Computer assisted analysis of contrast enhanced ultrasound images for quantification in vascular diseases

Contrast enhanced ultrasound (CEUS) with microbubble contrast agents has shown great potential in imaging microvasculature, quantifying perfusion and hence detecting vascular diseases. However, most existing perfusion quantification methods based on image intensity, and are susceptible to confounding factors such as attenuation artefacts. Improving reproducibility is also a key challenge to clinical translation. Therefore, this thesis aims at developing attenuation correction and quantification techniques in CEUS with applications for detection and quantification of microvascular flow / perfusion. Firstly, a technique for automatic correction of attenuation effects in vascular imaging was developed and validated on a tissue mimicking phantom. The application of this technique to studying contrast enhancement of carotid adventitial vasa vasorum as a biomarker of radiation-induced atherosclerosis was demonstrated. The results showed great potential in reducing attenuation artefact and improve quantification in CEUS of carotid arteries. Furthermore, contrast intensity was shown to significantly increase in irradiated carotid arteries and could be a useful imaging biomarker for radiation-induced atherosclerosis. Secondly, a robust and automated tool for quantification of microbubble identification in CEUS image sequences using a temporal and spatial analysis was developed and validated on a flow phantom. The application of this technique to evaluate human musculoskeletal microcirculation with contrast enhanced ultrasound was demonstrated. The results showed an excellent accuracy and repeatability in quantifying active vascular density. It has great potential for clinical translation in the assessment of lower limb perfusion. Finally, a new bubble activity identification and quantification technique based on differential intensity projection in CEUS was developed and demonstrated with an in-vivo study, and applied to the quantification of intraplaque neovascularisation in an irradiated carotid artery of patients who were previously treated for head and neck cancer. The results showed a significantly more specific identification of bubble signals and had good agreement between the differential intensity-based technique and clinical visual assessment. This technique has potential to assist clinicians to diagnose and monitor intraplque neovascularisation.Open Acces

The anthropometric, environmental and genetic determinants of right ventricular structure and function

BACKGROUND Measures of right ventricular (RV) structure and function have significant prognostic value. The right ventricle is currently assessed by global measures, or point surrogates, which are insensitive to regional and directional changes. We aim to create a high-resolution three-dimensional RV model to improve understanding of its structural and functional determinants. These may be particularly of interest in pulmonary hypertension (PH), a condition in which RV function and outcome are strongly linked. PURPOSE To investigate the feasibility and additional benefit of applying three-dimensional phenotyping and contemporary statistical and genetic approaches to large patient populations. METHODS Healthy subjects and incident PH patients were prospectively recruited. Using a semi-automated atlas-based segmentation algorithm, 3D models characterising RV wall position and displacement were developed, validated and compared with anthropometric, physiological and genetic influences. Statistical techniques were adapted from other high-dimensional approaches to deal with the problems of multiple testing, contiguity, sparsity and computational burden. RESULTS 1527 healthy subjects successfully completed high-resolution 3D CMR and automated segmentation. Of these, 927 subjects underwent next-generation sequencing of the sarcomeric gene titin and 947 subjects completed genotyping of common variants for genome-wide association study. 405 incident PH patients were recruited, of whom 256 completed phenotyping. 3D modelling demonstrated significant reductions in sample size compared to two-dimensional approaches. 3D analysis demonstrated that RV basal-freewall function reflects global functional changes most accurately and that a similar region in PH patients provides stronger survival prediction than all anthropometric, haemodynamic and functional markers. Vascular stiffness, titin truncating variants and common variants may also contribute to changes in RV structure and function. CONCLUSIONS High-resolution phenotyping coupled with computational analysis methods can improve insights into the determinants of RV structure and function in both healthy subjects and PH patients. Large, population-based approaches offer physiological insights relevant to clinical care in selected patient groups.Open Acces

Respiratory organ motion in interventional MRI : tracking, guiding and modeling

Respiratory organ motion is one of the major challenges in interventional MRI, particularly in interventions with therapeutic ultrasound in the abdominal region. High-intensity focused ultrasound found an application in interventional MRI for noninvasive treatments of different abnormalities. In order to guide surgical and treatment interventions, organ motion imaging and modeling is commonly required before a treatment start. Accurate tracking of organ motion during various interventional MRI procedures is prerequisite for a successful outcome and safe therapy. In this thesis, an attempt has been made to develop approaches using focused ultrasound which could be used in future clinically for the treatment of abdominal organs, such as the liver and the kidney. Two distinct methods have been presented with its ex vivo and in vivo treatment results. In the first method, an MR-based pencil-beam navigator has been used to track organ motion and provide the motion information for acoustic focal point steering, while in the second approach a hybrid imaging using both ultrasound and magnetic resonance imaging was combined for advanced guiding capabilities. Organ motion modeling and four-dimensional imaging of organ motion is increasingly required before the surgical interventions. However, due to the current safety limitations and hardware restrictions, the MR acquisition of a time-resolved sequence of volumetric images is not possible with high temporal and spatial resolution. A novel multislice acquisition scheme that is based on a two-dimensional navigator, instead of a commonly used pencil-beam navigator, was devised to acquire the data slices and the corresponding navigator simultaneously using a CAIPIRINHA parallel imaging method. The acquisition duration for four-dimensional dataset sampling is reduced compared to the existing approaches, while the image contrast and quality are improved as well. Tracking respiratory organ motion is required in interventional procedures and during MR imaging of moving organs. An MR-based navigator is commonly used, however, it is usually associated with image artifacts, such as signal voids. Spectrally selective navigators can come in handy in cases where the imaging organ is surrounding with an adipose tissue, because it can provide an indirect measure of organ motion. A novel spectrally selective navigator based on a crossed-pair navigator has been developed. Experiments show the advantages of the application of this novel navigator for the volumetric imaging of the liver in vivo, where this navigator was used to gate the gradient-recalled echo sequence

Automatic Spatiotemporal Analysis of Cardiac Image Series

RÉSUMÉ À ce jour, les maladies cardiovasculaires demeurent au premier rang des principales causes de décès en Amérique du Nord. Chez l’adulte et au sein de populations de plus en plus jeunes, la soi-disant épidémie d’obésité entraînée par certaines habitudes de vie tels que la mauvaise alimentation, le manque d’exercice et le tabagisme est lourde de conséquences pour les personnes affectées, mais aussi sur le système de santé. La principale cause de morbidité et de mortalité chez ces patients est l’athérosclérose, une accumulation de plaque à l’intérieur des vaisseaux sanguins à hautes pressions telles que les artères coronaires. Les lésions athérosclérotiques peuvent entraîner l’ischémie en bloquant la circulation sanguine et/ou en provoquant une thrombose. Cela mène souvent à de graves conséquences telles qu’un infarctus. Outre les problèmes liés à la sténose, les parois artérielles des régions criblées de plaque augmentent la rigidité des parois vasculaires, ce qui peut aggraver la condition du patient. Dans la population pédiatrique, la pathologie cardiovasculaire acquise la plus fréquente est la maladie de Kawasaki. Il s’agit d’une vasculite aigüe pouvant affecter l’intégrité structurale des parois des artères coronaires et mener à la formation d’anévrismes. Dans certains cas, ceux-ci entravent l’hémodynamie artérielle en engendrant une perfusion myocardique insuffisante et en activant la formation de thromboses. Le diagnostic de ces deux maladies coronariennes sont traditionnellement effectués à l’aide d’angiographies par fluoroscopie. Pendant ces examens paracliniques, plusieurs centaines de projections radiographiques sont acquises en séries suite à l’infusion artérielle d’un agent de contraste. Ces images révèlent la lumière des vaisseaux sanguins et la présence de lésions potentiellement pathologiques, s’il y a lieu. Parce que les séries acquises contiennent de l’information très dynamique en termes de mouvement du patient volontaire et involontaire (ex. battements cardiaques, respiration et déplacement d’organes), le clinicien base généralement son interprétation sur une seule image angiographique où des mesures géométriques sont effectuées manuellement ou semi-automatiquement par un technicien en radiologie. Bien que l’angiographie par fluoroscopie soit fréquemment utilisé partout dans le monde et souvent considéré comme l’outil de diagnostic “gold-standard” pour de nombreuses maladies vasculaires, la nature bidimensionnelle de cette modalité d’imagerie est malheureusement très limitante en termes de spécification géométrique des différentes régions pathologiques. En effet, la structure tridimensionnelle des sténoses et des anévrismes ne peut pas être pleinement appréciée en 2D car les caractéristiques observées varient selon la configuration angulaire de l’imageur. De plus, la présence de lésions affectant les artères coronaires peut ne pas refléter la véritable santé du myocarde, car des mécanismes compensatoires naturels (ex. vaisseaux----------ABSTRACT Cardiovascular disease continues to be the leading cause of death in North America. In adult and, alarmingly, ever younger populations, the so-called obesity epidemic largely driven by lifestyle factors that include poor diet, lack of exercise and smoking, incurs enormous stresses on the healthcare system. The primary cause of serious morbidity and mortality for these patients is atherosclerosis, the build up of plaque inside high pressure vessels like the coronary arteries. These lesions can lead to ischemic disease and may progress to precarious blood flow blockage or thrombosis, often with infarction or other severe consequences. Besides the stenosis-related outcomes, the arterial walls of plaque-ridden regions manifest increased stiffness, which may exacerbate negative patient prognosis. In pediatric populations, the most prevalent acquired cardiovascular pathology is Kawasaki disease. This acute vasculitis may affect the structural integrity of coronary artery walls and progress to aneurysmal lesions. These can hinder the blood flow’s hemodynamics, leading to inadequate downstream perfusion, and may activate thrombus formation which may lead to precarious prognosis. Diagnosing these two prominent coronary artery diseases is traditionally performed using fluoroscopic angiography. Several hundred serial x-ray projections are acquired during selective arterial infusion of a radiodense contrast agent, which reveals the vessels’ luminal area and possible pathological lesions. The acquired series contain highly dynamic information on voluntary and involuntary patient movement: respiration, organ displacement and heartbeat, for example. Current clinical analysis is largely limited to a single angiographic image where geometrical measures will be performed manually or semi-automatically by a radiological technician. Although widely used around the world and generally considered the gold-standard diagnosis tool for many vascular diseases, the two-dimensional nature of this imaging modality is limiting in terms of specifying the geometry of various pathological regions. Indeed, the 3D structures of stenotic or aneurysmal lesions may not be fully appreciated in 2D because their observable features are dependent on the angular configuration of the imaging gantry. Furthermore, the presence of lesions in the coronary arteries may not reflect the true health of the myocardium, as natural compensatory mechanisms may obviate the need for further intervention. In light of this, cardiac magnetic resonance perfusion imaging is increasingly gaining attention and clinical implementation, as it offers a direct assessment of myocardial tissue viability following infarction or suspected coronary artery disease. This type of modality is plagued, however, by motion similar to that present in fluoroscopic imaging. This issue predisposes clinicians to laborious manual intervention in order to align anatomical structures in sequential perfusion frames, thus hindering automation o

Analysis of strain in the human left ventricle using real-time 3D echocardiography and optical flow

Cardiovascular disease (CVD) consistently ranks among the leading causes of death in the United States. The most common subtype of CVD, ischemic heart disease, is a frequent precursor of myocardial infarction and heart failure, most commonly affecting the left ventricle (LV). Today, echocardiography is regarded as the gold standard in screening, diagnosis, and monitoring of LV dysfunction. But while global assessment of LV function tends to be quantitative, cardiologists with specific expertise still perform many regional evaluations subjectively. However, a more objective and quantitative measure of regional function – myocardial strain – has been developed and widely studied using 2D echocardiography. With recent developments in real-time 3D echocardiography (RT3DE), it has become possible to measure strain in its native 3D orientation as well. Our laboratory’s earlier work introduced the Optical Flow (OF) method of strain analysis, which was validated on simulated echocardiograms as well as through animal studies. The principal goal of this thesis is to translate this OF-based method of strain estimation from the research setting to the patient’s bedside. We have performed a series of studies to evaluate the feasibility, accuracy, and reproducibility of OF-based myocardial strain estimation in a routine clinical setting. The first investigation focused on the optimization of RT3DE acquisition and the OF processing pipeline for use in human subjects. Subsequently, we evaluated the capacity of this technique to distinguish abnormal strain patterns in patients with CVD and varying degrees of LV dysfunction. Our analysis revealed that segmental strain measures obtained by OF may have better sensitivity and specificity than the more commonly used global LV strains. Our third validation study examined the reproducibility of these strain measures in both healthy and diseased populations. We established that OF-based strain measures demonstrate repeatability comparable to that achieved by the latest commercial software commonly used in clinical research to estimate 2D or 3D strain. These studies were driven in large part by the absence of a ground truth or accepted gold standard of 3D strain measurements in the human LV. However, cardiac magnetic resonance imaging has had considerable success in measuring some forms of strain in the human LV. We therefore began to develop an image-processing pipeline to derive strain estimates from a new pulse sequence called 3D-DENSE. We further sought to improve the OF pipeline by automating the process of tracking the LV border. To this end, we developed a level-set based technique which tracks the LV endocardium. Our evaluation of its performance on RT3DE data confirmed that this method performs within the limits of inter-observer variability. Overall, our pilot studies of OF-based strain estimation demonstrate that the technique possesses several promising features for improving cardiologists’ ability to quantify and interpret the complex three-dimensional deformations of the human LV

Dual gated PET/CT imaging of heart

Coronary artery disease (CAD) resulting from atherosclerotic arterial changes, plaques, is a progressive process, which can be asymptomatic for many years. Asymptomatic CAD can cause a heart attack that leads to sudden death if the vulnerable coronary plaque ruptures and causes artery occlusion. The plaque inflammation plays an important role in the rupture susceptibility. Reliable anticipation of rupture is still clinically impossible for a single patient. Detection of the vulnerable coronary plaques before clinical signs remains a significant scientific challenge where positron emission tomography (PET) can play an important role. The aim of this dissertation was to find out whether a small, coronary plaque size, heart structures could be detected by a clinically available positron emission tomography and computed tomography (PET/CT) hybrid camera in realistically moving cardiac phantoms, a minipig model, and patients with CAD. Due to cardiac motions accurate detection of small heart structures are known to be problematic in PET imaging. Due to absence of commercial application at the beginning of the study, new dual gating method for cardiac PET imaging was developed and programmed that takes into account both contraction and respiratory induced cardiac motions. Cardiac phantom PET studies showed that small, active and moving plaques can be distinguished from myocardium activity and the gating methods improved the detection sensitivity and resolution of the plaques. In minipig and CAD patient cardiac PET studies small structures of myocardium and coronary arteries was detected more sensitive and accurately when using dual gating method than manufacturer gating methods. In cardiac patient PET study respiratory induced cardiac motions were shown to be linearly dependent with spirometry-measured respiratory volumes. Standard 3-lead electrocardiogram (ECG) measurement can be filtered by anesthesia monitor to detect lung impedance signal. In cardiac patient PET study this lung impedance signal were applied for respiratory gating. In this study was observed that the 3-lead ECG derived impedance signal gating method detects respiratory induced cardiac motion in PET as well as other externally used respiratory gating methods. In summary, the dual gated cardiac PET method is more sensitive and accurate to detect small cardiac structures, as coronary vessel wall pathology, than the commercial methods used in the study.Sydämen kaksoisliiketahdistettu PET/CT kuvantaminen Ateroskleroottisten valtimomuutosten, plakkien, seurauksena asteittain kehittyvä sepelvaltimotauti voi olla vuosia oireeton. Oireeton sepelvaltimotauti voi aiheuttaa äkkikuolemaan johtavan sydäninfarktin, mikäli sepelvaltimon seinämäplakin repeytymisestä aiheutuu verisuonen tukkiva hyytymä. Tutkimuksissa on osoitettu, että plakin tulehduksella on merkittävä rooli repeytymisalttiudelle. Repeytymisen luotettava ennakointi on yksittäisen potilaan kohdalla edelleen kliinisesti mahdotonta. Tulehtuneiden ja repeytymisalttiiden sepelvaltimoplakkien toteaminen ennen kliinisiä oireita on edelleen merkittävä tieteellinen haaste, missä positroniemissiotomografia (PET) kuvantamisella voi olla merkittävä rooli. Väitöskirjan tavoitteena oli selvittää, voidaanko kliinisessä käytössä olevalla positroniemissiotomografia ja tietokonetomografia (PET/TT) yhdistelmäkameralla havaita pieniä, sepelvaltimoplakkien kokoisia, sydämen rakenteita koneellisesti toimivissa todenmukaisissa sydänmalleissa, eläinmallissa ja sepelvaltimotautia sairastavilla potilailla. Sydämen pienten rakenteiden tarkka havaitseminen PET/TTkameroilla on haasteellista sydämen liikkumisen vuoksi. Tutkimuksessa kehitettiin ja ohjelmoitiin uusi sydämen PET-kuvantamisen liiketahdistusmenetelmä, joka ottaa huomioon sekä sydämen supistusliikkeen että hengitysliikkeen vaikutuksen sydämen PET kuvantamissa. Koneellisilla sydänmalleilla osoitettiin, että PET on riittävän herkkä havaitsemaan pieniä ja liikkuvia radioaktiivisia ”sepelvaltimoplakkeja”, ja että liiketahdistusmenetelmät parantavat plakkien havaitsemisherkkyyttä ja tarkkuutta. Eläinmallissa ja sepelvaltimotautipotilailla kaksoisliiketahdistusmenetelmän herkkyys ja tarkkuus havaita pieniä sydänlihaksen ja sepelvaltimoiden rakenteita todettiin kaupallisia tahdistusmenetelmiä paremmaksi. Potilastutkimuksissa todettiin hengityksen aiheuttama sydämen liike PET-kuvissa lineaarisesti riippuvaiseksi spirometrialla mitattujen hengitystilavuuksien kanssa. Tavallisesta 3-johtoisesta sydänsähkökäyrästä voidaan anestesiamonitorin avulla suodattaa keuhkojen impedanssisignaalia. Hengitysliikkeen aiheuttama potilaiden sydämen liike PETkuvissa havaittiin yhtä hyvin käyttämällä tätä keuhkojen impedanssisignaalia kuin muita yleisesti käytettäviä ulkoisia hengitystahdistussignaaleja. Todetaan, että kaksoisliiketahdistettu sydämen PET-kuvantamismenetelmä on tutkimuksessa käytettyjä kaupallisia menetelmiä herkempi ja tarkempi havaitsemaan sydämen pieniä rakenteita sekä sepelvaltimon seinämän tulehdusplakkeja