In the interest of furthering the understanding of hemodynamics, this study has developed a method for modeling fluid mechanics behavior in individual human carotid arteries. A computational model was constructed from magnetic resonance (MR) data of a phantom carotid bifurcation model, and relevant flow conditions were simulated. Results were verified by comparison with previous in vitro experiments. The methodology was extended to create subject-specific carotid artery models from geometry data and fluid flow boundary conditions which were determined from MR and phase contrast MR (PCMR) scans of human subjects. The influence of subject-specific boundary conditions on the flow field was investigated by comparing a model based on measured velocity boundary conditions to a model based on the assumption of idealized velocity boundary conditions. It is shown that subject-specific velocity boundary conditions in combination with a subject-specific geometry and flow waveform influence fluid flow phenomena associated with plaque development. Comparing a model with idealized Womersley flow boundary conditions to a model with subject-specific velocity boundary conditions demonstrated the importance of employing inlet and flow division data obtained from individual subjects in order to predict accurate, clinically relevant, fluid flow phenomena such as low wall shear stress areas and negative axial velocity regions. This study also illustrates the influence of the bifurcation geometry, especially the flow divider position, with respect to the velocity distribution of the common carotid artery on the development of flow characteristics. Overall it is concluded that accurate geometry and velocity measurements are essential for modeling fluid mechanics in individual human carotid arteries for the purpose of understanding atherosclerosis in the carotid artery bifurcation.

published_or_final_version / abstract / Mechanical Engineering / Doctoral / Doctor of Philosophy

Atherosclerosis and related cardiovascular diseases (CVDs) are amongst the largest causes of morbidity and mortality in the developed world, causing considerable monetary pressure on public health systems worldwide. Atherosclerosis is characterised by the build up of vascular plaque in medium and large arteries and is a direct precursor to acute vascular syndromes such a myocardial infarction, stroke or peripheral arterial diseases. The causative factors leading to CVD still remain relatively poorly understood, but are becoming increasingly identifiable as a dysfunction of the endothelial cells that line the arterial wall. It is well known that the endothelium responds to the prevailing fluid mechanic (i.e. haemodynamic) environment, which plays a crucial role in the localised occurrence of atherosclerosis near vessel bends and bifurcations. In these areas, disturbed haemodynamics lead to flow separation and very low wall shear stress (WSS), which directly affects the functionality of the endothelium and impedes the transport of important blood borne agonists and antagonists. Detailed full field measurements assessing complex haemodynamics are sparse and consequently this thesis aims to address some of the important questions related to arterial haemodynamics and CVD by performing in-vitro flow measurements in physiologically relevant conditions. In particular, this research develops and uses state-of-the-art Particle Image Velocimetry (PIV) techniques to measure three-dimensional velocity and WSS fields in scaled models of the human carotid artery. For this purpose, the necessary theoretical and experimental concepts are developed and in-depth analyses of the underlying factors affecting the local haemodynamics and their relation to CVD are carried out. In the first part, a methodology for the construct of transparent hydraulic flow phantoms from medical imaging data is developed. The arterial geometries are reproduced in optically clear silicone and the flowing blood is modelled with a refractive index matched blood analogue. Subsequently, planar and Stereo-PIV techniques are developed and verified. A novel interfacial PIV (iPIV) technique is introduced to directly measure WSS by inferring the velocity gradient from the recorded particle images. The new technique offers a maximal achievable resolution of 1 pixel and therefore removes the resolution limit near the wall usually associated with PIV. Furthermore, the iPIV performance is assessed on a number of numerical and experimental test cases and iPIV offers a significantly improved measurement accuracy compared to more traditional techniques. Subsequently, the developed methodologies are applied in three studies to characterise the velocity and WSS fields in the human carotid artery under a number of physiological and experimental conditions. The first study focuses on idealised vessel geometries with and without disease and establishes a general understanding of the haemodynamic environment. Secondly, a physiological accurate vessel geometry under pulsatile flow conditions is investigated to provide a more realistic representation of the true in-vivo flow conditions. The prevailing flow structure in both cases is characterised by flow separation, strong secondary flows and large spatial and temporal variations in WSS. Large spatial and temporal differences exist between the different geometries and flow conditions; spatial variations appear to be more significant than transient events. Thirdly, the three-dimensional flow structure in the physiological carotid artery model is investigated by means of stereoscopic and tomographic PIV, permitting for the first time the measurement of the full 3D-3C velocity field and shear stress tensor in such geometries. The flow field within the model is complex and three-dimensional and inherently determined by the vessel geometry and the build up of an adverse pressure gradient. The main features include strong heliocoidal flow motions and large spatial variations in WSS. Lastly, the physiological implications of the current results are discussed in detail and reference to previous work is given. In summary, the present research develops a novel and versatile PIV methodology for haemodynamic in vitro studies and the functionality and accuracy is demonstrated through a number of physiological relevant flow measurements.

During dynamic exercise the arterial baroreflexes have been thought to reset to the prevailing level of systemic pressure in order to modulate transient changes in blood pressure with the same sensitivity (gain) as at rest. To test this hypothesis, cardiovascular responses to dynamic exercise and carotid baroreflex responses to graded neck suction and neck pressure (NS/NP) were examined in seven men of moderate fitness (V02 = 41.4±3.6 ml O2*kg^-1*min^-1) during two levels (20% and 40% of peak oxygen uptake) of steady-state exercise. In addition, deactivation of cardiopulmonary baroreceptors has been thought to increase carotid baroreflex responsiveness in the quiescent state in man.

<p>Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. </p><p>The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. </p><p>Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. </p><p>In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. </p><p>In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.</p>

Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.

Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.

Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.

Unterschiedliche zerebrale Protektionssysteme zur Verhinderung neurologischer Ereignisse während einer Karotis-Angioplastie sind derzeit im Einsatz. Dennoch zeigen Studien, dass diese Systeme die distale Mikroembolisation während der Intervention nicht vollständig verhindern können. Die vorliegende Arbeit vergleicht die Effektivität von zwei verschiedenen Protektionssystemen unter Anwendung der Methode der transkraniellen Dopplersonographie (TCD). Es wurden 42 Patienten mit einer hochgradigen Stenose der A. carotis interna während der Karotisangioplastie mit Stentimplantation untersucht. Zur Neuroprotektion wurde entweder ein Filtersystem (E.P.I. FilterWireTM, Boston Scientific, USA) oder ein proximales Ballonokklusionssystem (MO.MA-System Invatec, Italien) verwendet. Bei jedem Patienten erfolgte während der Intervention mittels TCD die Detektion der mikroembolischen Signale (MES). Die Anzahl der MES wurde während fünf verschiedener Prozedurphasen gezählt und miteinander verglichen. Die Ergebnisse der Arbeit zeigen, dass die Karotis-Angioplastie unter Schutz des MO.MA-Systems vor allem in den Phasen der Passage der Stenose, der Stentimplantation und der Nachdilatation mit signifikant niedrigeren MES assoziiert war, verglichen zur Angioplastie der A. carotis interna unter einem Filtersystem.

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