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

Motion compensated iterative reconstruction for cardiac X-ray tomography

Within this Ph.D. project, three-dimensional reconstruction methods for moving objects (with a focus on the human heart) from cone-beam X-ray projections using iterative reconstruction algorithms were developed and evaluated. This project was carried in collaboration with the Digital Imaging Group of Philips Research Europe – Hamburg. In cardiac cone-beam computed tomography (CT) a large effort is continuously dedicated to increase scanning speed in order to minimize patient or organ motion during acquisition. In particular, motion causes severe artifacts such as blurring and streaks in tomographic images. While for a large class of applications the current scanning speed is sufficient, in cardiac CT image reconstruction improvements are still required. Whereas it is currently feasible to achieve stable image quality in the resting phases of the cardiac cycle, in the phase of fast motion data acquisition is too slow. A variety of algorithms to reduce or compensate for motion artifacts have been proposed in literature. Most of the correction methods address the calculation of consistent projection data belonging to the same motion state (gated CT reconstruction). Even if gated CT leads to better results, not only with respect to the processing time but also regarding the image quality, it is also limited in its temporal and spatial resolution due to the mechanical movement of the gantry. This can lead to motion blurring, especially in the phases of fast cardiac motion during the RR interval. A motion-compensated reconstruction method for CT can be used to improve the resolution of the reconstructed image and to suppress motion blurring. Iterative techniques are a promising approach to solve this problem, since no direct inversion methods are known for arbitrarily moving objects. In this work, we therefore introduced motion compensation into image reconstruction. In order to determine the unknown cardiac motion, 3 different cardiac-motion estimation methodologies were implemented. Visual and quantitative assessment of the method in a number of applications, including: phantoms; cardiac CT reconstructions; Region of Interest (ROI) CT reconstructions of left and right coronaries of several clinical patients, confirmed its potential

Computational modelling of diastole for human ventricle

Diastolic heart failure (DHF) with normal systolic pump function has been typically observed in the majority of HF patients. DHF changes regular diastolic behaviour of left-ventricle (LV), and increases the ventricular wall stress. Therefore, normalisation of increased LV wall stress is the cornerstone of many existing and new therapeutic treatments. However, information regarding such regional stress-strain distribution for human LV is extremely limited in the literature. Thus, the study aimed at estimating the normal range and regional variation of diastolic stress-strain field in healthy human LVs, and exploring the infl uence of fibre structure, geometrical heterogeneity and material properties on passive infl ation of LV. It is envisaged that such information could be used as targets for future in-silico studies to design optimised HF treatments. FE modelling of passive diastolic mechanics was carried out using personalised ventricular geometry, that was constructed from magnetic resonance imaging (MRI), and structure-based orthotropic constitutive law. Laplace-Dirichlet-Region growing-Finite element (LDRF) algorithm was developed in order to assign the myocardium fibre map on ventricular geometry. The effect of right ventricle (RV) deformation, that has not been taken into account by the majority of researchers due to modelling simplification, was investigated for the first time by comparing the results predicted by bi-ventricle (BV) and single LV models, constructed from the aforementioned MRI data. In addition, personalised in-vivo measurement of fibre structure, that might be different in individual subjects and diseased conditions, is still an open question. Therefore, the sensitivity of LV diastolic mechanics to the details of the fibre structure was accomplished for the first time using eight different fibre orientations. In-vivo passive orthotropic myocardium properties for healthy human myocardium, indispensable for personalised LV wall stress estimation, was identified, and subsequently, the regional variations of LV wall stress-strain were investigated by incorporating geometrical heterogeneity, personalised myocardium properties and LV base movements in the FE models. RV deformation increased average fibre and sheet stress-strain in LV wall during diastole, and therefore, the effect should always be included in cardiac biomechanics study. Any pathological remodelling, that increased the amount of transmural fibre angle, led to an additional LV infl ation. The study indicates that a change in fibre orientation may contribute to the heart failure with preserved ejection fraction (HFpEF) development. Future therapeutic intervention should consider the effect of altered fibre orientation for better outcome. Due to the ill-posed nature of the inverse optimisation problem, the average myocardial stiffness was extracted by identifying the normal ranges of the parameters. A novel method was developed by combining FE modelling, response surface method (RSM) and genetic algorithm (GA) to identify the passive orthotropic myocardium properties for healthy human myocardium using routinely used clinical data. These myocardium properties can directly be utilised in future computational studies. Although the regional stress-strain distribution of the LV wall was highly heterogeneous amongst the individuals, it was observed that the inner wall of the LV experienced higher fibre stress compared to the outer wall. The LV wall near the base and the lateral region received greater stress-strain compared to the other regions. The incorporation of LV base movement (not addressed in the literature) improved the FE model predictions, and therefore, it is recommended to be considered in later studies. In addition, normal ranges of various stress-strain components in different regions of LV wall were reported for five healthy human ventricles considering RV deformation, LV base movement, and subject-specific myocardium properties. This information could be used as a reference map for future studies. The study revealed that the FE modelling can be employed to analyse the effect of geometry, fibre-structure and material properties on normal ventricular mechanics, and therefore, can provide a greater insight into the underlying mechanics of failing heart and plan for optimised surgical intervention. Hence, the research has impacts on computational cardiac biomechanics as well as clinical cardiac physiology fields