167 research outputs found

    Investigating left ventricular infarct extension after myocardial infarction using cardiac imaging and patient-specific modelling

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    Acute myocardial infarction (MI) is one of the leading causes of death worldwide that commonly affects the left ventricle (LV). Following MI, the LV mechanical loading is altered and may undergo a maladaptive compensatory mechanism that progressively leads to adverse LV remodelling and then heart failure. One of the remodelling processes is the infarct extension which involves necrosis of healthy myocardium in the border zone (BZ), progressively enlarging the infarct zone (IZ) and recruiting the remote zone (RZ) into the BZ. The mechanisms underlying infarct extension remain unclear, but myocyte stretching has been suggested as the most likely cause. A recent personalized LV modelling work found that infarct extension was correlated to inadequate diastolic fibre stretch and higher infarct stiffness. However, other possible factors of infarct extension may not have been elucidated in this work due to the limited number of myocardial locations analysed at the subendocardium only. Using human patient-specific left- ventricular (LV) models established from cardiac magnetic resonance imaging (MRI) of 6 MI patients, the correlation between infarct extension and regional mechanics impairment was studied. Prior to the modelling, a 2D-4D registration-cum-segmentation framework for the delineation of LV in late gadolinium enhanced (LGE) MRI was first developed, which is a pre-requisite for infarct scar quantification and localization in patient-specific 3D LV models. This framework automatically corrects for motion artifacts in multimodal MRI scans, resolving the issue of inaccurate infarct mapping and geometry reconstruction which is typically done manually in most patient-specific modelling work. The registration framework was evaluated against cardiac MRI data from 27 MI patients and showed high accuracy and robustness in delineating LV in LGE MRI of various quality and different myocardial features. This framework allows the integration of LV data from both LGE and cine scans and to facilitate the reconstruction of accurate 3D LV and infarct geometries for subsequent computational study. In the patient-specific LV mechanical modelling, the LV mechanics were formulated using a quasi-static and nearly incompressible hyperelastic material law with transversely isotropic behaviour. The patient-specific models were incorporated with realistic fibre orientation and excitable contracting myocardium. Optimisation of passive and active material parameters were done by minimizing the myocardial wall distance between the reference and end-diastole/end-systole LV geometries. Full cardiac cycle of the LV models was then simulated and stress/strain data were extracted to determine the correlation between regional mechanics abnormality and infarct extension. The fibre stress-strain loops (FSSLs) were analysed and its abnormality was characterized using the directional regional external work (DREW) index, which measures FSSL area and loop direction. Sensitivity studies were also performed to investigate the effect of infarct stiffness on regional myocardial mechanics and potential for infarct extension. It was found that infarct extension was correlated to severely abnormal FSSL in the form of counter-clockwise loop, as indicated by negative DREW values. In regions demonstrating negative DREW values, substantial isovolumic relaxation (IVR) fibre stretching was observed. Further analysis revealed that the occurrence of severely abnormal FSSL near the RZ-BZ boundary was due to a large amount of surrounding infarcted tissue that worsen with excessively stiff IZ

    Computational modelling of diastole for human ventricle

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    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

    Modelling deformation in the failing heart

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    Digital Twin of Cardiovascular Systems

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    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

    Subtle Changes in Hyperelastic Properties of Myocardium With Cardiotoxicity Remodeling From Cardiac Magnetic Resonance

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    La doxorubicine (DOX) est un puissant agent antinĂ©oplasique frĂ©quemment administrĂ© dans le traitement de nombreux cancers pĂ©diatriques, notamment la leucĂ©mie lymphoblastique aiguĂ« (LLA). La doxorubicine possĂšde une efficacitĂ© dĂ©montrĂ©e dans le traitement du cancer, mais elle engendre Ă©galement un large spectre d'effets cardiaques indĂ©sirables. Les changements structurels du myocarde s'accompagnent de modifications progressives de la gĂ©omĂ©trie de la paroi du myocarde du ventricule gauche (VG). La dĂ©tĂ©rioration de la fonction myocardique peut progresser silencieusement pendant des annĂ©es et se manifester sans avertissement ou mĂȘme ne devenir apparente que longtemps aprĂšs la fin du traitement. Des doses cumulatives plus Ă©levĂ©es de DOX augmentent le risque d'effets nocifs associĂ©s au traitement. La faisabilitĂ© de la rĂ©sonnance magnĂ©tique cardiaque (RMC) a Ă©tĂ© Ă©tablie et plusieurs logiciels de modĂ©lisation gĂ©omĂ©trique 3D du coeur ont Ă©tĂ© dĂ©veloppĂ©s pour Ă©valuer la fraction d'Ă©jection, l'Ă©paisseur de la parois, et le volume tĂ©lĂ©systolique et le volume tĂ©lĂ©diastolique du VG. La modĂ©lisation par Ă©lĂ©ments finis (EF) de la mĂ©canique du ventricule gauche et les stratĂ©gies inverses d'identification des paramĂštres des matĂ©riaux ont ensuite Ă©tĂ© introduites pour tenir compte du comportement mĂ©canique passif du tissu myocardique. Compte tenu de cela, nous avons entrepris une Ă©tude visant Ă  analyser en dĂ©tail les subtils changements asymptomatiques dans la gĂ©omĂ©trie et dans la fonction du ventricule gauche chez 84 survivants de la LLA infantile traitĂ©s par chimiothĂ©rapie utilisant la doxorubicine (dose faible Ă  modĂ©rĂ©e). Étant donnĂ© le grand potentiel de la modĂ©lisation numĂ©rique du coeur, cette Ă©valuation a Ă©tĂ© rĂ©alisĂ©e Ă  l'aide d'une approche basĂ©e sur un modĂšle EF qui intĂšgre la forme et le mouvement spĂ©cifiques de la chambre ventriculaire directement Ă  partir des donnĂ©es RMC. 84 survivants de la LLA, ĂągĂ©s de 23 ± 7 ans, ont Ă©tĂ© recrutĂ©s prospectivement et rĂ©partis en deux groupes distincts, nommĂ©s respectivement risque standard (SR, n = 19) et risque Ă©levĂ© en fonction du risque de rĂ©cidive. En outre, les sujets du groupe associĂ© Ă  un risque Ă©levĂ© de rĂ©cidive ont Ă©tĂ© subdivisĂ©s en deux sous-groupes selon qu’ils avaient reçu (HRdex, n = 36) ou non (HR, n = 45) la thĂ©rapie cardioprotectrice (dexrazoxane) dans le but de rĂ©duire le risque de lĂ©sions cardiaques Ă  long terme. Par ailleurs, Ă  des fins de comparaison, 10 volontaires en santĂ©, d’ñge similaire aux survivants (22 ± 4 ans) et n’ayant jamais Ă©tĂ© atteints de leucĂ©mie aiguĂ« ou de cardiomyopathie, ont formĂ© un groupe tĂ©moin. Dans le cadre de l'Ă©tude de la cardiotoxicitĂ© tardive, tous les sujets ont subi une imagerie RMC, une Ă©chocardiographie transthoracique et des tests d'effort. À partir des donnĂ©es RMC acquises, un opĂ©rateur formĂ© a extrait la forme et le mouvement spĂ©cifiques du ventricule gauche Ă  l'aide d'un cadre de points de repĂšre (CIM v8.1, University of Auckland, Nouvelle-ZĂ©lande). Les bordures intĂ©rieures et extĂ©rieures des parois du ventricule gauche ont Ă©tĂ© dessinĂ©es semi-automatiquement Ă  partir de six points de guidage placĂ©s par l'opĂ©rateur, puis corrigĂ©s manuellement en cas d'erreurs d'alignement. À partir de ce tracĂ©, on a calculĂ© la fraction d'Ă©jection, le volume de course, la masse myocardique, l'Ă©paisseur de la paroi, le volume diastolique final et le volume systolique final pour chacun des participants de l'Ă©tude. Par la suite, la reproductibilitĂ© inter- et intra-observateurs des rĂ©sultats de la segmentation a Ă©tĂ© quantifiĂ©e par des coefficients de corrĂ©lation intra-classe (ICC) sur quatre reconstructions de 15 survivants du cancer, chacune Ă©tant rĂ©alisĂ©e par quatre opĂ©rateurs formĂ©s, et sur trois reconstructions du mĂȘme sujet, chacune Ă©tant effectuĂ©e par un seul opĂ©rateur. Pour un sous-ensemble de la population des survivants de la leucĂ©mie (n = 48), un modĂšle 3D conçu par Ă©lĂ©ments finis a Ă©tĂ© utilisĂ© pour calculer la propriĂ©tĂ© hyperĂ©lastique (C1) Ă  partir d’une stratĂ©gie d'identification des paramĂštres inverses des matĂ©riaux basĂ©s sur la gĂ©omĂ©trie du VG lors de la diastase. Au dĂ©part, nous avons supposĂ© des valeurs physiologiquement raisonnables de 0.75, 1.0 et 1.25 kPa comme contraintes de charge de pression pour tous les participants. Une fois les pressions ventriculaires spĂ©cifiques au sujet (au repos et Ă  l'exercice maximal) connues, nous avons incorporĂ© ces donnĂ©es dans le modĂšle et rĂ©pĂ©tĂ© l'analyse aux Ă©lĂ©ments finis. Les valeurs rĂ©sultantes de C1 ont Ă©tĂ© notĂ©es et comparĂ©es entre les groupes pour chacun des cinq scĂ©narios de charge. Les comparaisons statistiques ont Ă©tĂ© effectuĂ©es par analyse de variance Ă  sens unique (ANOVA) sur les paramĂštres gĂ©omĂ©triques globaux et rĂ©gionaux et par analyse de variance Ă  mesures rĂ©pĂ©tĂ©es bidirectionnelles sur les paramĂštres gĂ©omĂ©triques dĂ©pendants du temps. Enfin, une analyse de sensibilitĂ© a Ă©tĂ© effectuĂ©e pour Ă©valuer la dĂ©pendance de la propriĂ©tĂ© hyperĂ©lastique de la diastase et de la pression. Dans le cas de notre Ă©tude, la reproductibilitĂ© intra-observateur Ă©tait bonne pour les paramĂštres gĂ©omĂ©triques rĂ©gionaux (ICC, 0.60-0.74) et excellente pour les paramĂštres gĂ©omĂ©triques globaux (ICC, 0.75-1.00), alors que la reproductibilitĂ© inter-observateur Ă©tait excellente pour les deux types de paramĂštres (ICC, 0.75-1.00). Aucune diffĂ©rence significative entre les quatre groupes n’a Ă©tĂ© observĂ©e relativement Ă  la fraction d’éjection, au dĂ©bit systolique, Ă  la masse, au volume systolique final et au volume diastolique final. Quelques diffĂ©rences de volume Ă©picardique ont Ă©tĂ© observĂ©es, mais seulement entre la phase finale de la systole et la diastase (p<0.01) Ă  l’intĂ©rieur des groupes HRdex et HV ou SR, et parmi les groupes HV et HR. Il est intĂ©ressant de noter que la propriĂ©tĂ© hyperĂ©lastique pour les pressions standard Ă©tait lĂ©gĂšrement plus faible dans le groupe HR comparativement au groupe HRdex ou SR et aussi relativement au groupe contrĂŽle (p<0.05). En revanche, aucune diffĂ©rence apprĂ©ciable n’a pu ĂȘtre dĂ©tectĂ©e dans la propriĂ©tĂ© hyperĂ©lastique Ă  des pressions intraventriculaires au repos (p>0.5) et Ă  l’exercice maximal (p>0.6). Il ressort clairement de cette analyse que les paramĂštres gĂ©omĂ©triques globaux et rĂ©gionaux ne sont pas suffisamment sensibles pour dĂ©tecter les changements subtils induits par la cardiotoxicitĂ© tardive de la doxorubicine dans la structure et la fonction du ventricule gauche. Toutefois, les paramĂštres globaux dĂ©pendants du temps constituent des preuves prĂ©liminaires que l’exposition Ă  la doxorubicin a un effet plus nĂ©faste sur la diastole prĂ©coce que sur la systole ou la diastole tardive. La propriĂ©tĂ© hyperĂ©lastique, plus faible dans le groupe HR, suggĂšre un tissu myocardique plus enclin Ă  la dilatation si une pression intra-ventriculaire plus Ă©levĂ©e est appliquĂ©e, comparativement aux autres groupes d'Ă©tude. Cette constatation concorde avec ce qui a Ă©tĂ© observĂ© chez les survivants Ă  long terme ayant eu la leucĂ©mie adulte et traitĂ©s par chimiothĂ©rapie Ă  forte dose Ă  base de doxorubicine. Il convient toutefois de noter que ces estimations ne peuvent tenir compte que des effets gĂ©omĂ©triques du remodelage du myocarde sur la mĂ©canique ventriculaire passive, puisque la pression intra-ventriculaire gauche spĂ©cifique au sujet n'Ă©tait pas incluse dans ces simulations. Des rĂ©sultats similaires ont Ă©tĂ© obtenus lors de l'application de pressions intra-ventriculaires mesurĂ©es au repos et pendant l'exercice maximal. En conclusion, cette Ă©tude dĂ©montre que la cardiotoxicitĂ© subclinique de la doxorubicine peut ĂȘtre Ă©valuĂ©e par l’analyse du comportement mĂ©canique du ventricule gauche sur des images RMC. Nos rĂ©sultats doivent toutefois ĂȘtre confirmĂ©s par des analyses additionnelles avant d’en tirer une conclusion solide sur la signification pronostique, Ă  long terme, des altĂ©rations de la raideur myocardique et de leur relation avec le statut de risque dans la cohorte de survivants Ă©tudiĂ©e ou dans une cohorte similaire. Il serait trĂšs pertinent, dans le cadre d’études ultĂ©rieures, d’inclure la simulation de la mĂ©canique ventriculaire, avec la mĂ©thode des Ă©lĂ©ments finis, pendant la diastole prĂ©coce et la systole afin de mieux analyser les changements de rigiditĂ© dans les groupes. Dans le mĂȘme but, il pourrait ĂȘtre utile d'augmenter la rĂ©solution temporelle des donnĂ©es d'imagerie chez les survivants de la leucĂ©mie et les sujets tĂ©moins. Mots-clĂ©s : survivants de la leucĂ©mie lymphoblastique aiguĂ«, cardiotoxicitĂ© induite par la doxorubicine, imagerie par rĂ©sonance magnĂ©tique cardiaque, rigiditĂ© passive du myocarde, modĂ©lisation par Ă©lĂ©ments finis personnalisĂ©e, mĂ©canique ventriculaire gauche.----------ABSTRACT Doxorubicin (DOX) is a potent chemotherapeutic agent routinely administered in the treatment of several pediatric malignancies, including acute lymphoblastic leukemia (ALL). Despite its efficacy to improve the outlook of cancer patients, doxorubicin is known to cause a wide spectrum of cardiac adverse effects. The structural changes in the myocardium are accompanied by progressive changes in LV myocardial wall geometry. The deterioration of myocardial function can progress silently for many years before the manifestation of clinical symptoms and become apparent even long time after completion of treatment. Higher cumulative doses of this agent increase the risk for late cardiac complications. The feasibility of CMR imaging has been established and a variety of software for 3D geometric modeling of the heart have been developed to assess wall thicknesses, ejection fraction, end-systolic and end-diastolic volumes. Finite element (FE) modelling and inverse material parameter identification strategies were then introduced to take into account the passive mechanical behavior of the myocardial tissue. In light of the above, we undertook a study to assess the asymptomatic changes in LV structure and function in a group of long-term survivors of childhood ALL treated with low to moderate doses of doxorubicin therapy. Given the high potential of numerical cardiac modeling, this evaluation was conducted using a FE model-based approach that integrates the subject-specific shape and motion of the ventricular chamber directly from imaging data. Eighty-four ALL survivors (23±7 years old) were prospectively enrolled and stratified into two different groups, designated as standard-risk (SR, n=19) and high-risk groups, according to their risk of tumor recurrence. Subjects treated for high-risk ALL were further divided into two groups depending upon whether they did (HRdex, n=36) or did not (HR, n=45) receive the protective therapy (dexrazoxane) in an attempt to reduce the likelihood of late cardiotoxicity. Furthermore, for purposes of comparison, 10 healthy volunteers (HV, 22±4 years), with no prior history of cancer or cardiac pathologies and similar in age to the survivors, were used as controls. As a part of the investigation of late-onset cardiotoxicity, all subjects underwent CMR imaging, transthoracic echocardiography, and exercise stress testing. From the acquired CMR data, a trained operator extracted the subject-specific shape and motion of the LV using a guide-point framework (CIM v8.1, University of Auckland, New Zealand). The inner and outer borders of the LV walls were semi-automatically drawn from six guidepoints placed by the operator at end-systole and then manually corrected for mis-registration errors. From this tracing, ejection fraction, stroke volume, myocardial mass, wall thickness, end-diastolic and end-systolic volumes were computed for each of the study participants. After that, inter- and intraobserver repeatability of the segmentation results were quantified by intra-class coefficients (ICC) on four reconstructions of 15 leukemia survivors, each by four trained operators, and on three reconstructions of the same subject, each by a single operator. For a subset of the leukemia survivor population (n=48), a 3D finite element model was used to quantify the hyperelastic property (C1) from inverse material parameters identification strategies based on the LV geometry at diastasis. This biomechanical parameter was initially calculated by assuming physiologically realistic values of 0.75, 1.0, and 1.25 kPa as pressure loading constraints for all participants. Once the subject-specific LV pressures (at rest and peak exercise) became available, we incorporated such data in the model and repeated the FE analysis. The resulting values of C1 were reported and compared between groups for each of the five loading scenarios. Statistical comparisons were performed by one-way analysis of variance (ANOVA) on global and regional geometrical parameters, and two-way repeated-measures ANOVA on time-dependent geometrical parameters. Ultimately, a sensitivity analysis was conducted to evaluate the dependence of the hyperelastic property on the diastasis frame and the pressure load. In our experience, inter-observer repeatability was good for regional geometrical parameters (ICC, 0.60-0.74) and excellent for global geometrical parameters (ICC, 0.75-1.00), while intra-observer repeatability was excellent for both regional and global parameters (ICC, 0.75-1.00). Groups had similar LV function values. No significant differences were observed among the four study groups in ejection fraction, stroke volume, mass, end-diastolic or end-systolic volumes. Some differences were detected in epicardial volume only between end-systole and diastasis phases (p<0.01) among the HRdex and HV or SR groups, and among the HV and HR groups. Interestingly, the hyperelastic property for standard pressures was slightly lower in the HR group when compared against the HRdex or SR group, and also when compared against the control group (p<0.05). In contrast, no appreciable difference could be noted in the hyperelastic property for intra-ventricular pressures at rest (p>0.5) and peak exercise (p>0.6). From this analysis, it is clear that the global and regional geometrical parameters are not sufficiently sensitive to capture the subtle changes induced by late doxorubicin cardiotoxicity in LV structure and function. Nevertheless, the time-dependent global parameters provided preliminary evidence that early diastole was more affected by doxorubicin exposure than systole or late diastole. The smaller hyperelastic property in the high-risk group suggested a myocardial tissue more prone to dilatation if increased intra-ventricular pressure is applied than in the other study groups. This finding is consistent with what has been observed in long-term survivors of adult leukemia treated with high-dose doxorubicin-based chemotherapy. It should be noted, however, that these estimates could account only for the geometrical effects of myocardial remodeling on the passive ventricular mechanics since the subject-specific LV cavity pressure was not included in these simulations. Similar results were obtained when applying intra-ventricular pressures at rest and peak exercise. In conclusion, this study demonstrated that the subclinical cardiotoxicity of doxorubicin can be non-invasively assessed through the mechanical behavior analysis of the LV on CMR images. Additional investigations will be necessary to confirm our results and draw a firm conclusion about the long-term prognostic significance of alterations in myocardial stiffness and their relationship with ALL risk status in this or similar cohort of survivors. In future works, we hope to include the FE simulation of the left ventricular mechanics during systole and early diastole in order to better capture the changes in stiffness across groups. To the same purpose, it might be convenient to increase the temporal resolution of the image data in both leukemia survivors and control subjects. Keywords: acute lymphoblastic leukemia survivors, doxorubicin-mediated cardiotoxicity, cardiac magnetic resonance imaging, passive myocardial stiffness, personalized FE modeling, in vivo left ventricular mechanics

    A multiple-network poroelastic model for biological systems and application to subject-specific modelling of cerebral fluid transport

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    Biological tissue can be viewed as porous, permeable and deformable media infiltrated by fluids, such as blood and interstitial fluid. A finite element model has been developed based on the multiple-network poroelastic theory to investigate transport phenomenon in such biological systems. The governing equations and boundary conditions are adapted for the cerebral environment as an example. The numerical model is verified against analytical solutions of classical consolidation problems and validated using experimental data of infusion tests. It is then applied to three-dimensional subject-specific modelling of brain, including anatomically realistic geometry, personalised permeability map and arterial blood supply to the brain. Numerical results of smoking and non-smoking subjects show hypoperfusion in the brains of smoking subjects, which also demonstrate that the numerical model is capable of capturing spatio-temporal fluid transport in biological systems across different scales

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

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    RÉSUMÉ La chimiothĂ©rapie Ă  la doxorubicine est efficace et est largement utilisĂ©e pour traiter la leucĂ©mie lymphoblastique aiguĂ«. Toutefois, son efficacitĂ© est entravĂ©e par un large spectre de cardiotoxicitĂ©s incluant des changements affectant Ă  la fois la morphologie et la fonction du myocarde. Ces changements dĂ©pendent principalement de la dose cumulĂ©e administrĂ©e au patient. Actuellement, trĂšs peu de techniques sont disponibles pour dĂ©tecter de telles cardiotoxicitĂ©s. L'utilisation d’images de fibres musculaires (par exemple, Ă  l’aide de l’imagerie des tenseurs de diffusion par IRM) ou des techniques d'imagerie 3D (par exemple, cinĂ© DENSE IRM) sont des alternatives prometteuses, cependant, leur application en clinique est limitĂ©e en raison du temps d'acquisition d’images et les erreurs d'estimation qui en rĂ©sultent. En revanche, l'utilisation de l'IRM multi-paramĂ©trique ainsi que le cinĂ© IRM sont des alternatives prometteuses, puisque ces techniques sont dĂ©jĂ  disponibles au niveau clinique. L’IRM multiparamĂ©trique incluant l’imagerie des temps de relaxation T1 et T2 peut ĂȘtre utile dans la dĂ©tection des lĂ©sions dans le tissu du myocarde alors que l’imagerie cinĂ© IRM peut ĂȘtre plus appropriĂ©e pour dĂ©tecter les changements fonctionnels au sein du myocarde. La combinaison de ces deux techniques peut Ă©galement permettre une caractĂ©risation complĂšte de la fonction du tissu myocardique. Dans ce projet, l'utilisation des temps de relaxation T1 prĂ©- et post-gadolinium et T2 est d'abord Ă©valuĂ©e et proposĂ©e pour dĂ©tecter les dommages myocardiques induits par la chimiothĂ©rapie Ă  la doxorubicine. En second lieu, l'utilisation de patrons 2D de dĂ©placements myocardiques est Ă©valuĂ©e dans le cadre de la dĂ©tection des dommages myocardiques et altĂ©ration fonctionnelle due au traitement Ă  la doxorubicine. Enfin, l'utilisation de la modĂ©lisation par Ă©lĂ©ments finis, incluant les contraintes et dĂ©formations mĂ©caniques est proposĂ©e pour Ă©valuer les changements dans les propriĂ©tĂ©s mĂ©caniques au niveau du myocarde, avec l’hypothĂšse que le traitement Ă  base de doxorubicine induit des changements importants Ă  la fois dans le tissu et au niveau de la fonction myocardique. Dans notre cohorte de survivants de cancer, des changements myocardiques locaux ont Ă©tĂ© trouvĂ©s entre le groupe Ă  risque standard et le groupe Ă  risque Ă©levĂ© lorsque le T1 prĂ©-gadolinium fut utilisĂ©. Ces changements ont Ă©tĂ© amplifiĂ©s avec l’utilisation d’agent de contraste tel que confirmĂ© par le coefficient de partition, ce qui suggĂšre 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

    Improved outcome prediction in tetralogy of Fallot

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    Successful advances in cardiac surgery have led to a paradigm shift in the management of an expanding population of repaired tetralogy of Fallot (rTOF) patients. However, late morbidity and mortality have not been abolished, with patients vulnerable to arrhythmia and sudden death. Outcome prediction remains challenging, mandating the identification of novel sensitive and specific non-invasive biomarkers. Cardiac fibrosis in rTOF has been shown to correlate to adverse clinical features, and therefore merits further study, particularly with regards to interstitial fibrosis. Cardiac remodelling following surgical pulmonary valve replacement in patients with rTOF was investigated. Structural reverse remodelling was observed to occur immediately after surgery, followed by gradual biological remodelling. A proactive surgical approach before right ventricular (RV) end-systolic indexed volumes exceed 82ml/m2 confers optimal postoperative RV normalisation. Novel cardiovascular magnetic resonance T1 mapping techniques were developed and tested to improve identification of RV interstitial cardiac fibrosis in rTOF. Multi-echo imaging to separate fat from myocardium, combined with blood signal suppression is promising as a feasible method in saturation-recovery T1 mapping, but requires further technical study prior to clinical application and validation. The genomic signatures of the pathological RV in rTOF were investigated by next generation RNA sequencing. Differential gene expression was evident, and potential molecular determinants of fibrotic and restrictive phenotypes were ascertained. Ubiquitin C may have important functional implications as a ‘network hub’ gene in rTOF. Finally, the longitudinal predictive role of neurohormone expression in patients with rTOF was examined. Neurohormonal activation was confirmed in rTOF, with serum brain natriuretic peptide being prognostic for mortality and sustained arrhythmias during extended follow-up. In conclusion, this work reflects the complex interplay of candidate biomarkers in influencing clinical outcomes. Myocardial fibrosis in rTOF remains a key diagnostic and therapeutic target for improving risk stratification and ameliorating morbidity in the lifelong care of these individuals.Open Acces
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