Early Detection of Doxorubicin-Induced Cardiotoxicity Using Combined Biomechanical Modeling and Multi-Parametric Cardiovascular MRI

RÉSUMÉ La chimiothérapie à la doxorubicine est efficace et est largement utilisée pour traiter la leucémie lymphoblastique aiguë. Toutefois, son efficacité est entravée par un large spectre de cardiotoxicités incluant des changements affectant à la fois la morphologie et la fonction du myocarde. Ces changements dépendent principalement de la dose cumulée administrée au patient. Actuellement, très peu de techniques sont disponibles pour détecter de telles cardiotoxicités. L'utilisation d’images de fibres musculaires (par exemple, à l’aide de l’imagerie des tenseurs de diffusion par IRM) ou des techniques d'imagerie 3D (par exemple, ciné DENSE IRM) sont des alternatives prometteuses, cependant, leur application en clinique est limitée en raison du temps d'acquisition d’images et les erreurs d'estimation qui en résultent. En revanche, l'utilisation de l'IRM multi-paramétrique ainsi que le ciné IRM sont des alternatives prometteuses, puisque ces techniques sont déjà disponibles au niveau clinique. L’IRM multiparamétrique incluant l’imagerie des temps de relaxation T1 et T2 peut être utile dans la détection des lésions dans le tissu du myocarde alors que l’imagerie ciné IRM peut être plus appropriée pour détecter les changements fonctionnels au sein du myocarde. La combinaison de ces deux techniques peut également permettre une caractérisation complète de la fonction du tissu myocardique. Dans ce projet, l'utilisation des temps de relaxation T1 pré- et post-gadolinium et T2 est d'abord évaluée et proposée pour détecter les dommages myocardiques induits par la chimiothérapie à la doxorubicine. En second lieu, l'utilisation de patrons 2D de déplacements myocardiques est évaluée dans le cadre de la détection des dommages myocardiques et altération fonctionnelle due au traitement à la doxorubicine. Enfin, l'utilisation de la modélisation par éléments finis, incluant les contraintes et déformations mécaniques est proposée pour évaluer les changements dans les propriétés mécaniques au niveau du myocarde, avec l’hypothèse que le traitement à base de doxorubicine induit des changements importants à la fois dans le tissu et au niveau de la fonction myocardique. Dans notre cohorte de survivants de cancer, des changements myocardiques locaux ont été trouvés entre le groupe à risque standard et le groupe à risque élevé lorsque le T1 pré-gadolinium fut utilisé. Ces changements ont été amplifiés avec l’utilisation d’agent de contraste tel que confirmé par le coefficient de partition, ce qui suggère que l’utilisation du T1 post-gadolonium et le coefficient de----------ABSTRACT Doxorubicin chemotherapy is effective and widely used to treat acute lymphoblastic leukemia. However, its effectiveness is hampered by a wide spectrum of dose-dependent cardiotoxicity including both morphological and functional changes affecting the myocardium. Currently, very few techniques are available for detecting such cardiotoxic effect. The use of muscle fibers orientation (e.g., diffusion tensor imaging DT-MRI) or 3D imaging techniques (e.g., cine DENSE MRI) are possible alternatives, however, their clinical application is limited due to the acquisition time and their estimation errors. In contrast, the use of multi-parametric MRI along with cine MRI is a promising alternative, since theses techniques are already available at a clinical level. Multiparametric MRI including T1 and T2 imaging may be helpful in detecting myocardial tissue damage, while cine MRI may be more appropriate to detect functional changes within the myocardium. The combination of these two techniques may further allow an extensive characterization of myocardial tissue function. In this doctoral project, the use of pre- and post-gadolinium T1 and T2 relaxation times is firstly assessed and proposed to detect myocardial damage induced by doxorubicin chemotherapy. Secondly, the use of 2D myocardial displacement patterns is assessed in detecting myocardial damage and functional alteration due to doxorubicin-based treatment. Finally, the use of finite element modeling including mechanical strains and stresses to evaluate mechanical properties changes within the myocardium is alternatively proposed, assuming that doxorubicin-based treatment induces significant changes to both myocardial tissue morphology and function. In our cohort of cancer survivors, local myocardial changes were found between standard risk and high risks group using pre-gadolinium T1 relaxation times. These changes were further amplified with gadolinium enhancement, as confirmed by the use of partition coefficient, suggesting this MRI parameter along with partition coefficient as candidates imaging markers of doxorubicin induced cardiomyopathy. The use of T2 on the other hand showed that the high risk group of cancer survivors had higher T2 relaxation times compared to the standard risk group and similar to reported values. Though, a larger cohort of cancer survivors may be required to assess the use of T1 and T2 relaxation time as possible indices for myocardial tissue damage in the onset of doxorubicin-induced cardiotoxicity

Digital Twin of Cardiovascular Systems

Patient specific modelling using numerical methods is widely used in understanding diseases and disorders. It produces medical analysis based on the current state of patient’s health. Concurrently, as a parallel development, emerging data driven Artificial Intelligence (AI) has accelerated patient care. It provides medical analysis using algorithms that rely upon knowledge from larger human population data. AI systems are also known to have the capacity to provide a prognosis with overallaccuracy levels that are better than those provided by trained professionals. When these two independent and robust methods are combined, the concept of human digital twins arise. A Digital Twin is a digital replica of any given system or process. They combine knowledge from general data with subject oriented knowledge for past, current and future analyses and predictions. Assumptions made during numerical modelling are compensated using knowledge from general data. For humans, they can provide an accurate current diagnosis as well as possible future outcomes. This allows forprecautions to be taken so as to avoid further degradation of patient’s health.In this thesis, we explore primary forms of human digital twins for the cardiovascular system, that are capable of replicating various aspects of the cardiovascular system using different types of data. Since different types of medical data are available, such as images, videos and waveforms, and the kinds of analysis required may be offline or online in nature, digital twin systems should be uniquely designed to capture each type of data for different kinds of analysis. Therefore, passive, active and semi-active digital twins, as the three primary forms of digital twins, for different kinds of applications are proposed in this thesis. By the virtue of applications and the kind of data involved ineach of these applications, the performance and importance of human digital twins for the cardiovascular system are demonstrated. The idea behind these twins is to allow for the application of the digital twin concept for online analysis, offline analysis or a combination of the two in healthcare. In active digital twins active data, such as signals, is analysed online in real-time; in semi-active digital twin some of the components being analysed are active but the analysis itself is carried out offline; and finally, passive digital twins perform offline analysis of data that involves no active component.For passive digital twin, an automatic workflow to calculate Fractional Flow Reserve (FFR) is proposed and tested on a cohort of 25 patients with acceptable results. For semi-active digital twin, detection of carotid stenosis and its severity using face videos is proposed and tested with satisfactory results from one carotid stenosis patient and a small cohort of healthy adults. Finally, for the active digital twin, an enabling model is proposed using inverse analysis and its application in the detection of Abdominal Aortic Aneurysm (AAA) and its severity, with the help of a virtual patient database. This enabling model detected artificially generated AAA with an accuracy as high as 99.91% and classified its severity with acceptable accuracy of 97.79%. Further, for active digital twin, a truly active model is proposed for continuous cardiovascular state monitoring. It is tested on a small cohort of five patients from a publicly available database for three 10-minute periods, wherein this model satisfactorily replicated and forecasted patients’ cardiovascular state. In addition to the three forms of human digital twins for the cardiovascular system, an additional work on patient prioritisation in pneumonia patients for ITU care using data-driven digital twin is also proposed. The severity indices calculated by these models are assessed using the standard benchmark of Area Under Receiving Operating Characteristic Curve (AUROC). The results indicate that using these models, the ITU and mechanical ventilation can be prioritised correctly to an AUROC value as high as 0.89

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

Bridging spatiotemporal scales in biomechanical models for living tissues : from the contracting Esophagus to cardiac growth

Appropriate functioning of our body is determined by the mechanical behavior of our organs. An improved understanding of the biomechanical functioning of the soft tissues making up these organs is therefore crucial for the choice for, and development of, efficient clinical treatment strategies focused on patient-specific pathophysiology. This doctoral dissertation describes the passive and active biomechanical behavior of gastrointestinal and cardiovascular tissue, both in the short and long term, through computer models that bridge the cell, tissue and organ scale. Using histological characterization, mechanical testing and medical imaging techniques, virtual esophagus and heart models are developed that simulate the patient-specific biomechanical organ behavior as accurately as possible. In addition to the diagnostic value of these models, the developed modeling technology also allows us to predict the acute and chronic effect of various treatment techniques, through e.g. drugs, surgery and/or medical equipment. Consequently, this dissertation offers insights that will have an unmistakable impact on the personalized medicine of the future.Het correct functioneren van ons lichaam wordt bepaald door het mechanisch gedrag van onze organen. Een verbeterd inzicht in het biomechanisch functioneren van deze zachte weefsels is daarom van cruciale waarde voor de keuze voor, en ontwikkeling van, efficiënte klinische behandelingsstrategieën gefocust op de patiënt-specifieke pathofysiologie. Deze doctoraatsthesis brengt het passieve en actieve biomechanisch gedrag van gastro-intestinaal en cardiovasculair weefsel, zowel op korte als lange termijn, in kaart via computermodellen die een brug vormen tussen cel-, weefsel- en orgaanniveau. Aan de hand van histologische karakterisering, mechanische testen en medische beeldvormingstechnieken worden virtuele slokdarm- en hartmodellen ontwikkeld die het patiënt-specifieke orgaangedrag zo accuraat mogelijk simuleren. Naast de diagnostische waarde van deze modellen, laat de ontwikkelde modelleringstechnologie ook toe om het effect van verschillende behandelingstechnieken, via medicatie, chirurgie en/of medische apparatuur bijvoorbeeld, acuut en chronisch te voorspellen. Bijgevolg biedt deze doctoraatsthesis inzichten die een onmiskenbare impact zullen hebben op de gepersonaliseerde geneeskunde van de toekomst

Comportement mécanique du tissu cardiaque par flux optique et méthode des champs virtuels

Les maladies cardiovasculaires (CVD) sont connues pour être l’une des principales causes de mortalité non accidentelles, en particulier dans les pays développés. La détection précoce de ces maladies est donc indispensable pour réduire le taux de mortalité qu’elles engendrent. Pour traiter la leucémie de nos jours, la chimiothérapie à la Doxorubicine est largement utilisée. Toutefois, ce traitement engendre une cardiotoxicité qui affecte la morphologie et la fonction du myocarde. La dose de Doxorubicine cumulée dicte le degré de ces changements anatomiques et fonctionnels. Actuellement, très peu de techniques sont disponibles pour détecter de telles cardiotoxicités. Les oncologues utilisent des paramètres, comme le LVEF (fraction d’éjection du ventricule gauche), pour détecter cette cardiotoxicité. Ces méthodes n'arrivent pas à détecter cette cardiotoxicité d'une façon précoce. Les paramètres mécaniques jouent un rôle important dans le fonctionnement du muscle cardiaque, qui est un organe qui change de forme tout le long du cycle cardiaque. Le suivi des changements des propriétés mécaniques du tissu cardiaque pourrait nous informer sur la viabilité de celui-ci et détecter une cardiomyopathie. Dans ce projet, les patrons 2D de déformations myocardiques sont évalués dans le cadre de la détection des dommages myocardiques et altérations fonctionnelles dus au traitement à la Doxorubicine. En second lieu, ces déformations sont utilisées comme données d'entrée à notre modèle numérique basé sur la méthode des champs virtuels spéciaux, dans le but de quantifier les propriétés mécaniques du myocarde, avec l’hypothèse que le traitement à base de Doxorubicine induit des changements importants à la fois dans le tissu myocardique et au niveau de la fonction cardiaque. Nous appliquons sur des images ciné-IRM, une des méthodes iconiques qui se base sur le flux optique, pour obtenir les champs de déplacements et de déformations internes des tissus cardiaques, tout au long du cycle cardiaque. Une méthode d’inversion basée sur la méthode des champs virtuels, permettant de déduire les champs de contraintes à partir des déformations obtenues par flux optique, est utilisée en choisissant des champs virtuels cinématiquement admissibles. La cohorte évaluée dans notre étude se compose de 4 groupes, constitués chacun de 3 volontaires, 3 groupes de survivants de leucémie du projet PETALE et un groupe de sujets sains. Les survivants de leucémie présentent différents niveaux de risque basé sur la dose cumulative de doxorubicine reçue. Ces survivants sont séparés en deux groupes à haut risque, dont un groupe qui prend un agent protecteur (Dexrazoxane), et un groupe à risque standard. L'acquisition des images se fait avec un appareil IRM (Skyra™, Siemens Healthcare, Erlangen, Germany), de 3Tesla avec une antenne tronc de 32 canaux. Le protocole RM consiste en une séquence ciné ECG- gated Steady state Free Precession (SSFP). Les paramètres d'acquisition sont l'épaisseur de la tranche (8 mm), le temps de répétition (TR=34.5 sec), le temps d’écho (TE=1.2 sec), l'angle de bascule (36 degrés), le facteur iPAT (3), et la taille de la matrice (210×208). Approximativement, 14 tranches sont acquises dans le plan axial, 5 tranches pour la coupe 4 chambres et 5 tranches pour la coupe 2 chambres, avec une résolution spatiale de 1.4 ×1.4× 0.8 mm. Pour chaque tranche, 25 phases du cycle cardiaque sont acquises pour chaque tranche. Pour la vue 2 chambres, nous avons constaté des différences dans les champs de déformations entre les quatre groupes. Pour le groupe à haut risque qui a reçu un agent protecteur (dexrazoxane), l’amplitude des champs de déformations est inférieure à celle du groupe à haut risque qui n’a pas reçu d'agent protecteur, quelle que soit la phase du cycle cardiaque (systole, diastole précoce, diastole retardée). Pour cette même vue 2 chambres, la contrainte en cisaillement et la contrainte de Von Mises sont inférieures, en systole, pour le groupe à haut risque qui reçoit un agent cardioprotecteur (HRdex) par rapport au groupe à haut risque (HR) qui n'en reçoit pas. Nous notons que le module d'élasticité est inférieur pour le groupe à risque standard (SR), comparé aux groupes HR et HRdex, pour la systole et la diastole tardive. La même différence est observée pour le module de cisaillement pour le groupe à risque standard SR, juste pour la systole. Pour la vue 4 chambres, le module d'élasticité est significativement plus élevé pour le groupe HRdex, comparé aux groupes HR, SR et à celui du groupe de volontaires sains (HV), pour les trois phases (Systole, Diastole précoce, Diastole tardive). En considérant la vue axiale, les contraintes de cisaillement et de Von Mises sont inférieures pour le groupe HR par rapport au groupe HRdex. Le module d'élasticité est inférieur pour le groupe SR par rapport aux groupes HR et HRdex. La même différence est observée pour le module de cisaillement pour le groups SR en systole. Dans la coupe axiale, en systole, les changements entre les quatre groupes pour les contraintes de cisaillement et de Von Mises ne concordent pas avec les différences trouvées pour les coupes 2 chambres et 4 chambres, probablement due à l’orientation différentes des fibres musculaires entre les coupes. Pour le module de Young, les changements en systole et en diastole retardée en coupe axiale concordent avec les différences trouvées pour les coupes 2 chambres et 4 chambres. Ces changements observés entre les groupes peuvent être expliqués par le fait que le muscle cardiaque des patients ayant survécu à un cancer se comporte différemment à cause d'une réduction de la quantité de fibres musculaires et d'une augmentation du tissu interstitiel. La sévérité de ces changements est proportionnelle à la dose totale d'anthracyclines, ce qui fait que le muscle cardiaque se dilate plus facilement, surtout, en diastole. Notre modèle nous a permis de constater des changements dans les champs de déformations, de contraintes, ainsi que pour les propriétés mécaniques du tissu cardiaque, qui présente une carditoxicité due au traitement à la Doxorubicine, ce qui vérifie notre hypothèse et montre la faisabilité d’une telle approche. Une des perspectives de cette étude est de constituer une base de données, comme les courbes de pressions individuelles ou les modules d’élasticité pour des personnes saines et des personnes présentant une cardiomyopathie, pour fin de comparaison préliminaire, afin de classer les patients par ordre de sévérité de cardiomyopathie.----------ABSTRACT Cardiovascular disease (CVD) is known to be one of the leading non-accidental causes of death, early detection of these diseases is therefore essential to reduce the mortality rate they generated. One of these causes is the effect of the chemotherapy. To treat leukemia today, chemotherapy with doxorubicin is widely used. However, this treatment leads to cardiotoxicity that affects the morphology and function of the myocardium. The cumulative doxorobicine dose dictates the degree of these anatomical and functional changes. Currently, very few techniques are available to detect such cardiotoxicities. Oncology uses the parameters like LVEF (Left ventricle ejection fraction or fractional shortening) to detect this cardiotoxicity. However, these methods fail to detect this cardiotoxicity in an early manner. Mechanical parameters play an important role in the functioning of the heart muscle, which is an organ that changes shape throughout the cardiac cycle. Tracking changes in the mechanical properties of a cardiac tissue informs us about his viability. We apply on cine-MRI images, one of the iconic methods based on optical flow, to obtain the fields of internal deformation of cardiac tissues throughout the cardiac cycle. The optical flow does not require information on the content of the image, so it is not necessary to know the organ to study its movement. An inversion method based on the virtual field method, which makes it possible to deduce the stress fields from the deformations obtained by optical flow, is used, by choosing cinematically admissible virtual fields; special virtual fields. Our study included 9 cancer survivors from the PETALE project and 3 healthy control volunteers. The cancer survivors were separated into 3 risk groups according to the cumulative doxorubicin dose received during the treatment, The standard risk (SR), group (n=3), the high risk (HR) group (n=3), the high risk with Dexrazoxane, HRdex group (n=3) that received the same median cumulative dose of Doxorubicin as the HR group along with a dose of a cardioprotective agent. In this project, the use of 2D patterns of myocardial strain is evaluated as part of the detection of myocardial damage and functional impairment due to doxorubicin treatment. Secondly, the use of these strain obtained by optical flow method as input to our model which is based on the method of special virtual fields to have the mechanical properties as well as the internal stresses of the myocardium, with the assumption that the treatment based on Doxorubicin induces significant changes in both tissue and myocardial function. MRI acquisition was done on a 3T device (Skyra™, Siemens Healthcare, Erlangen, Germany) using 18-channel phased array body matrix coil and an ECG-gated Steady State Free Precession (SSFP) cine sequence. Acquisition parameters were: slice thickness 8mm, repetition time 34.6ms, effective echo time 1.2ms, flip angle 38°, iPAT factor 3, matrix 208×210 and in-plane pixel size 1.25×1.25mm. Around 14 slices were acquired in the axial plane, and 5 slices in 2 chambers and 4 chambers planes. For the entire cardiac cycle, 25 images were acquired for each slice, with multiple breath holds. Within the 2-chambers view, significant changes were found for the strain fields between the four groups. Strain within HRdex were lower than in HR for the three considered phases (Systole, Early diastole, Late diastole). For the same view, shear stress and Von Mises stress, are inferior, in systole for the HRdex compared to HR. the module of elasticity is inferior for the SR compared to HR and HRdex, for the systole and the late diastole. The same difference is found for the shear modulus for the SR, in systole. Considering the 4CH view, the module of elasticity is significantly higher for the HRdex, compared to HR, and compared to SR's group and healthy volunteers HV's group, for the three considered phases (Systole, Early Diastole, Late diastole). Considering the axial view, shear and Von Mises stress were lower in systole for HR than for HRdex. The modulus of elasticity was found lower for SR than for HR and HRdex, same difference was observed for the shear modulus for the SR group in systole. In the axial view, in systole, significant changes were found between groups, for the shear and Von Mises stress. However, these changes were not found in 2CH and 4CH views, probably due to trhe different collagen fiber orientation between the views. For the modulus of elasticity, the changes in systole and late diastole were in agreement with the results obtained in 2CH and 4CH views. This difference between groups can be explained by the fact that the heart muscle of HR cancer behaves differently due to a reduction in the amount of the muscle fibers and an increase of the interstitial tissue. The severity of these changes is proportional to the cumulative anthracycline dose. If enough damage occurs, the heart expands in size and the chamber wall become thinner, creating a picture similar to dilated cardiomyopathy, in agreement with our results. Our model allowed us to observe the changes in strain fields, stress fields, as well as the mechanical properties of cardiac tissue presenting doxorubicin induced carditoxicity, which verifies our hypothesis and shows the feasibility of our approach. The perspectives of this study is to build a database for healthy volunteers and those presenting a cardiomyopathy, for preliminary comparison purposes, to rank patients according to the severity of the disease. This could help early detection of these cardiomyopathies

Translating computational modelling tools for clinical practice in congenital heart disease

Increasingly large numbers of medical centres worldwide are equipped with the means to acquire 3D images of patients by utilising magnetic resonance (MR) or computed tomography (CT) scanners. The interpretation of patient 3D image data has significant implications on clinical decision-making and treatment planning. In their raw form, MR and CT images have become critical in routine practice. However, in congenital heart disease (CHD), lesions are often anatomically and physiologically complex. In many cases, 3D imaging alone can fail to provide conclusive information for the clinical team. In the past 20-30 years, several image-derived modelling applications have shown major advancements. Tools such as computational fluid dynamics (CFD) and virtual reality (VR) have successfully demonstrated valuable uses in the management of CHD. However, due to current software limitations, these applications have remained largely isolated to research settings, and have yet to become part of clinical practice. The overall aim of this project was to explore new routes for making conventional computational modelling software more accessible for CHD clinics. The first objective was to create an automatic and fast pipeline for performing vascular CFD simulations. By leveraging machine learning, a solution was built using synthetically generated aortic anatomies, and was seen to be able to predict 3D aortic pressure and velocity flow fields with comparable accuracy to conventional CFD. The second objective was to design a virtual reality (VR) application tailored for supporting the surgical planning and teaching of CHD. The solution was a Unity-based application which included numerous specialised tools, such as mesh-editing features and online networking for group learning. Overall, the outcomes of this ongoing project showed strong indications that the integration of VR and CFD into clinical settings is possible, and has potential for extending 3D imaging and supporting the diagnosis, management and teaching of CHD