Atherosclerosis, the leading cause of mortality in Western societies, affects large elastic arteries, causing focal deposition of proliferative inflammatory and lipid-laden cells within the artery. Several risk factors have been causally implicated in the ???reaction to injury??? hypothesis first described by Ross in 1969. The ???injury??? sustained by endothelial cells may be either mechanical or chemical. Environmental factors have a role in the production of chemical agents that are injurious to the endothelium. Mechanical stresses such as wall tensile stress are proportional to systemic blood pressure and pulse pressure. Essentially, these systemic pressures are fairly evenly distributed throughout the circulation. However, atherosclerotic lesions characteristically occur at focal sites within the human vasculature; at or near bifurcations, within the ostia of branch arteries and at regions of marked or complex curvature, where local haemodynamic abnormalities occur. The most discussed haemodynamic factor seems to be low or highly oscillating wall shear stress which exists on the outer wall of bifurcations and on the inner aspect of curving vessels. The magnitude of these haemodynamic forces may not be great but the subtleties of their variable spatial distribution may help to explain the multifocal distribution of atherosclerotic plaques. With the altered haemodynamics there is endothelial injury and phenotypic changes in the endothelium result, which in turn lead to endothelial cell dysfunction. These haemodynamic variables are difficult to measure directly in vivo. In this work a novel model is developed utilising human autologous vein bypass grafts as a surrogate vessel for the observation of pathological structural changes in response to altered haemodynamics. The influence of haemodynamic factors (such as wall shear stress) in the remodeling of the vein graft wall and the pathogenesis of Myointimal Hyperplasia (MIH) and resultant wall thickening in femoral bypass grafts is analysed. The haemodynamic determinants of MIH (which have been established in many animal models) are similar to those implicated in atherosclerosis. The accelerated responses of the vein (Intimal hyperplasia develops much more rapidly than atherosclerotic lesions in native vessels) make it an ideal model to expediently examine the hypothesised relationships prospectively in an in vivo setting. Furthermore, the utilisation of in vivo data acquired from non-invasive diagnostic methods (such as Magnetic Resonance Angiography (MRA) and Duplex ultrasound) combined with the application of state-of-the-art Computational Fluid Dynamic (CFD) techniques makes the model essentially non-invasive. The following hypotheses are examined: 1) regions of Low shear and High tensile stress should develop disproportionately greater wall thickening, 2) regions of greater oscillatory blood flow should develop greater wall thickening, and 3) regions of lower wall shear should undergo inward (or negative) remodelling and result in a reduction in vessel calibre. The conclusions reached are that abnormal haemodynamic forces, namely low Time-averaged Wall Shear Stress, are associated with subsequent wall thickening. These positive findings have great relevance to the understanding of vein graft MIH and atherosclerosis. It was also evident that with non-invasive data and CFD techniques, some of the important haemodynamic factors are realistically quantifiable (albeit indirectly). The detection of parameters known to be causal in the development of graft intimal hyperplasia or other vascular pathology may improve ability to predict clinical problems. From a surgical perspective this might be employed to facilitate selection of at-risk grafts for more focused postoperative surveillance and reintervention. On a broader stage the utilisation of such analyses may be useful in predicting individuals at greater risk of developing atherosclerotic deposits, disease progression, and the likelihood of clinical events such as heart attack, stroke and threat of limb loss.

Atherosclerosis, the leading cause of mortality in Western societies, affects large elastic arteries, causing focal deposition of proliferative inflammatory and lipid-laden cells within the artery. Several risk factors have been causally implicated in the ???reaction to injury??? hypothesis first described by Ross in 1969. The ???injury??? sustained by endothelial cells may be either mechanical or chemical. Environmental factors have a role in the production of chemical agents that are injurious to the endothelium. Mechanical stresses such as wall tensile stress are proportional to systemic blood pressure and pulse pressure. Essentially, these systemic pressures are fairly evenly distributed throughout the circulation. However, atherosclerotic lesions characteristically occur at focal sites within the human vasculature; at or near bifurcations, within the ostia of branch arteries and at regions of marked or complex curvature, where local haemodynamic abnormalities occur. The most discussed haemodynamic factor seems to be low or highly oscillating wall shear stress which exists on the outer wall of bifurcations and on the inner aspect of curving vessels. The magnitude of these haemodynamic forces may not be great but the subtleties of their variable spatial distribution may help to explain the multifocal distribution of atherosclerotic plaques. With the altered haemodynamics there is endothelial injury and phenotypic changes in the endothelium result, which in turn lead to endothelial cell dysfunction. These haemodynamic variables are difficult to measure directly in vivo. In this work a novel model is developed utilising human autologous vein bypass grafts as a surrogate vessel for the observation of pathological structural changes in response to altered haemodynamics. The influence of haemodynamic factors (such as wall shear stress) in the remodeling of the vein graft wall and the pathogenesis of Myointimal Hyperplasia (MIH) and resultant wall thickening in femoral bypass grafts is analysed. The haemodynamic determinants of MIH (which have been established in many animal models) are similar to those implicated in atherosclerosis. The accelerated responses of the vein (Intimal hyperplasia develops much more rapidly than atherosclerotic lesions in native vessels) make it an ideal model to expediently examine the hypothesised relationships prospectively in an in vivo setting. Furthermore, the utilisation of in vivo data acquired from non-invasive diagnostic methods (such as Magnetic Resonance Angiography (MRA) and Duplex ultrasound) combined with the application of state-of-the-art Computational Fluid Dynamic (CFD) techniques makes the model essentially non-invasive. The following hypotheses are examined: 1) regions of Low shear and High tensile stress should develop disproportionately greater wall thickening, 2) regions of greater oscillatory blood flow should develop greater wall thickening, and 3) regions of lower wall shear should undergo inward (or negative) remodelling and result in a reduction in vessel calibre. The conclusions reached are that abnormal haemodynamic forces, namely low Time-averaged Wall Shear Stress, are associated with subsequent wall thickening. These positive findings have great relevance to the understanding of vein graft MIH and atherosclerosis. It was also evident that with non-invasive data and CFD techniques, some of the important haemodynamic factors are realistically quantifiable (albeit indirectly). The detection of parameters known to be causal in the development of graft intimal hyperplasia or other vascular pathology may improve ability to predict clinical problems. From a surgical perspective this might be employed to facilitate selection of at-risk grafts for more focused postoperative surveillance and reintervention. On a broader stage the utilisation of such analyses may be useful in predicting individuals at greater risk of developing atherosclerotic deposits, disease progression, and the likelihood of clinical events such as heart attack, stroke and threat of limb loss.

Intracranial monitoring after severe traumatic brain injury offers the possibility for early detection and amelioration of physiological insults. In this thesis, I explore cerebral insults due raised intracranial pressure, decreased cerebral perfusion pressure and impaired cerebral pressure reactivity after traumatic brain injury. In chapter 2, the importance of intracranial pressure, cerebral perfusion pressure and pressure reactivity in regulating the cerebral circulation is elucidated along with a summary of the existing evidence supporting intracranial monitoring in traumatic brain injury. In chapter 4, intracranial pressure, cerebral perfusion pressure, and pressure reactivity insults are demonstrated to be common, prognostically important, and responsive to long-term changes in management policies. Further, while these insults often occur independently, coexisting insults portend worse prognosis. In chapter 5, I examine possible imaging antecedents of raised intracranial pressure and demonstrate that initial subarachnoid haemorrhage is associated with the subsequent development of elevated intracranial pressure. In addition, elevated glucose during the intensive care stay is associated with worse pressure reactivity. Cortical blood flow and brain tissue oxygenation are demonstrated to be sensitive to increases in intracranial pressure in chapter 6. In chapter 7, a method is proposed to estimate the cerebral perfusion pressure limits of reactivity in real-time, which may allow for more nuanced intensive care treatment. Finally, I explore a recently developed visualisation technique for intracranial physiological insults and apply it to the cerebral perfusion pressure limits of reactivity. Taken together, this thesis outlines the scope, risk factors and consequences of intracranial insults after severe traumatic brain injury. Novel signal processing applications are presented that may serve to facilitate a physiological, personalised and precision approach to patient therapy.

The diploma thesis deals with non-invasive and invasive monitoring of the cardiovascular system, focusing on non-medical health workers. The aim of the work was to analyze the knowledge of non-medical health workers in selected areas of cardiovascular monitoring. The data was obtained in the form of a non- standardized questionnaire created by myself. For the research were selected non-medical health workers working in Prague hospitals in coronary units and postoperative cardiac surgery units. The total number of respondents who participated in the research was 108. The results of the survey revealed that non-medical staff are relatively well versed in the issue of cardiovascular monitoring. A rather surprising finding was that most respondents did not use foreign literature to study cardiovascular monitoring. As part of the comparison of the respondents, the better knowledge of cardiovascular monitoring was presented in non-medical staff of the Department of Postoperative Cardiac Surgery. Compared in relation to the highest educational attainment, university graduates have demonstrated a higher level of knowledge than others. Based on achieved data, it was created a study text for newcomers, which contains basic information for better orientation in the given issue. keywords: cardiovascular...

The thesis is concerned with the analysis of measuring pulse wave velocity in human body with the aid of whole-body multichannel bioimpedance which was developed at ISI AS CR, v.v.i.. The evaluation of pulse wave velocity can provide us with important information about the state of vessel compliance which is one of the basic parameters informing on their physiological state. The examination of the state of vascular system is a very important part of early diagnostics because its pathological states are the main contributor to the rise of cardiovascular diseases and disease mortality. The thesis is concerned with the theoretical analysis together with the available methods of valuation of the state of vascular system that use measuring of pulse wave velocity. The main part of the thesis deals with the analysis of the whole-body multichannel bioimpedance measurement. The proposed and programmed protocol that summarizes and visualizes all obtained information is a part of this thesis. This is currently used as an output of the experimental measurement by this method. Data file for statistical processing contains the values of the pulse wave velocity of 35 healthy volunteers and subsequently the properties of pulse wave are assessed at various excitations.

In this thesis we introduce a new fluid-structure interaction model in the Eulerian description. This model is developed for blood flow in viscoelastic artery. For the fluid part a non-Newtonian model Oldroyd-B is used and for the structure part Kelvin-Voigt model is employed. Kelvin-Voigt model will be reached by a limiting process of the Oldroyd-B model. Interface between these two materials is guaranteed by conservative level-set method. Numerical tests of this model is performed by finite element method. This model is used for a simulation of two problems: a two dimensional channel with viscoelastic walls and pulsating inflow and Turek-Hron FSI benchmark. 1

Background: Oxidative stress and myocyte apoptosis are thought to play an important role in the pathogenesis, progression and prognosis of heart failure (HF). Heat shock protein 27 (Hsp27) has been found to confer resistance to oxidative stress in cultured cells; however, the role of Hsp27 in in-vivo hearts remains to be determined. Aim: To investigate the effects of Hsp27 over-expression on doxorubicin-induced HF. Methods and Results: Transgenic mice (TG) with cardiac specific over-expression of Hsp27 and their wild type littermates (WT) were challenged with doxorubicin (25 mg/kg, IP) to induce HF. At day 5, TG mice had significantly improved cardiac function and viability and decreased loss of heart weight following doxorubicin exposure compared with WT. In another parallel experiment, doxorubicin-induced increased levels of reactive oxygen species, protein carbonylation, apoptosis and morphologic changes were detected in the mitochondria in WT hearts, whereas these effects were markedly attenuated in TG hearts. In addition, upregulation of heat shock protein 70 and heme oxygenase-1 was present in the TG hearts after doxorubicin stimulation in comparison to WT hearts. Conclusion: These findings indicate that Hsp27 may play a key role in resistance to doxorubicin-induced cardiac dysfunction.

The cardiovascular systems in ectothermic reptiles have long been studied and its development represent a transition state between a single- and a double circulation. This literature review focus on the typical-reptilian heart and therefore distinguishes between orders within the class of Reptilia. The typical-reptilian heart is found in the non-crocodilian reptiles referring to the orders Chelonia and Squamata. The heart is composed of two atria and one common ventricle, compartmentalized into three interconnected ventricular cava. However, there is some species-specific variation in gross anatomy where the monitor lizard Varanus and Python pose a striking exception to the typical-reptilian heart. The cardiac building plan exhibits variation in size and relative dimensions, in particular the relationship between cava and the degree of ventricular septation. Varanus and Python have a larger and more muscular systemic side of the ventricle, a highly developed vertical septum and muscular ridge. Today, it is known that a ventricle with a less developed muscular ridge acts as a single pressure source, subsequently allowing admixture of oxygenated- and deoxygenated blood within the ventricle. In contrast, a ventricle with a more developed muscular ridge and vertical septum may function as a dual pressure source during parts of systole, temporarily separating the ventricle in a high-pressure systemic side and a low-pressure pulmonary side. Septal development provides different haemodynamic conditions and yield diverse functions. This literature review is a combination of practical laboratory work and a literature study. Dissections of the typical-reptilian hearts provide information about exterior and interior morphology, and findings are then compared to existing literature.

Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway. Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects. Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects. Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05). Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.

An intracranial aneurysm (IA) is a balloon-like focal lesion on the cerebral arterial wall. IAs are poorly understood, but are commonly considered to be a disease caused by multiple factors. Current interventional treatments are accompanied with risks. Given the low incidence of rupture, it would be ideal to only treat aneurysms identified with rupture risk. Numerical models of aneurysm development may provide insight into the disease mechanisms, and contribute to the prediction of disease progression. Better understanding of the disease aetiology will also guide clinical decision making. Different hypotheses have been proposed on the influence of haemodynamic stimuli on IA inception. We investigate this influence by examining the haemodynamic stimuli of the 'pre-aneurysmal' vasculature in the locations of IA formation in 22 clinical cases. The 'pre aneurysmal' geometries are obtained by applying a novel numerical vessel reconstruction method on the aneurysmal geometries. This automated reconstruction method propagates a closed curve along the vessel skeleton using the local Frenet frames to smoothly morph the upstream boundary into the downstream boundary. We observe that locally elevated wall shear stress (WSS) and gradient oscillatory number (GON) are highly correlated with regions susceptible to sidewall IA formation, whilst haemodynamic indices associated with the oscillation of the WSS vectors have much lower correlations. A common assumption made in the literature on arterial growth and remodelling (G&R) is that the 'state of stretch' (denoted as the attachment stretch) at which collagen fibres are configured in the extracellular matrix (ECM) is assumed to be constant. This will lead to an unrealistically thickened arterial wall in modelling aneurysm evolution. We propose a novel 1D mathematical model of collagen microstructural adaption during IA evolution. We assume new collagen fibres are configured into the ECM in a state of attachment stretch distribution which can be temporally adaptive. We explicitly define the functional form of this distribution and model its temporal adaption during IA evolution. This model is then implemented into two 3D models of IA evolution: a solid structural model and Fluid-Solid-Growth (FSG) model. In the solid structural model, the artery is modelled as a two-layer, nonlinear elastic cylindrical membrane using a physiologically realistic constitutive model. The development of the aneurysm is considered as a consequence of the growth and remodelling of its material constituents: elastinous constituents are prescribed to degrade in a localised circular patch; collagen concentration and recruitment variables enable the growth and remodelling of collagen fabric to be simulated; adaption of the attachment stretch distribution is confined locally within the region of aneurysm evolution. The sophisticated solid model predicts stabilised saccular IAs with realistic sizes and wall thicknesses. The FSG model simulates the IA development on patient-specific vasculature: the updated 3D solid structural model is integrated into a patient-specific geometry of the vasculature and the growth and remodelling of the constituents is now linked to the local haemodynamic stimuli obtained from a rigid-wall computational fluid dynamics analysis. Adaption of the attachment stretch distribution is also confined locally in the region where the constituents degrade. An illustrative case of IA development on patient specific geometry is provided. Based on our study, we conclude that incorporating the adaption of attachment stretch distribution is necessary to simulate IA evolution with physiological evolving wall thicknesses. However, how vascular cells confine this adaption heterogeneously needs further investigation. Improved understanding and modelling of the biology of the arterial wall is needed for more sophisticated models of aneurysm evolution. It will in turn assist in understanding the aetiology of IA formation. Ultimately we hope to have a patient-specific growth model that could have the potential be used to assist diagnostic decisions.