Uncertainty-aware Visualization in Medical Imaging - A Survey

Medical imaging (image acquisition, image transformation, and image visualization) is a standard tool for clinicians in order to make diagnoses, plan surgeries, or educate students. Each of these steps is affected by uncertainty, which can highly influence the decision-making process of clinicians. Visualization can help in understanding and communicating these uncertainties. In this manuscript, we aim to summarize the current state-of-the-art in uncertainty-aware visualization in medical imaging. Our report is based on the steps involved in medical imaging as well as its applications. Requirements are formulated to examine the considered approaches. In addition, this manuscript shows which approaches can be combined to form uncertainty-aware medical imaging pipelines. Based on our analysis, we are able to point to open problems in uncertainty-aware medical imaging

The importance of blood rheology in patient-specific computational fluid dynamics simulation of stenotic carotid arteries

The initiation and progression of atherosclerosis, which is the main cause of cardiovascular diseases, correlate with local haemodynamic factors such as wall shear stress (WSS). Numerical simulations such as computational fluid dynamics (CFD) based on medical imaging have been employed to analyse blood flow in different arteries with and without luminal stenosis. Patient-specific CFD models, however, have assumptions on blood rheology. The differences in the calculated haemodynamic factors between different rheological models have not been fully evaluated. In this study, carotid magnetic resonance imaging (MRI) was performed on six patients with different degrees of carotid stenosis and two healthy volunteers. Using the 3D reconstructed carotid geometries and the patient-specific boundary conditions, CFD simulations were performed by applying a Newtonian and four non-Newtonian models (Carreau, Cross, Quemada and Power-law). WSS descriptors and pressure gradient were analysed and compared between the models. The differences in the maximum and the average oscillatory shear index between the Newtonian and the non-Newtonian models were lower than 12.7% and 12%, respectively. The differences in pressure gradient were also within 15%. The differences in the mean time-averaged WSS (TAWSS) between the Newtonian and Cross, Carreau and Power-law models were lower than 6%. In contrast, a higher difference (26%) was found in Quemada. For the low TAWSS, the differences from the Newtonian to the non-Newtonian models were much larger, in the range of 0.4–31% for Carreau, 3–22% for Cross, 5–51% for Quemada and 10–41% for Power-law. The study suggests that the assumption of a Newtonian model is reasonable when the overall flow pattern or the mean values of the WSS descriptors are investigated. However, the non-Newtonian model is necessary when the low TAWSS region is the focus, especially for arteries with severe stenosis

Magnetic Nanoparticle Targeting of a 3D Bioprinted Model of Pulmonary Vasculature to Address Restenosis

Pulmonary Vein Stenosis (PVS) is a cardiovascular condition characterized by progressive lumen size reduction in one or more of the pulmonary veins. Central characteristics associated with pathological PVS state include the overgrowth of connective tissue and the deposition of fibrotic tissue within the lumen of the affected vessels. Neointimal lesions in PVS are characterized by deposition of myofibroblast-like cells which originate, in part, from vascular endothelial cells (ECs), a process known as endothelial-to-mesenchymal transition (EndMT), during which ECs lose their lineage-specific cell markers and take on myofibroblast properties. These cells can then move into the neointima, proliferate, secrete extracellular matrix (ECM) proteins, and form stenoses. As a result of these uncontrolled cellular overgrowths, typical in PVS, the condition causes obstruction of blood flow from the lungs to the heart and can result in elevated pulmonary venous pressure, pulmonary hypertension, potentially cardiac failure, and death. Current treatment options for PVS are limited to the use of catheterization or surgery techniques to keep the veins patent. Furthermore, these methods only remove the lesion cells and cannot prevent their regrowth and restenosis. Currently, there are no treatments that can ensure a long-lasting control over restenosis mechanisms in the surgically treated pulmonary veins. Untreated restenosis can ultimately lead to catastrophic outcomes for the patient, including impairment of cardiac functions, hypoxia, and even death. Recent clinical trials have demonstrated that adding chemotherapy (systemic administration of anti-proliferative drugs) to the standard treatment regimens can significantly inhibit the abnormal cellular growth, and hence, reduce the risk of restenosis. However, noticeable toxic side-effects have been reported from such systemic delivery of antiproliferative drugs. In this thesis work, we investigated a novel approach involving the delivery of magnetic nanoparticles (NPs), coated with an anti-proliferative drug (rapamycin), to locally control cellular overgrowth in a 3D bioprinted in vitro model of pulmonary vasculature. Bioprinted bifurcated vein-like constructs with 2 mm lumens were seeded with human ECs and perfused using a custom-designed bioreactor platform to simulate the in vivo flow hemodynamics. Computational flow dynamics (CFD) modeling identified a vascular geometry recapitulated by an idealized bifurcation intersection model as a region at high risk of (re)stenosis, with greatest levels of alterations in wall shear stress. A 3.96 mm rare-earth magnet was incorporated within the perfusion chamber to target NP delivery to this vascular region at risk of intimal hypoplasia. The results of this study demonstrated the robust capacity of the engineered model to recapitulate the flow perturbation and endothelial dysfunction in the context of PVS. Targeted delivery of rapamycin-loaded NPs was successfully conducted under a 7-day dynamic culture, yielding a significant impact on the human vascular cell proliferation and overgrowth within the lumen space. Together, these results support the robust potential of 3D bioprinted in vitro platforms, such as the one described here, to develop, analyze, and optimize novel pharmacotherapeutic approaches to treat PVS and be adapted to address other cardiovascular pathologies.M.S

Haemodynamics analysis of carotid artery stenosis and carotid artery stenting

Carotid stenosis is a local narrowing of the carotid artery, and is usually found in the internal carotid artery. The presence of a high-degree stenosis in a carotid artery may provoke transition from laminar to turbulent flow during part of the cardiac cycle. Turbulence in blood flow can influence haemodynamic parameters such as velocity profiles, shear stress and pressure, which are important in wall remodelling. Patients with severe stenosis could be treated with a minimally invasive clinical procedure, carotid artery stenting (CAS). Although CAS has been widely adopted in clinical practice, the complication of in-stent restenosis (ISR) has been reported after CAS. The incidence of ISR is influenced by stent characteristics and vessel geometry, and correlates strongly with regions of neointimal hyperplasia (NH). Therefore, the main purpose of this study is to provide more insights into the haemodynamics in stenosed carotid artery and in post-CAS geometries via computational simulation. The first part of the thesis presents a computational study on flow features in a stenotic carotid artery bifurcation using two computational approaches, large eddy simulation (LES) and Reynolds-averaged Navier-Stokes (RANS) incorporating the Shear Stress Transport model with the γ-Reθ transition (SST-Tran) models. The computed flow patterns are compared with those measured with particle image velocimetry (PIV). The results show that both SST-Tran and LES can predict the PIV results reasonably well, but LES is more accurate especially at locations distal to the stenosis where flow is highly disturbed. The second part of the thesis is to determine how stent strut design may influence the development of ISR at the carotid artery bifurcation following CAS. Key parameters that can be indicative of ISR are obtained for different stent designs and compared; these include low and oscillating wall shear stress (WSS), high residence time, and wall stress. A computationally efficient methodology is employed to reproduce stent strut geometry. This method facilitates the accurate reconstruction of actual stent geometry and details of strut configuration and its inclusion in the fluid domain. Computational simulations for flow patterns and low-density lipoprotein (LDL) transport are carried out in order to investigate spatial and temporal variations of WSS and LDL accumulation in the stented carotid geometries. Furthermore, finite element (FE) analysis is performed to evaluate the wall stress distribution with different stent designs. The results reveal that the closed-cell stent design is more likely to create atheroprone and procoagulant flow conditions, causing larger area to be exposed to low wall shear stress (WSS), elevated oscillatory shear index, as well as to induce higher wall stress compared to the open-cell stent design. This study also demonstrates the suitability of SST-Tran and LES models in capturing the presence of complex flow patterns in post-stenotic region.Open Acces

Fully non-invasive pressure drop measurements and post treatment prediction in congenital heart diseases via cardiac magnetic resonance and computer flow dynamics

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2017De acordo com os dados de 2017 da Organização Mundial da Saúde, as doenças cardiovasculares são a principal causa de morte a nível mundial. Se estes tipos de doenças não forem diagnosticadas e tratadas atempadamente, podem levar a insuficiências cardíacas ou outras complicações irreversíveis. As duas doenças cardiovasculares congénitas estudadas neste trabalho são a coarctação aórtica (CoA), caracterizada por uma estenose, habitualmente, na zona do arco da artéria aorta, e a doença da válvula aórtica (AvD), uma malformação ao nível da válvula aórtica. Estas doenças são responsáveis por cerca de 50,000 intervenções por ano. Deste modo, a melhoria métodos de diagnóstico e de intervenção adequados e eficientes é uma prioridade e pode levar ao decréscimo no número das intervenções, bem como reduzir a morbilidade e a mortalidade. A área de imagiologia médica de diagnóstico tem tido uma evolução significativa ao longo dos anos e é de extrema importância nas tentativas de substituição de métodos de diagnóstico invasivos. As imagens médicas são adquiridas e posteriormente processadas e analisadas, com recurso a programas adequados. Atualmente, é possível obter os valores de gradientes de pressão relativa a partir de Ecocardiografia Doppler e Ressonância Magnética. Contudo, os gradientes de pressão medidos no cateterismo cardíaco, o método gold standard para o diagnóstico de CoA e AvD, são gradientes de pressão absoluta. Nesta dissertação desenvolveu-se um método de diagnóstico de CoA e AvD, a partir dos mapas de pressão relativa no estreitamento da aorta e na válvula aórtica, respectivamente. O método matemático desenvolvido tem por base as equações de Poisson, resolvida com a condição de fronteira de Neumann utilizando os métodos de elementos finitos, e a de Navier Stokes para a conservação do momento. O método desenvolvido também tem em conta a informação proveniente da função de Windkessel da artéria aorta, uma artéria distensível. Esta função dá-nos o comportamento da propagação do pulso de pressão com uma velocidade de pulso de propagação. Deste modo, é observado um desfasamento temporal entre as curvas de fluxo da pressão e da velocidade, entre as duas regiões de interesse escolhidas. Deste modo, o método, denominado de Time-shift Corrected Pressure Maps (TCPM, sigla em inglês), permite obter os mapas de pressão absoluta, isto é, mapas de pressão que têm em conta o intervalo de tempo entre os picos de pressão na aorta descendente e ascendente, no caso do primeiro estudo, e antes e depois da válvula aórtica, no caso do segundo estudo. Os pacientes de ambos os estudos tinham indicação clínica para cateterismo cardíaco e foram submetidos a ressonância magnética cardiovascular de contraste de fase em tempo real (4D PC MRI, em inglês), para recolher as imagens ao nível da aorta e da válvula aórtica e os respectivos campos de velocidade da corrente sanguínea. O primeiro estudo tem como objetivo a aplicação do método TCPM a 27 pacientes de CoA (n=16 masculinos, n=11 femininos, faixa etária de 4 a 52 anos, idade média de 20±15 anos). Após aquisição das imagens, estas foram processadas usando programas específicos. Em primeiro lugar foi necessário segmentar a aorta, seguiu-se a seleção das regiões de interesse e, finalmente, a obtenção dos campos de velocidade e dos mapas de pressão relativa entre as duas regiões de interesse selecionadas. Após aplicação do método TCPM, foram aplicados testes estatísticos (correlação, teste t e Bland-Altman) para comparar os valores obtidos a partir de TCPM com os valores obtidos no cateterismo cardíaco. Após processamento das imagens dos 27 pacientes, 6 pacientes foram retirados do estudo. N=3 pacientes foram retirados porque a percentagem de fluxo que passa pelo estreitamento é insuficiente para calcular o gradiente de pressão a partir de TCPM e N=3 pacientes foram retirados porque a aorta não estava inserida por completo no FOV. As medições obtidas a partir de TPCM e cateterismo cardíaco têm uma correlação linear significante (R²=0,90; p<0,001). A partir dos gráficos Bland-Altman é possível verificar uma boa concordância entre as medições de ambos os métodos, com bias de -2,69 mmHg e os limites de concordância de ±4,74 mmHg. O teste de equivalência mostrou uma relação significante entre os métodos (p=0,007). O segundo estudo tem como objetivo a aplicação do método TPCM e o método da Área de Gorlin a 4 pacientes de AvD (n=4 masculinos, faixa etária 17 a 36 anos, idade média 27±7 anos). O método da Área de Gorlin permite obter o gradiente de pressão absoluta a partir da área geométrica da válvula e do fluxo total que passa nessa área. Após a aquisição das imagens, foi feito o processamento das mesmas. Numa primeira fase, as imagens foram segmentadas na região da válvula aórtica. Depois, as imagens segmentadas foram analisadas em dois programas distintos. O primeiro foi utilizado de forma a obter os campos de velocidade e os mapas de pressão relativa entre dois pontos antes e depois da válvula aórtica. O segundo permitiu definir a região da válvula como região de interesse e exportar os valores de velocidade, área, pressão relativa e fluxo absoluto nessa região. Os resultados mostram uma correlação linear significativa entre os valores de cateterismo cardíaco e de TCPM (R²=0,99; p<0,001). Os gráficos de Bland-Altman mostram uma boa concordância entre os valores de TCPM (24,75±22,50 mmHg) e de cateterismo (20,88±19,51 mmHg), com um bias de -3,87 mmHg e limites de concordância de ±3,64 mmHg. Os resultados também sugeriram uma ligeira subestimação dos valores do cateterismo cardíaco a partir do método da Área de Gorlin (14,47±13,00 mmHg), com um bias de 6,41 mmHg e limites de concordância de ±7,15 mmHg. Este estudo foi feito com uma amostra diminuta de 4 pacientes, o que não é suficiente para retirar conclusões com significância. Contudo, foi uma primeira abordagem positiva, que mostra a potencialidade que este método pode vir a apresentar. O método TCPM proposto neste projeto permite a medição não invasiva de gradientes de pressão absoluta a partir de mapas de pressão relativa em pacientes de CoA e AvD. Vários aspectos têm que ser tidos em conta de forma a garantir a eficácia deste método. Por exemplo, as regiões de interesse escolhidas têm que se cuidadosamente selecionadas de forma a serem perpendicular à direção do fluxo naquele local. Só desta maneira é possível obter o fluxo, os campos de velocidade e as pressões relativas corretas. Também, se o raio da estenose for menor que 2 voxéis, a relação sinal-ruído aumenta substancialmente, e a resolução especial da aquisição é insuficiente. Contudo, a aplicação do método TPCM a casos de grande estreitamento não é necessária visto que estes casos já são tipicamente identificados em imagens anatómicas de ressonância magnética e que o paciente segue automaticamente para intervenção quando a área do estreitamente representa cerca de 50% do valor de área típico da aorta. O método não invasivo TCPM apresenta uma boa concordância com o cateterismo cardíaco em termos da medição dos gradientes de pressão em CoA e AvD. Os bias e os limites de concordância entre cateterismo e TCPM foram substancialmente mais pequenos que os bias e os limites de concordância entre cateterismo e ecocardiografia Doppler e entre o cateterismo e o método da Área de Gorlin. Com os resultados apresentados já é possível ver o potencial desta técnica no processo de diagnóstico e decisão de intervenção em casos de CoA e AvD. Contudo, estudos com populações maiores será extremamente benéfico para validar clinicamente este método.This dissertation aims to validate MRI-based time-shift corrected pressure mapping (TCPM) against cardiac catheterization in CoA and AvD patients. Also, in AvD patients, catheterization will be compared against Gorlin Area method. This project is divided in two independent studies: the first one for CoA patients and the second one for AvD patients, all with clinical indication for cardiac catheterization. In both CoA and AvD, clinical guidelines recommend treatment in the presence of a relevant pressure gradient. While reliable non-invasive measurement approaches would be crucial, the accuracy of currently available methods has been limited. In both studies, 4D PC-MRI was performed to compute relative pressure maps via Pressure-Poisson equation. To consider the patient-specific peak pressure time-shift from the ascending to the descending aorta and before and after the aortic valve, relative pressure gradient maps were corrected by the inertial term. Comparison between TCPM and invasive peak-to-peak measurements was performed using correlation, Bland-Altman plots and mean-equivalence t-test. In the first study, with a cohort of 21 patients with CoA, TCPM and catheter measurements showed significant linear correlation (R²=0.90; p<0.001). Bland-Altman plots demonstrated good agreement between TCPM and catheter derived pressure gradients with mean differences of -2.69 mmHg and 95% limits of agreement between -6.38 and 1.00 mmHg between methods. The mean-equivalence test was significant (p=0.007). In the second study, with a cohort of 4 patients with AvD, the catheterization measurements were compared against TPCM measurements. The results showed significant linear correlation (R²=0.99; p<0.001). Bland Altman plots showed a good agreement between TCPM (24.75±22.50 mmHg) and catheter derived peak-to-peak pressure gradients (20.88±19.51 mmHg), and suggested slight underestimation of the pressure gradients by the Gorlin Area method (14.47±13.00 mmHg). Non-invasive TCPM showed equivalence to pressure gradients from invasive heart catheterization in patients with CoA and AvD. However, in the AvD study, they were obtained for a very small cohort of patients and do not have sufficient statistical significance to validate the method for AvD patients

Carotid plaque stress analysis by fluid structure interaction based on in-vivo MRI: Implications to plaque vulnerability assessment

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University, 2010.Stroke is one of the leading causes of death in the world, resulting mostly from the sudden rupture of atherosclerotic plaques. From a biomechanical view, plaque rupture can be considered as a mechanical failure caused by extremely high plaque stress. In this PhD project, we are aiming to predict 3D plaque stress based on in-vivo MRI by using fluid structure interaction (FSI) method, and provide information for plaque rupture risk assessment. Fluid structure interaction was implemented with ANSYS 11.0, followed by a parameter study on fibrous cap thickness and lipid core size with realistic carotid plaque geometry. Twenty patients with carotid plaques imaged by in-vivo MRI were provided in the project. A framework of reconstructing 3D plaque geometry from in-vivo multispectral MRI was designed. The followed reproducibility study on plaque geometry reconstruction procedure and its effect on plaque stress analysis filled the gap in the literature on imaging based plaque stress modeling. The results demonstrated that current MRI technology can provide sufficient information for plaque structure characterization; however stress analysis result is highly affected by MRI resolution and quality. The application of FSI stress analysis to 4 patients with different plaque burdens has showed that the whole procedure from plaque geometry reconstruction to FSI stress analysis was applicable. In the study, plaque geometries from three patients with recent transient ischemic attack were reconstructed by repairing ruptured fibrous cap. The well correlated relationship between local stress concentrations and plaque rupture sites indicated that extremely high plaque stress could be a factor responsible for plaque rupture. Based on the 20 reconstructed carotid plaques from two groups (symptomatic and asymptomatic), fully coupled fluid structure interaction was performed. It was found that there is a significant difference between symptomatic and asymptomatic patients in plaque stress levels, indicating plaque stress could be used as one of the factors for plaque vulnerability assessment. A corresponding plaque morphological feature study showed that plaque stress is significantly affected by fibrous cap thickness, lipid core size and fibrous cap surface irregularities (curvedness). A procedure was proposed for predicting plaque stress by using fibrous cap thickness and curvedness, which requires much less computational time, and has the potential for clinical routine application. The effects of residual stress on plaque stress analysis and arterial wall material property characterization by using in-vivo MRI data were also discussed for patient specific modeling. As the further development, histological study of plaque sample has been combined with conventional plaque stress analysis by assigning material properties to each computational element, based on the data from histological analysis. This method could bridge the gap between biochemistry and biomechanical study of atherosclerosis plaques. In conclusion, extreme stress distributions in the plaque region can be predicted by modern numerical methods, and used for plaque rupture risk assessment, which will be helpful in clinical practice. The combination of plaque MR imaging analysis, computational modelling, and clinical study/ validation would advance our understandings of plaque rupture, prediction of future rupture, and establish new procedures for patient diagnose, management, and treatment.Financial Support was obtained from British Heart Foundation, Brunel Institute for Bioengineering and Brunel Graduate School