditions spread even to the undeformed arterial walls downstream of the AAA. Finally, by considering two equivalent AAA shapes modeled by a sinusoidal and a gaussian function, the sensitivity

There is a huge unmet clinical need for a new, safe and effective minimally invasive treatment for Acute Ascending Aortic Dissection (AAAD) (1). In 2012 AAAD has a mortality rate of 1-2% per hour within the first 24 hours, and even with contemporary surgical techniques, advanced intensive and post operative care, the mortality from AAAD following surgery in most series remains in the unacceptable range of 10-30% at 30 days (2;3). 28% of patients presenting with AAAD are denied life saving surgery often because of age or co-morbidity - medical therapy alone associated with an in hospital mortality rate in excess of 50% (2;4-6). Currently available endovascular stent grafts used in the descending thoracic and abdominal aorta are not adequately designed to be utilised within the ascending aorta. They have a large stowed diameter 22-25 French (F), with a rigid covering of either Dacron or ePTFE, and a stiff inflexible delivery system unlikely to traverse the aortic arch without complication. While the contemporary results of elective surgery for ascending thoracic aortic aneurysm (ATAA) are good, with an elective mortality of <5%, surgical results for AAAD have improved little over the last 20 years, with a 30 day mortality rate between 10-30% (3;7). With the emerging role of endovascular stent grafts in the treatment of thoracic aneurysm and dissection, with shorter hospital stays and improved outcomes I believe now is the time for the development of a percutaneous solution for AAAD. Potential ascending thoracic aortic graft (ATAG) designs must take into account the very close proximity of intimal tear to both the coronary arteries and aortic valve, allowing a 4 good proximal graft seal without compromising coronary flow or aortic valve competence. ATAG should have a low profile, with a thin non porous covering and a flexible delivery sheath with accurate and precise deployment characteristics. Following a literature review and novel anatomical data collection from computerised tomography (CT) and magnetic resonance imaging (MRI) scans of AAAD and ATAA patient cohorts, it seems that 3 embodiments of ATAG should be designed and developed, all sharing advanced core technologies including a laser-cut nitinol stent frame, thin polyurethane (PU) material covering and accurate and precise deployment mechanisms: 1) The “supra-coronary tubular ATAG”, for treating AAAD with an intimal tear in the ascending aorta, no coronary or aortic valve involvement and adequate landing zones above the coronary arteries and before the right brachiocephalic trunk (RBCT). It is likely that this graft will be capable of treating at least a third of all patients with AAAD (8). 2) The “inverted t-shirt ATAG” to proactively protect coronary artery flow and achieve proximal seal within the sinuses in patients with an intimal tear in close association or involving the coronary arteries. 3) The “valved ATAG” to treat patients who have significant aortic regurgitation (AR), to achieve a proximal seal at the annulus when anatomy suggests it would be difficult to achieve with embodiment 1) or 2), and in those patients who have a hugely dilated aortic root, so that the ATAG can seal proximally at a relatively normal annulus size, and seal distally at a normal ascending aorta diameter 5 proximal to the RBCT. This could be the treatment option for the 25-35% of AAAD patients who currently require aortic valve repair or replacement (9). The most complex of the 3 devices above is embodiment 2), the “inverted t-shirt ATAG”, as it must ensure proximal aortic seal within an often dilated sinus, without compromise to aortic valve and proactively protect both coronary arteries with 2 coronary sleeves. Basic proof of concept (PoC) of this embodiment has been demonstrated in vitro within a normal sized aortic glass model, with some important study limitations, nevertheless it does demonstrate that tracking an ATAG branched graft with 2 coronary sleeves is possible over 3 guidewires and deploying accurately within the aortic root under both direct vision and fluoroscopy. Following successful PoC deployment I then specified and had manufactured a 2nd Generation ATAG (2G ATAG), with a laser-cut nitinol frame, longitudinal tie bars, and a novel thin PU graft covering material. The 2G ATAG has been shown to have adequate radial strength when compared to competitor devices, and can be stowed to 28 F for deployment. During ATAG development 2 patents have been filed, and I wrote with Professor Rothman a successful NIHR I4I grant for £743,000 to take ATAG from the current 28 F 2G device, towards the goal of an 18 F device with bench testing, in vitro flow rig and deployment analysis, and in collaboration with the Royal Veterinary College (RVC) into an animal model over the next 3 years (beyond the scope of this thesis). I hope that within this next development cycle ATAG can be iterated into a device that might be ready to embark on a first in man (FIM) trial to offer the AAAD population an effective and less invasive treatment strategy.

Abdominal aortic aneurysms (AAA) are a pathological dilation of the aorta greater than 2.5cm and affect more than 4% of the male population and 1% of women aged 60 years or older. Screening is recommended among men and women older than age 65, and is covered by Medicare for patients with a family history and men with a history of smoking. Due to its asymptomatic nature, AAA is usually found incidentally during another radiological investigation. Many factors are associated with AAA development, but it is most commonly found in conjunction with atherosclerosis. There is currently no pharmacological intervention specifically for AAA, though statin therapy has shown some promise. The aneurysm will invariably grow, with an average rate of expansion of less than 0.5cm per year. As the aneurysm grows larger the chance of the rupture increases significantly with this outcome carrying an extremely high rate of mortality. Surgical intervention is recommended once the diameter reaches 5.5cm in men or about 5cm in women. There are two approaches to the repair of the aorta: the open surgical approach and the endovascular approach. The open surgical procedure replaces the affected portion of the aorta with a graft. The endovascular procedure places an endograft within the intact aneurysm, effectively excluding the affected section of vessel. The endovascular method carries a lower perioperative mortality rate than the open procedure, but over time can require additional surgeries to prevent continued aneurysm expansion due to blood flow in the aneurysm sac. Additionally, lifetime surveillance of the endograft is required to monitor its integrity and effectiveness. Lifestyle changes and possible pharmacological interventions in patients with AAA should focus on cardiovascular health changes to improve overall health and minimize risk factors for continued development of the aneurysm. In patients who will require repair particular attention should be paid to individual risks and preferences. The open repair procedure may be preferable in patients with better overall health and a longer life expectancy, while endovascular repair may be beneficial for more elderly or frail patients. Research and technology in this area are developing quickly, particularly for endovascular procedures, and the near future may see important changes in the risk-benefit analysis of AAA surgical interventions.

The baroreflex is a well-studied physiological mechanism that provides instantaneous nerve impulses to higher brain centers about fluctuations in blood pressure. Located within the aortic arch and carotid sinuses, the baroreceptors are mechanosensitive stretch receptors activated by physical distention. When stretched by elevated blood pressure, the baroreflex is activated and serves to reduce sympathetic nerve activity through increased parasympathetic nerve output, ultimately reducing heart rate, contractility and total vascular peripheral resistance. Therefore, through physical perturbation, the baroreflex can be activated and ensuing physiological changes result. Several medical devices have been developed to treat and manage cardiovascular diseases that are affected by blood pressure dysregulation. A significant portion of devices have their mechanistic application at locations at or near the aortic and carotid baroreceptors, which results in alterations of baroreflex activation. This literature review serves to highlight three clinically important cardiovascular devices and the effects they have on the baroreflex through a summarized review of published work in the scientific community. Intra-aortic balloon pumps, left ventricular assist devices and carotid sinus stimulators are cardiovascular devices that have shown promising development and clinical impact since each devices’ initial application in research trials. Each device has been thoroughly reviewed here and the impact that each device has on blood pressure regulation has been investigated via available published work. Results from a limited number of studies have shown that each device has a definite effect on baroreflex activation and subsequent changes in autonomic nervous system function. Modifications in blood pressure through device use appear to be a potential therapeutic approach to managing pathophysiological states, including hypertension and heart failure. Hypertension and heart failure will be discussed in greater detail, reviewing current approaches to disease management and care. The results from the available publications surrounding device use are specific to certain diseases, however, they are also quite generalizable in the sense that these results have shown an overall true effect on blood pressure modification by the baroreflex. Conclusions established from this literature review are that although promising work has been recognized through studying these cardiovascular devices and their effects on blood pressure regulation, much research and development is still needed in order to gain a better understanding of device use and impact in the clinical setting.