No description available.

Over the last 20 years endovascular aneurysm repair (EVAR) has advanced dramatically. Early devices incorporated infra-renal fixation (IR), and were prone to delayed mechanical failure. Later devices incorporated bare metal stents that deploy in the supra-renal aorta (SR), improving durability, but potentially affecting long term renal function. This is the subject of continued research. Cystatin C (CC) is a low molecular weight protein, which has demonstrated great sensitivity at detecting renal dysfunction, despite only modest decreases in glomerular filtration rate (GFR). To date it has not been used to evaluate mid to long term renal function following EVAR. Neutrophil gelatinase associated lipocalin (NGAL) is a member of the lipocalin family of proteins, and rises considerably following renal insult due to surgery or nephro-toxicity. With increasing numbers of abdominal aortic aneurysm (AAA) repairs, it’s important to have a reliable indicator and predictor of potential renal dysfunction following surgery.

Currently, tissue-engineered heart valves (TEHV) have shown a great prospective to replace the conventional prosthetics heart valves for their ability to grow and remodel. It is well established that in order for the seeded cells to behave in an appropriate manner and infiltrate, populate and remodel during in vitro culture, they need to be exposed to appropriate levels of mechanical stimulation that favour the regeneration of the valve-equivalent tissue with appropriate valvular-tissue- specific functionality. Mathematical modelling is an important tool that can be used alongside TEHV bioreactors with a view to optimising their function by relating the stress-strain distributions in the valve leaflets to the flow and pressure conditions generated by the bioreactor. For that, physiologically accurate 3D fluid structure interaction (FSI) models of fresh and decellularised aortic valves were developed. At first two FSI methods were used to study FSI of a 20 aortic valve, the Arbitrary Lagrangian Eulerian (ALE) method and the Multi-Material Arbitrary Lagrangian Eulerian (MM- ALE) method. The ALE method uses a dynamic mesh in the fluid domain to account for the valve deformations, while in the MM-ALE method, the fluid mesh remains fixed during the computation. Good agreement was found between the results of the two FSI methods. Furthermore, the MM-ALE method was employed to perform FSI of a bileaflet mechanical valve and the results were validated by comparison with pulsatile flow experim~nts. 3D FSI models of the natural aortic valve were developed using three material models for the leaflet (nonlinear isotropic, fiber-reinforced and Fung-type nonlinear orthotropic) and comparisons were conducted to in vivo and in vitro data. Finally, FSI models of decellularised aortic valve scaffolds cultured in vitro under different operation conditions were performed using the nonlinear orthotropic model for optimising a TEHV bioreactor.

Congenital bicuspid aortic valve (BAV) is the commonest cardiac defect occurring in 2% of the general population causing aortic valve disease and is associated with ascending aortic aneurysms. Different genetic, metabolic and haemodynamic studies have tried to explain the aetiology of BA V and the development of aortic aneurysm. However, to date, the aetiology of BA V is not fully understood. 1.1.2 Aims To determine whether BAV is due to a genetic mutation in GATA5, fibrillin-l (FBN]) or transforming growth factor beta receptor-2 (TGFBR2), genes recognised as essential for valvulogenesis and aortogenesis. In addition, to perform a comprehensive transcriptomics analysis of the extracellular matrix (ECM) of BA V aortas with or without aneurysm. A third aim was to determine the dilatation of the aorta following aortic valve and/or root replacement. Our aims can aid us in understanding the different pathologies involved in aortic aneurysm development and its outcome. 1.1.3 Methods A consecutive series of 65 patients were included in the study. Thirty-five patients with BAV and 30 with tricuspid aortic valve (TA V) with and without aortic aneurysm were studied prospectively. Twenty millilitres of venous blood was collected from patients and a small aortic sample was taken from the aortotomy site during surgery. Different methods were used to analyse the samples; blood was used for genomic DNA analysis to determine the presence of genetic mutations. Gene microarray was performed on 24 aortic tissue samples to determine the differentially expressed genes amongst the different groups and real time polymerase chain reaction (qPCR) analysis was performed to validate the results. 9 • In addition 395 BAV and TAV patients with and without aortic aneurysms were studied retrospectively by collecting 2D echo cardiograms and CT scan data to determine dilatation of the remaining aorta following aortic valve and/or root replacement at 5 years follow-up. 1.1.4 Results In the cohort of 35 patients with confirmed BA V at surgery, one patient exhibited a missense mutation in GATA5 in the coding position 698 T>C; therefore, demonstrating for the first time in human cardiac disease that mutation in GATA5 might be causative of BAV. Gene expression data revealed impaired expression of VEGFA and COL3AI genes in TAV with aneurysm; a finding not present in the BA V group. Our clinical data showed no significant dilatation of the ascending aorta following A VR when aortic diameter <4.5cm at the time of surgery. Similarly, dilatation of the arch was not seen in patients with ascending aorta diameter 24.5cm following ARR comparing BA V with TAV patients at 5 years following surgery. This supports intervention with ascending aorta 24.5cm in BA V patients with concomitant valvular disease. 1.1.5 Conclusion -. Our findings can help a better understanding of the aetiology, pathology and progression of aortic aneurysms and a better identification of this phenotype and risk prediction. 10 •

An abdominal aortic aneurysm (AAA) is an abnormal enlargement of the aorta which is related to weakness of the vessel wall (associated with degradation of connective tissue), and if left untreated will lead to rupture and cause death in 78% to 94% of cases. Approximately 7,000 deaths each year in the United Kingdom are caused by AAA rupture. AAA repair requires surgical intervention but the surgery itself has a mortality rate of about 5% in patients with stable AAA. The decision to undertake the surgery is made depending on the aortic maximum diameter of ≥5 cm. However, it is observed that rupture sometimes occurs in aneurysms with smaller diameter, thereby creating the need for better criteria for surgical intervention. Therefore, (biomechanical) indicators of AAA rupture were introduced as a superior criterion to the maximum diameter for predicting the risk AAA rupture. Several studies that have been conducted on abdominal aortic aneurysms have suggested that peak wall stress may be a more reliable predictor of the risk of AAA rupture. This thesis is a continuation of a previous study undertaken at the University of Hull which investigated a number of biomechanical factors that affect the AAA wall stress magnitude and distribution. Novel results were gained which may help in the understanding of AAA growth and rupture events. For the first time, it is proposed that aspect ratio has an effect on the stress magnitude, location and distribution of the outer wall of AAA. These findings were used to introduce an empirical relationship between the aneurysm aspect ratio and maximum wall stress. This empirical relationship could be used as an additional clinical indicator to predict the location and magnitude of maximum wall stress where a rupture may develop. Analysis of the porosity of the thrombus was introduced for the first time in this work using the simulation of mass transport of blood flow in an AAA, showing novel results for the possible role of blood flow on the site of growth and rupture for AAA. Furthermore, the results of this research may also explain the conflicting views on aneurysm shape and the role of the thrombus as previously reported in the literature. The work carried out in this research used simplified AAA geometries to allow the isolation of specific aneurysm parameters. Clearly, the next stage would include the application of the ideas and results developed here to more complex patient-specific geometries.

Globally, heart valve dysfunction constitutes a large portion of the cardiovascular disease load, causing high rates of mortality in European and industrialized countries. This is reflected in the database of the American Heart Association and the UK Valve Registry, showing a progressive increase in the number and age of patients in need of surgical interventions. Aortic valve (AV) dysfunction is significantly more prevalent than pathologies associated with other heart valves, accounting for approximately 43% of all patients having valvular disease. These statistics highlight the essential need for efficient and long term substitutes. However, the two types of replacement valves currently available in practice, i.e. mechanical and bioprosthetic valves, have only an estimated lifetime of around 10 years, after which the associated problems necessitate re-operation in at least 50-60% of the patients. Moreover, for patients under 35, the failure rate is nearly 100% within 5 years of the valve replacement surgery. The significant numbers of patients suffering from AV dysfunction, shortcomings to currently available valve substitutes, and the market demands for replacement valves has prompted increasing interest in the study of AV biomechanics. A fundamental study of the AV structure-function biomechanics is presented in this thesis. The mechanical behaviour of the AV is characterised at the tissue level, and the associated microstructural mechanisms established. In addition to the experiments, in depth mathematical models are developed and presented, to explain the observed experimental data and elucidate the micromechanics of the AV constituents and their contribution to the tissue behaviour. Tissue-level results indicate that the AV shows ‘shear-thinning’ behaviour, as well as anisotropic time-dependent characteristics. The microstructural experimental data indicates that there is no direct translation of tissue level mechanical stimuli to the ECM, implying that strain transfer is non-affine. Modelling micro-structural mechanics has confirmed that collagen fibres do not need to become fully straight before they contribute to load bearing, while the elastin network has been shown to contribute to load bearing even at high strains, further exacerbating the non-linear stress-strain relationship of the valve. The structural mechanisms underlying time-dependent behaviour of the tissue can be explained at the fibre level, stemming from fibre sliding and the dissipative effects arising due to fibre-fibre and fibre-matrix frictional interactions, suggesting a unified structural mechanism for both the stress-relaxation and creep phenomena. These outcomes contribute to an improved understanding of the physiological biomechanics of the native AV, and may therefore assist in optimising the design processes for substitute valves and selecting appropriate materials to effectively mimic the native valve function. Understanding AV micromechanics also helps quantify the mechanical environment perceived by the residing cells, which can have significant implications for cell-mediated tissue engineering strategies.

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.

Στην υπό μελέτη διατριβή διερευνήθηκε μια σειρά υποθέσεων που οδήγησαν: 1) Στη ανεύρεση μαθηματικών μοντέλων που δύνανται να υπολογίζουν το μήκος σημαντικών ανατομικών μεγεθών στη κατιούσα αορτή και κατ επέκταση να προσφέρουν βοήθεια στη επιλογή του ιδανικού μεγέθους ασκού ανά μεμονωμένο ασθενή. Δείξαμε ότι αυτά τα μοντέλα έχουν αυξημένο βαθμό προβλεπτικής αξίας. Περαιτέρω τα συγκρίναμε με τον κλασικό τρόπο επιλογής του ιδανικού μεγέθους και ευρέθησαν ανώτερα. 2)Στη δημιουργία και εξέταση των συνθηκών όπου συμβαίνει η τραυματική διαταραχή του έσω χιτώνα της κατιούσης αορτής κατά την διάρκεια της λειτουργίας του ενδοαορτικου ασκού. Η κίνηση του ασκού εντός του αορτικού αυλού είναι πολύπλοκη. Είναι σημαντική η παρατηρούμενη επαναλαμβανόμενη «επίδραση κρούσης δικην μαστιγίου» (whipping effect) του καθετήρα του ασκού στο οπίσθιο- πλάγιο αορτικό τοίχωμα. Αυτή η κίνηση φάνηκε να ενισχύεται κατά την παρατεταμένη φάση της σύμπτυξης του ασκού όταν ο ρυθμός λειτουργίας του IABP είναι 1:3. Κάτω από τέτοιες συνθήκες σημειώθηκε επιδείνωση του «score αορτικού τραύματος» που συνηγορεί υπέρ της αποφυγής του απογαλακτισμού με σταδιακή ελάττωση του ρυθμού λειτουργίας του ασκού (mode). Η επαναλαμβανόμενη κυκλική κίνηση του ενδοαορτικου ασκού επιβεβαιώθηκε κατά την διάρκεια της λειτουργίας του σε πτωματικές αθηρωματικες αορτές. Καταγραφή διαταραχών και αποκόλλησης ( fissuring) πλακών αποδόθηκε στο κύμα πίεσης που δημιουργήθηκε από την κίνηση του ασκού και λιγότερο σε άμεσο τραυματισμό. 3) Στη κλινική εξέταση των επιπλοκών καρδιοχειρουργικών ασθενών που χρειάσθηκαν θεραπεία με ενδοαορτικο ασκό, όπου βρέθηκαν συγκεκριμένα γκρουπ αυξημένου ρίσκου. Ασθενείς όπου η χρήση του ασκού χρησιμοποιηθηκε μετεγχειρητικά καθώς και ασθενείς όπου χρειάστηκαν θεραπεία με IABP μετά από αντικατάσταση βαλβίδας (ιδιαίτερα μιτροειδούς βαλβίδας) παρουσίασαν υψηλή μετεγχειρητική θνητότητα. Οι ακόλουθες μεταβλητές εμφανίσθηκαν ως παράγοντες κινδύνου αυξημένης θνησιμότητας: Θηλυκό γένος, κάπνισμα, αυξημένη προ-εγχειρητική κρεατινινη, ισχαιμικός χρόνος>80min και εισαγωγή του ασκού την μετεγχειρητική περίοδο. Με χρήση παλίνδρομης ανάλυσης, βρέθηκε ότι ιστορικό περιφερικής αγγειοπαθειας, και κλάσμα εξώθησης κάτω από 30% αποτελούν παράγοντας κινδύνου για την ανάπτυξη αγγειακών επιπλοκών. Επιπρόσθετα με την χρήση προδρομικής τυχαιοποιημένης μελέτης φάνηκε ότι απογαλακτισμός μέσω μείωσης του όγκου πλήρωσης του ασκού απετέλεσε προφυλακτικό παράγοντα για την ανάπτυξη αγγειακών επιπλοκών. Συμπερασματικά από αυτή την εργασία απορρέουν προτάσεις που πιθανώς θα επηρεάσουν την κλινική πράξη. Συγκεκριμένα προτίθεται ένας τρόπος επιλογής του ιδανικού μεγέθους ασκού που δύναται να οδηγήσει σε αποφυγή χρησιμοποίησης μεγάλων ασκών σε μικρόσωμες γυναίκες με αθηρωματικες αορτές με αποτέλεσμα περαιτέρω ελάττωση των αγγειακών επιπλοκών. Επιπρόσθετα έχοντας μελετήσει τον τρόπο κίνησης του ασκού κάτω από διαφορετικά αιμοδυναμικα σενάρια οδηγούμεθα στο συμπέρασμα ότι ο «απογαλακτισμός» πρέπει να γίνεται με ελάττωση του όγκου του ασκού (augmentation). Δείξαμε ότι αυτός ο τρόπος «απογαλακτισμού» έχει τη τάση να οδηγεί σε λιγότερες εμβολικες επιπλοκές. Τέλος έγινε ταυτοποίηση συγκεκριμένων γκρουπ ασθενών όπου αλλαγή πρακτικής όσο αναφορά την πιο πρώιμη χρησιμοποίηση του ασκού η την αλλαγή στον τρόπο απογαλακτισμού από αυτό μπορεί δυνητικά να οδηγήσει σε μείωση της θνητότητας και νοσηρότητας. / IAB size selection is based on patients height with the known risks of under or over sizing, although size selection should rely on individual hemodynamics & measurements of the length & diameter of the aorta from the left subclavian artery to the celiac axis. The first part of this project is a pilot study whereby an attempt was made, in order to predict thoracic aortic dimensions from easily obtainable external anatomical landmarks. That would potentially lead to an optimal selection of balloon sizes for an individual patient and thus reducing adverse effects of its use. The second part of the project is an experimental Angioscopic and Pathological study that set off to investigate in a mock pig circulation model, whether weaning by mode or by augmentation produces more aortic intimal trauma. The third part of this work, studied the interaction between the intraaortic balloon catheter and the human atherosclerotic aorta. With the use of an artificial circulation we obtained direct visualisation of the dynamic action of the balloon catheter within the cadaveric human aorta. Sequelae of traumatic atherosclerotic plaque rapture due to the balloon action was observed. The last study was a clinical outcome analysis with an interest in complications in a cohort of patients requiring treatment with IABP in a single Cardiothoracic Unit over a five year period. During the initial part of the project, measurements were carried out from a series of 40 cadavers during autopsy. Internal Aortic dimensions and also external somatometric distances of the thoracic cage were obtained. Using multiple regression analysis a model was devised in order to predict aortic lengths. Being able to calculate internal aortic lengths, one could be lead to a better intraaortic balloon sizing. During the second part of the study an artificial pulsatile pump was used and an intact porcine aorta was incorporated into the circuit with the inflow at the aortic valve and the outflow at the right common iliac artery. Direct angioscopic images of the interior of the aorta were obtained. Keeping steady hemodynamic conditions, an “aortic impact score” was calculated taking into account angioscopic observational variables and biopsies of the aorta at 30min, 6hours and 12 hours following counterpulsation at 1:1, 1:2 ,1:3 Versus 1:1 and 75%, 50% and 25% augmentation. The previous model was extrapolated in to the third study whereby an artificial circulation was constructed using of PVC tubing, a filter and a roller pump. A series of 5 intact cadaveric human aortas were then individually studied by placing each in series within the circuit. A balloon catheter was advanced via the left common iliac artery into the descending aorta under direct angioscopic vision. Balloon pumping was then commenced. The circuit was perfused with Normal saline at a flow rate of 3L/minute. Pump actions of 1:1 and 1:2 were simulated. A microporous filter was incorporated into the system in order to collect embolic material during balloon action. Each aorta at the end of the experiment was subjected to histological examination. During the last study data were prospectively collected within a 5 year period from a single Cardiothoracic Unit. 2697 adult patients underwent cardiac surgery, out of which 136patients (5%) required IABP. Those patients were studied in terms of balloon associated complications. We create a model of optimal balloon sizing with a high prediction value. The performance of the model was tested against the current quidelines in a cross validation way and was found to be superior. Together with height, somatometric measurements of thoracic cage could lead to more optimal IAB size selection. During the angioscopic observational studies with porcine and also cadaveric aortas the movement of the balloon catheter in relation to the aorta was observed. The balloon catheter moves relative to the wall of the aorta during inflation and deflation. Contact between the balloon and the aorta only occurs during deflation. Side branches of the aorta are not occluded by the catheter. Plaque disruption and embolus formation appear to result from pressure wave action rather than direct contact with the balloon. By calculating the aortic impact score it appears that weaning by mode produces more aortic intimal trauma. 1:3 mode produces marked intimal disruption that worsens with time. Lastly during the clinical study of patients requiring treatment with an IABP we detected significant early mortality and morbidity associated with IABP, however intermediate follow up reveals favourable outcome.