Advances in computational modelling for personalised medicine after myocardial infarction

Myocardial infarction (MI) is a leading cause of premature morbidity and mortality worldwide. Determining which patients will experience heart failure and sudden cardiac death after an acute MI is notoriously difficult for clinicians. The extent of heart damage after an acute MI is informed by cardiac imaging, typically using echocardiography or sometimes, cardiac magnetic resonance (CMR). These scans provide complex data sets that are only partially exploited by clinicians in daily practice, implying potential for improved risk assessment. Computational modelling of left ventricular (LV) function can bridge the gap towards personalised medicine using cardiac imaging in patients with post-MI. Several novel biomechanical parameters have theoretical prognostic value and may be useful to reflect the biomechanical effects of novel preventive therapy for adverse remodelling post-MI. These parameters include myocardial contractility (regional and global), stiffness and stress. Further, the parameters can be delineated spatially to correspond with infarct pathology and the remote zone. While these parameters hold promise, there are challenges for translating MI modelling into clinical practice, including model uncertainty, validation and verification, as well as time-efficient processing. More research is needed to (1) simplify imaging with CMR in patients with post-MI, while preserving diagnostic accuracy and patient tolerance (2) to assess and validate novel biomechanical parameters against established prognostic biomarkers, such as LV ejection fraction and infarct size. Accessible software packages with minimal user interaction are also needed. Translating benefits to patients will be achieved through a multidisciplinary approach including clinicians, mathematicians, statisticians and industry partners

Fast left ventricle tracking using localized anatomical affine optical flow

Fast left ventricle tracking using localized anatomical affine optical flowIn daily clinical cardiology practice, left ventricle (LV) global and regional function assessment is crucial for disease diagnosis, therapy selection, and patient follow-up. Currently, this is still a time-consuming task, spending valuable human resources. In this work, a novel fast methodology for automatic LV tracking is proposed based on localized anatomically constrained affine optical flow. This novel method can be combined to previously proposed segmentation frameworks or manually delineated surfaces at an initial frame to obtain fully delineated datasets and, thus, assess both global and regional myocardial function. Its feasibility and accuracy were investigated in 3 distinct public databases, namely in realistically simulated 3D ultrasound, clinical 3D echocardiography, and clinical cine cardiac magnetic resonance images. The method showed accurate tracking results in all databases, proving its applicability and accuracy for myocardial function assessment. Moreover, when combined to previous state-of-the-art segmentation frameworks, it outperformed previous tracking strategies in both 3D ultrasound and cardiac magnetic resonance data, automatically computing relevant cardiac indices with smaller biases and narrower limits of agreement compared to reference indices. Simultaneously, the proposed localized tracking method showed to be suitable for online processing, even for 3D motion assessment. Importantly, although here evaluated for LV tracking only, this novel methodology is applicable for tracking of other target structures with minimal adaptations.The authors acknowledge funding support from FCT - Fundacao para a Ciência e a Tecnologia, Portugal, and the European Social Found, European Union, through the Programa Operacional Capital Humano (POCH) in the scope of the PhD grants SFRH/BD/93443/2013 (S. Queiros) and SFRH/BD/95438/2013 (P. Morais), and by the project ’PersonalizedNOS (01-0145-FEDER-000013)’ co-funded by Programa Operacional Regional do Norte (Norte2020) through the European Regional Development Fund (ERDF).info:eu-repo/semantics/publishedVersio

Computational biomechanics of acute myocardial infarction and its treatment

The intramyocardial injection of biomaterials is an emerging therapy for myocardial infarction. Computational methods can help to study the mechanical effect s of biomaterial injectates on the infarcted heart s and can contribute to advance and optimise the concept of this therapy. The distribution of polyethylene glycol hydrogel injectate delivered immediately after the infarct induction was studied using rat infarct model. A micro-structural three-dimensional geometrical model of the entire injectate was reconstructed from histological micro graphs. The model provides a realistic representation of biomaterial injectates in computational models at macroscopic and microscopic level. Biaxial and compression mechanical testing was conducted for healing rat myocardial infarcted tissue at immediate (0 day), 7, 14 and 28 days after infarction onset. Infarcts were found to be mechanically anisotropic with the tissue being stiffer in circumferential direction than in longitudinal direction. The 0, 7, 14 and 28 days infarcts showed 443, 670, 857 and 1218 kPa circumferential tensile moduli. The 28 day infarct group showed a significantly higher compressive modulus compared to the other infarct groups (p= 0.0055, 0.028, and 0.018 for 0, 7 and 14 days groups). The biaxial mechanical data were utilized to establish material constitutive models of rat healing infarcts. Finite element model s and genetic algorithms were employed to identify the parameters of Fung orthotropic hyperelastic strain energy function for the healing infarcts. The provided infarct mechanical data and the identified constitutive parameters offer a platform for investigations of mechanical aspects of myocardial infarction and therapies in the rat, an experimental model extensively used in the development of infarct therapies. Micro-structurally detailed finite element model of a hydrogel injectate in an infarct was developed to provide an insight into the micromechanics of a hydrogel injectate and infarct during the diastolic filling. The injectate caused the end-diastolic fibre stresses in the infarct zone to decrease from 22.1 to 7.7 kPa in the 7 day infarct and from 35.7 to 9.7 kPa in the 28 day infarct. This stress reduction effect declined as the stiffness of the biomaterial increased. It is suggested that the gel works as a force attenuating system through micromechanical mechanisms reducing the force acting on tissue layers during the passive diastolic dilation of the left ventricle and thus reducing the stress induced in these tissue layers

Myocardial tagging by Cardiovascular Magnetic Resonance: evolution of techniques--pulse sequences, analysis algorithms, and applications

Cardiovascular magnetic resonance (CMR) tagging has been established as an essential technique for measuring regional myocardial function. It allows quantification of local intramyocardial motion measures, e.g. strain and strain rate. The invention of CMR tagging came in the late eighties, where the technique allowed for the first time for visualizing transmural myocardial movement without having to implant physical markers. This new idea opened the door for a series of developments and improvements that continue up to the present time. Different tagging techniques are currently available that are more extensive, improved, and sophisticated than they were twenty years ago. Each of these techniques has different versions for improved resolution, signal-to-noise ratio (SNR), scan time, anatomical coverage, three-dimensional capability, and image quality. The tagging techniques covered in this article can be broadly divided into two main categories: 1) Basic techniques, which include magnetization saturation, spatial modulation of magnetization (SPAMM), delay alternating with nutations for tailored excitation (DANTE), and complementary SPAMM (CSPAMM); and 2) Advanced techniques, which include harmonic phase (HARP), displacement encoding with stimulated echoes (DENSE), and strain encoding (SENC). Although most of these techniques were developed by separate groups and evolved from different backgrounds, they are in fact closely related to each other, and they can be interpreted from more than one perspective. Some of these techniques even followed parallel paths of developments, as illustrated in the article. As each technique has its own advantages, some efforts have been made to combine different techniques together for improved image quality or composite information acquisition. In this review, different developments in pulse sequences and related image processing techniques are described along with the necessities that led to their invention, which makes this article easy to read and the covered techniques easy to follow. Major studies that applied CMR tagging for studying myocardial mechanics are also summarized. Finally, the current article includes a plethora of ideas and techniques with over 300 references that motivate the reader to think about the future of CMR tagging

QUANTIFICATION OF MYOCARDIAL MECHANICS IN LEFT VENTRICLES UNDER INOTROPIC STIMULATION AND IN HEALTHY RIGHT VENTRICLES USING 3D DENSE CMR

Statistical data from clinical studies indicate that the death rate caused by heart disease has decreased due to an increased use of evidence-based medical therapies. This includes the use of magnetic resonance imaging (MRI), which is one of the most common non-invasive approaches in evidence-based health care research. In the current work, I present 3D Lagrangian strains and torsion in the left ventricle of healthy and isoproterenol-stimulated rats, which were investigated using Displacement ENcoding with Stimulated Echoes (DENSE) cardiac magnetic resonance (CMR) imaging. With the implementation of the 12-segment model, a detailed profile of regional cardiac mechanics was reconstructed for each subject. Statistical analysis revealed that isoproterenol induced a significant change in the strains and torsion in certain regions at the mid-ventricle level. In addition, I investigated right ventricular cardiac mechanics with the methodologies developed for the left ventricle. This included a comparison of different regions within the basal and mid-ventricular regions. Despite no regional variation found in the peak circumferential strain, the peak longitudinal strain exhibited regional variation at the anterior side of the RV due to the differences in biventricular torsion, mechanism of RV free wall contraction, and fiber architecture at RV insertions. Future applications of the experimental work presented here include the construction and validation of biventricular finite element models. Specifically, the strains predicted by the models will be statistically compared with experimental strains. In addition, the results of the present study provide an essential reference of RV baseline evaluated with DENSE MRI, a highly objective technique

Analysis of cardiac amyloidosis progression using model-based markers

Deposition of amyloid in the heart can lead to cardiac dilation and impair its pumping ability. This ultimately leads to heart failure with worsening symptoms of breathlessness and fatigue due to the progressive loss of elasticity of the myocardium. Biomarkers linked to clinical deterioration can be crucial in developing effective treatments. However, to date progression of cardiac amyloidosis is poorly characterized, and there is an urgent need to identify key features that can predict the disease progression and cardiac tissue function. In this proof of concept study, we estimate a group of new markers based on mathematical models of the left ventricle derived from routine clinical magnetic resonance imaging and follow-up scans from the National Amyloidosis Centre at the Royal Free in London. Using mechanical modelling and statistical classification, we show that it is possible to predict disease progression. Our predictions agree with clinical assessments in a double-blind test in six out of the seven sample cases studied. Importantly, we find that multiple factors need to be used in the classification, which includes mechanical, geometrical and shape features. No single marker can yield reliable prediction given the complexity of the growth and remodelling process of diseased hearts undergoing high-dimensional shape changes. Our approach is promising in terms of clinical translation but the results presented should be interpreted with caution due to the small sample size

Flow pattern analysis for magnetic resonance velocity imaging

Blood flow in the heart is highly complex. Although blood flow patterns have been investigated by both computational modelling and invasive/non-invasive imaging techniques, their evolution and intrinsic connection with cardiovascular disease has yet to be explored. Magnetic resonance (MR) velocity imaging provides a comprehensive distribution of multi-directional in vivo flow distribution so that detailed quantitative analysis of flow patterns is now possible. However, direct visualisation or quantification of vector fields is of little clinical use, especially for inter-subject or serial comparison of changes in flow patterns due to the progression of the disease or in response to therapeutic measures. In order to achieve a comprehensive and integrated description of flow in health and disease, it is necessary to characterise and model both normal and abnormal flows and their effects. To accommodate the diversity of flow patterns in relation to morphological and functional changes, we have described in this thesis an approach of detecting salient topological features prior to analytical assessment of dynamical indices of the flow patterns. To improve the accuracy of quantitative analysis of the evolution of topological flow features, it is essential to restore the original flow fields so that critical points associated with salient flow features can be more reliably detected. We propose a novel framework for the restoration, abstraction, extraction and tracking of flow features such that their dynamic indices can be accurately tracked and quantified. The restoration method is formulated as a constrained optimisation problem to remove the effects of noise and to improve the consistency of the MR velocity data. A computational scheme is derived from the First Order Lagrangian Method for solving the optimisation problem. After restoration, flow abstraction is applied to partition the entire flow field into clusters, each of which is represented by a local linear expansion of its velocity components. This process not only greatly reduces the amount of data required to encode the velocity distribution but also permits an analytical representation of the flow field from which critical points associated with salient flow features can be accurately extracted. After the critical points are extracted, phase portrait theory can be applied to separate them into attracting/repelling focuses, attracting/repelling nodes, planar vortex, or saddle. In this thesis, we have focused on vortical flow features formed in diastole. To track the movement of the vortices within a cardiac cycle, a tracking algorithm based on relaxation labelling is employed. The constraints and parameters used in the tracking algorithm are designed using the characteristics of the vortices. The proposed framework is validated with both simulated and in vivo data acquired from patients with sequential MR examination following myocardial infarction. The main contribution of the thesis is in the new vector field restoration and flow feature abstraction method proposed. They allow the accurate tracking and quantification of dynamic indices associated with salient features so that inter- and intra-subject comparisons can be more easily made. This provides further insight into the evolution of blood flow patterns and permits the establishment of links between blood flow patterns and localised genesis and progression of cardiovascular disease.Open acces

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

La doxorubicine (DOX) est un puissant agent antinéoplasique fréquemment administré dans le traitement de nombreux cancers pédiatriques, notamment la leucémie lymphoblastique aiguë (LLA). La doxorubicine possède une efficacité démontrée dans le traitement du cancer, mais elle engendre également un large spectre d'effets cardiaques indésirables. Les changements structurels du myocarde s'accompagnent de modifications progressives de la géométrie de la paroi du myocarde du ventricule gauche (VG). La détérioration de la fonction myocardique peut progresser silencieusement pendant des années et se manifester sans avertissement ou même ne devenir apparente que longtemps après la fin du traitement. Des doses cumulatives plus élevées de DOX augmentent le risque d'effets nocifs associés au traitement. La faisabilité de la résonnance magnétique cardiaque (RMC) a été établie et plusieurs logiciels de modélisation géométrique 3D du coeur ont été développés pour évaluer la fraction d'éjection, l'épaisseur de la parois, et le volume télésystolique et le volume télédiastolique du VG. La modélisation par éléments finis (EF) de la mécanique du ventricule gauche et les stratégies inverses d'identification des paramètres des matériaux ont ensuite été introduites pour tenir compte du comportement mécanique passif du tissu myocardique. Compte tenu de cela, nous avons entrepris une étude visant à analyser en détail les subtils changements asymptomatiques dans la géométrie et dans la fonction du ventricule gauche chez 84 survivants de la LLA infantile traités par chimiothérapie utilisant la doxorubicine (dose faible à modérée). Étant donné le grand potentiel de la modélisation numérique du coeur, cette évaluation a été réalisée à l'aide d'une approche basée sur un modèle EF qui intègre la forme et le mouvement spécifiques de la chambre ventriculaire directement à partir des données RMC. 84 survivants de la LLA, âgés de 23 ± 7 ans, ont été recrutés prospectivement et répartis en deux groupes distincts, nommés respectivement risque standard (SR, n = 19) et risque élevé en fonction du risque de récidive. En outre, les sujets du groupe associé à un risque élevé de récidive ont été subdivisés en deux sous-groupes selon qu’ils avaient reçu (HRdex, n = 36) ou non (HR, n = 45) la thérapie cardioprotectrice (dexrazoxane) dans le but de réduire le risque de lésions cardiaques à long terme. Par ailleurs, à des fins de comparaison, 10 volontaires en santé, d’âge similaire aux survivants (22 ± 4 ans) et n’ayant jamais été atteints de leucémie aiguë ou de cardiomyopathie, ont formé un groupe témoin. Dans le cadre de l'étude de la cardiotoxicité tardive, tous les sujets ont subi une imagerie RMC, une échocardiographie transthoracique et des tests d'effort. À partir des données RMC acquises, un opérateur formé a extrait la forme et le mouvement spécifiques du ventricule gauche à l'aide d'un cadre de points de repère (CIM v8.1, University of Auckland, Nouvelle-Zélande). Les bordures intérieures et extérieures des parois du ventricule gauche ont été dessinées semi-automatiquement à partir de six points de guidage placés par l'opérateur, puis corrigés manuellement en cas d'erreurs d'alignement. À partir de ce tracé, on a calculé la fraction d'éjection, le volume de course, la masse myocardique, l'épaisseur de la paroi, le volume diastolique final et le volume systolique final pour chacun des participants de l'étude. Par la suite, la reproductibilité inter- et intra-observateurs des résultats de la segmentation a été quantifiée par des coefficients de corrélation intra-classe (ICC) sur quatre reconstructions de 15 survivants du cancer, chacune étant réalisée par quatre opérateurs formés, et sur trois reconstructions du même sujet, chacune étant effectuée par un seul opérateur. Pour un sous-ensemble de la population des survivants de la leucémie (n = 48), un modèle 3D conçu par éléments finis a été utilisé pour calculer la propriété hyperélastique (C1) à partir d’une stratégie d'identification des paramètres inverses des matériaux basés sur la géométrie du VG lors de la diastase. Au départ, nous avons supposé 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 spécifiques au sujet (au repos et à l'exercice maximal) connues, nous avons incorporé ces données dans le modèle et répété l'analyse aux éléments finis. Les valeurs résultantes de C1 ont été notées et comparées entre les groupes pour chacun des cinq scénarios de charge. Les comparaisons statistiques ont été effectuées par analyse de variance à sens unique (ANOVA) sur les paramètres géométriques globaux et régionaux et par analyse de variance à mesures répétées bidirectionnelles sur les paramètres géométriques dépendants du temps. Enfin, une analyse de sensibilité a été effectuée pour évaluer la dépendance de la propriété hyperélastique de la diastase et de la pression. Dans le cas de notre étude, la reproductibilité intra-observateur était bonne pour les paramètres géométriques régionaux (ICC, 0.60-0.74) et excellente pour les paramètres géométriques globaux (ICC, 0.75-1.00), alors que la reproductibilité inter-observateur était excellente pour les deux types de paramètres (ICC, 0.75-1.00). Aucune différence significative entre les quatre groupes n’a été observée relativement à la fraction d’éjection, au débit systolique, à la masse, au volume systolique final et au volume diastolique final. Quelques différences de volume épicardique ont été observées, mais seulement entre la phase finale de la systole et la diastase (p<0.01) à l’intérieur des groupes HRdex et HV ou SR, et parmi les groupes HV et HR. Il est intéressant de noter que la propriété hyperélastique pour les pressions standard était légèrement plus faible dans le groupe HR comparativement au groupe HRdex ou SR et aussi relativement au groupe contrôle (p<0.05). En revanche, aucune différence appréciable n’a pu être détectée dans la propriété hyperélastique à des pressions intraventriculaires au repos (p>0.5) et à l’exercice maximal (p>0.6). Il ressort clairement de cette analyse que les paramètres géométriques globaux et régionaux ne sont pas suffisamment sensibles pour détecter les changements subtils induits par la cardiotoxicité tardive de la doxorubicine dans la structure et la fonction du ventricule gauche. Toutefois, les paramètres globaux dépendants du temps constituent des preuves préliminaires que l’exposition à la doxorubicin a un effet plus néfaste sur la diastole précoce que sur la systole ou la diastole tardive. La propriété hyperélastique, plus faible dans le groupe HR, suggère un tissu myocardique plus enclin à la dilatation si une pression intra-ventriculaire plus élevée est appliquée, comparativement aux autres groupes d'étude. Cette constatation concorde avec ce qui a été observé chez les survivants à long terme ayant eu la leucémie adulte et traités par chimiothérapie à forte dose à base de doxorubicine. Il convient toutefois de noter que ces estimations ne peuvent tenir compte que des effets géométriques du remodelage du myocarde sur la mécanique ventriculaire passive, puisque la pression intra-ventriculaire gauche spécifique au sujet n'était pas incluse dans ces simulations. Des résultats similaires ont été obtenus lors de l'application de pressions intra-ventriculaires mesurées au repos et pendant l'exercice maximal. En conclusion, cette étude démontre que la cardiotoxicité subclinique de la doxorubicine peut être évaluée par l’analyse du comportement mécanique du ventricule gauche sur des images RMC. Nos résultats doivent toutefois être confirmés par des analyses additionnelles avant d’en tirer une conclusion solide sur la signification pronostique, à long terme, des altérations de la raideur myocardique et de leur relation avec le statut de risque dans la cohorte de survivants étudiée ou dans une cohorte similaire. Il serait très pertinent, dans le cadre d’études ultérieures, d’inclure la simulation de la mécanique ventriculaire, avec la méthode des éléments finis, pendant la diastole précoce et la systole afin de mieux analyser les changements de rigidité dans les groupes. Dans le même but, il pourrait être utile d'augmenter la résolution temporelle des données d'imagerie chez les survivants de la leucémie et les sujets témoins. Mots-clés : survivants de la leucémie lymphoblastique aiguë, cardiotoxicité induite par la doxorubicine, imagerie par résonance magnétique cardiaque, rigidité passive du myocarde, modélisation par éléments finis personnalisée, mécanique 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