MyoPS A Benchmark of Myocardial Pathology Segmentation Combining Three-Sequence Cardiac Magnetic Resonance Images

Assessment of myocardial viability is essential in diagnosis and treatment management of patients suffering from myocardial infarction, and classification of pathology on myocardium is the key to this assessment. This work defines a new task of medical image analysis, i.e., to perform myocardial pathology segmentation (MyoPS) combining three-sequence cardiac magnetic resonance (CMR) images, which was first proposed in the MyoPS challenge, in conjunction with MICCAI 2020. The challenge provided 45 paired and pre-aligned CMR images, allowing algorithms to combine the complementary information from the three CMR sequences for pathology segmentation. In this article, we provide details of the challenge, survey the works from fifteen participants and interpret their methods according to five aspects, i.e., preprocessing, data augmentation, learning strategy, model architecture and post-processing. In addition, we analyze the results with respect to different factors, in order to examine the key obstacles and explore potential of solutions, as well as to provide a benchmark for future research. We conclude that while promising results have been reported, the research is still in the early stage, and more in-depth exploration is needed before a successful application to the clinics. Note that MyoPS data and evaluation tool continue to be publicly available upon registration via its homepage (www.sdspeople.fudan.edu.cn/zhuangxiahai/0/myops20/)

Texture Analysis of Late Gadolinium Enhanced Cardiac Magnetic Resonance Images for Characterizing Myocardial Fibrosis and Infarction

Le tiers de la population aux États-Unis est affecté par des cardiomyopathies. Lorsque le muscle du coeur, le myocarde, est altéré par la maladie, la santé du patient est détériorée et peut même entrainer la mort. Les maladies ischémiques sont le résultat d’artères coronariennes bloquées (sténose), limitant l’apport sanguin vers le myocarde. Les cardiomyopathies non-ischémiques sont les maladies dues à d’autres causes que des sténoses. Les fibres de collagène (fibrose) s’infiltrent dans le muscle cardiaque dans le but de maintenir la forme et les fonctions cardiaques lorsque la structure du myocarde est affectée par des cardiomyopathies. Ce principe, nécessaire au fonctionnement du coeur en présence de maladies, devient mal adapté et mène à des altérations du myocarde aux conséquences négatives, par exemple l’augmentation de la rigidité du myocarde. Une partie du diagnostic clinique lors de cardiomyopathies consiste à évaluer la fibrose dans le coeur avec différentes modalités d’imagerie. Les fibres de collagène s’infiltrent et s’accumulent dans la zone extracellulaire du myocarde ou peuvent remplacer progressivement les cardiomyocytes compromises. L’infiltration de fibrose dans le myocarde peut possiblement être réversible, ce qui rend sa détection particulièrement importante pour le clinicien. Différents tests diagnostiques existent pour aider le clinicien à établir l’état du patient en présence de cardiomyopathies. L’imagerie par résonance magnétique (IRM) est une modalité d’imagerie qui offre une haute résolution pour la visualisation du myocarde. Parmi les séquences disponibles avec cette modalité, l’imagerie par rehaussement tardif (RT) augmente le contraste du signal existant entre les tissus sains et les tissues malades du myocarde. Il s’agit d’images en pondération T1 avec administration d’agent de contraste qui se propage dans la matrice extracellulaire et résulte en un rehaussement du signal à cet endroit. Les images IRM RT permettent d’évaluer la présence et l’étendue des dommages au myocarde. Le clinicien peut évaluer la sévérité des cardiomyopathies et poser un pronostique à l’aide de ces images. La détection de fibrose diffuse dans ces images peut informer le clinicien sur l’état du patient et est un important marqueur de cardiomyopathies. Il est important d’établir l’occurrence de l’infarctus en présence de maladies ischémiques. En effet, l’approche interventionnelle varie selon que le clinicien fait face à une ischémie aigue ou chronique. Lors du diagnostic, Il serait donc bénéfique de différencier les infarctus du myocarde aigu de ceux chronique. Ceci s’est avéré difficile à l’aide des images IRM RT où l’intensité du signal ou la taille des régions sont similaires dans les deux types d’ischémie. Le but de la présente thèse est donc d’appliquer les méthodes d’analyse de texture à des images IRM RT afin de détecter la présence de fibrose diffuse dans le myocarde et de plus de déterminer l’âge de l’infarctus du myocarde. La première étude portait sur la détection de fibrose diffuse dans le myocarde à l’aide de l’analyse de texture appliquée à des images IRM RT afin d’établir si un lien existe entre la variation du signal d’intensité et la structure sous-jacente du myocarde. La présence de collagène dans le myocarde augmente avec l’âge et nous avons utilisé un modèle animal de rats jeunes et âgés. Nous avons fait une étude ex-vivo afin d’obtenir des images IRM RT de haute résolution avec absence de mouvement et ainsi permettre une comparaison des images avec des coupes histologiques des coeurs imagés. Des images IRM RT ont été acquises sur vingt-quatre animaux. Les coupes histologiques ont été traitées avec la méthode utilisant un marqueur ‘picrosirius red’ qui donne une teinte rouge au collagène. La quantification de la fibrose obtenue avec les images IRM RT a été comparée à la quantification obtenue sur les coupes histologiques. Ces quantifications ont de plus été comparées à l’analyse de texture appliquée aux images IRM RT. La méthode de texture a été appliquée en créant des cartes de texture basées sur la valeur de Contraste, cette mesure étant obtenue par des calculs statistiques sur la matrice de cooccurrence. Les régions montrant une plus grande complexité de signal d’intensité sur les images IRM RT ont été rehaussées avec les cartes de textures. Un calcul de régression linéaire a permis d’étudier le lien entre les différentes méthodes de quantification. Nous avons trouvés que la quantification de fibrose dans le myocarde à l’aide de l’analyse de texture appliquée sur des images IRM RT concordait avec le niveau de collagène identifié avec les images IRM et avec les coupes histologiques. De plus, nous avons trouvés que l’analyse de texture rehausse la présence de fibrose diffuse dans le myocarde. La seconde étude a pour but de discriminer les infarctus aigus du myocarde de ceux qui sont chroniques sur des images IRM RT de patients souffrant de cardiomyopathies ischémiques. Vingt-deux patients ont subi l’imagerie IRM (12 avec infarctus aigu du myocarde et 12 avec infarctus chronique). Une segmentation des images a permis d’isoler les différentes zones du myocarde, soit la zone d’infarctus, la zone grise au rebord de l’infarctus et la zone du myocarde sain, dans les deux groupes de patients. L’analyse de texture s’est faite dans ces régions en comparant les valeurs obtenues dans les deux groupes. Nous avons obtenu plus de valeurs de texture discriminantes dans la zone grise, en comparaison avec la région du myocarde sain, où aucune valeur de texture n’était significativement différente, et à la zone d’infarctus, où seule la valeur de texture statistique Moyenne était différentes dans les deux groupes. La zone grise a déjà fait l’objet d’études ayant établis cette région comme composée de cardiomyocytes sains entremêlés avec des fibres de collagène. Notre étude montre que cette région peut exhiber des différences structurelles entre les infarctus aigus du myocarde et ceux qui sont chroniques et que l’analyse de texture a réussi à les détecter. L’étude de la présence de collagène dans le myocarde est importante pour le clinicien afin qu’il puisse faire un diagnostic adéquat du patient et pour qu’il puisse faire un choix de traitement approprié. Nous avons montrés que l’analyse de texture sur des images IRM RT de patients peut différencier et même permettre la classification des ischémies aigues des ischémies chroniques, ce qui n’était pas possible avec uniquement ce type d’images. Nous avons de plus démontrés que l’analyse de texture d’images IRM RT permettait d’évaluer le contenu de fibrose diffuse dans un modèle animal de haute résolution avec validation histologique. Une telle relation entre les résultats d’analyse de texture d’images IRM RT et la structure sous-jacente du myocarde n’avait pas été étudiée dans la littérature. Notre méthode pourra être améliorée en effectuant d’autres calculs statistiques sur la matrice de cooccurrence, en testant d’autres méthodes d’analyse de texture et en appliquant notre méthode à de nouvelles séquences d’acquisition IRM, tel les images en pondération T1. D’autres améliorations possibles pourraient porter sur une évaluation de matrice de cooccurrence avec voisinage circulaire suivant la forme du myocarde sur les tranches d’images IRM RT. Plusieurs matrice de cooccurrence pourraient aussi être évaluées en fonction de la position dans l’espace du voisinage afin d’intégrer une composante directionnelle dans les calculs de texture. D’autres études sont nécessaires afin d’établir si une analyse de texture des images IRM RT pourrait différencier le stade de la fibrose pour un même patient lors d’une étude de suivi. De même, d’autres études sont nécessaires afin de valider l’utilisation de texture sur des scanners IRM différents. Établir l’âge de l’infarctus du myocarde permettra de planifier les interventions thérapeutiques et d’évaluer le pronostique pour le patient.----------ABSTRACT A third of the United States population is affected by cardiomyopathies. Impairment of the heart muscle, the myocardium, puts the patient’s health at risk and could ultimately lead to death. Ischemic cardiomyopathies result from lack of blood (ischemia) reaching the myocardium from blocked coronary arteries. Non-ischemic cardiomyopathies are diseases from other etiology than ischemia. Often collagen fibers infiltrate the heart (fibrosis), as a means to maintain its shape and function in the presence of disease that affects the myocardial cellular structure. This necessary phenomenon ultimately becomes maladaptive and results in the heart’s impairment. Part of the heart’s involvement in disease can be assessed through the analysis of myocardial fibrosis. Cardiomyopathy diagnosis involves the investigation of the presence of myocardial fibrosis, either infiltrative, defined as the increased presence of collagen protein in the extracellular space, or replacement fibrosis, when collagen fibers progressively replace diseased cardiomyocytes. The infiltrative fibrosis is believed to be reversible in some instances and consequently, myocardial fibrosis analysis has decisional impact on the interventional procedure that would benefit the health of the patient. The heart contracts and relaxes as it pumps blood to the rest of the body, an action directly impaired by myocardial damage. Any myocardial involvement should be assessed by the clinician to identify the severity of the myocardial damage, establish a prognosis and plan therapeutic intervention. Different diagnostic tests are required to image the myocardium and help the clinician in the diagnostic process. Cardiac magnetic resonance (CMR) imaging has emerged as a high resolution imaging modality that offers precise structural analysis of the heart. Among the different imaging sequences available with CMR, late gadolinium enhancement (LGE) shows the myocardium and enhances any impairments that may exist with the use of a contrast agent. It is a T1-weighted image with extracellular contrast agent (CA) administration. Increased signal intensity in the infarct scar is created from the CA dynamics. LGE CMR imaging offers information on the scar size and its location. The clinician can estimate the severity of the disease and establish prognosis with LGE CMR images. In ischemic cardiomyopathy, it is important to establish the occurrence of the infarction and know the age of the infarct to plan surgical intervention. Differentiation of acute from chronic MI is therefore important in the diagnostic process. In LGE CMR the level of signal intensity or the size of infarction are both similar in acute or in chronic MI. It has therefore been challenging to distinguish acute MI from chronic MI scars with LGE CMR images alone. The aim of this thesis was to investigate texture analysis of LGE CMR images to determine if acute MI could be distinguished from chronic MI and to detect increased presence of diffuse myocardial fibrosis in the myocardium. The first study was performed to investigate if texture analysis of LGE CMR images could detect variations in the presence of diffuse myocardial fibrosis and if the underlying myocardial structure could be related to the texture measures. Collagen content increased with aging and we used an animal model of young versus old rat. An ex-vivo animal model was necessary to allow for higher image resolution in LGE CMR images and to perform validation of our texture measures with histology images. Twenty four animals were scanned for LGE CMR images and texture analysis was applied to the heart images. Histology slices were stained with picrosirius red and collagen fibers were isolated based on their color content. LGE CMR quantification was compared to histological slices of the heart stained with the picrosirius red method. Texture analysis of LGE CMR images was also compared to the original LGE CMR image quantification and to histology. Texture analysis was done by creating contrast texture maps extracted from Haralick’s gray level co-occurrence matrix (GLCM). Regions of complex signal intensity combination were enhanced in LGE CMR images and in contrast texture maps. Regression analysis was performed to assess the level of agreement between the different analysis methods. We found that LGE CMR images could assess the different levels of collagen content in the different aged animal model, and that moreover texture analysis enhanced those differences. The location of enhancement from texture analysis images corresponded to location of increased collagen content in the old compared to the young rat hearts. Histological validation was shown for texture analysis applied to LGE CMR images to assess myocardial fibrosis. Our second study aimed at discriminating acute versus chronic MI from LGE CMR patient images alone through the use of texture analysis. Twenty two patients who had LGE CMR images were included in our study (12 acute and 12 chronic MI). Regional segmentation was performed and texture features were compared in those regions between both groups of patient. Texture analysis resulted in significantly different values between the two groups. More specifically the peri-infarct zone had the most number of discriminative features compared to the remote myocardium which had none and to the infarct core where only the mean features was significantly different. The border zone has been shown to be composed of healthy cardiomyocytes intermingled with the scar’s collagen fibers. Our study indicates this region might exhibit structural differences in the myocardium in acute from chronic MI patients that texture analysis of LGE CMR images can detect. Characterization of myocardial collagen content is important while clinicians analyze the state of the patient since it influences the course of action required to treat cardiomyopathies. LGE CMR images have been thoroughly used and validated to characterize focal myocardial scar, however it was limited in characterizing the age of infarction or quantifying diffuse collagen content. We have shown texture analysis of LGE CMR images alone can differentiate and even classify, acute from chronic MI patients, which was not previously possible. Characterization of myocardial infarction according to age will prove important in planning therapeutic interventions in clinical practice. Moreover, we have established texture analysis as a means to characterize the myocardium and detect variation in fibrosis content from high resolution LGE CMR images with histology validation. To our knowledge, such a relation between texture analysis of LGE CMR images and the underlying myocardial structure had not been done previously. Improvements could be done to our method, as we can increase the number of texture features that were analyzed from the GLCM, include other texture analysis methods such as the run-length matrix, and apply our method to other CMR imaging sequences such as T1 mapping. Adapting the GLCM to the heart could also be investigated, such as considering circular GLCM computation to consider the round shape of the myocardium in the short axis LGE CMR image slices. Directional GLCM could also be computed individually and analyzed for any myocardial or collagen fiber orientation indication. Further analysis is also required to establish if texture analysis could differentiate the age of MI in the same individual through a follow-up study. The measures of texture analysis from LGE CMR images obtained through different CMR scanners remains to be investigated as well. Knowing the age of infarct and evaluating the presence of diffuse myocardial fibrosis will help the clinician plan therapeutic interventions and establish a prognosis for the patient

A Pharmaceutical Paradigm for Cardiovascular Composite Risk Assessment Using Novel Radiogenomics Risk Predictors in Precision Explainable Artificial Intelligence Framework: Clinical Trial Tool

Background: Cardiovascular disease (CVD) is challenging to diagnose and treat since symptoms appear late during the progression of atherosclerosis. Conventional risk factors alone are not always sufficient to properly categorize at-risk patients, and clinical risk scores are inadequate in predicting cardiac events. Integrating genomic-based biomarkers (GBBM) found in plasma/serum samples with novel non-invasive radiomics-based biomarkers (RBBM) such as plaque area, plaque burden, and maximum plaque height can improve composite CVD risk prediction in the pharmaceutical paradigm. These biomarkers consider several pathways involved in the pathophysiology of atherosclerosis disease leading to CVD. Objective: This review proposes two hypotheses: (i) The composite biomarkers are strongly correlated and can be used to detect the severity of CVD/Stroke precisely, and (ii) an explainable artificial intelligence (XAI)-based composite risk CVD/Stroke model with survival analysis using deep learning (DL) can predict in preventive, precision, and personalized (aiP 3 ) framework benefiting the pharmaceutical paradigm. Method: The PRISMA search technique resulted in 214 studies assessing composite biomarkers using radiogenomics for CVD/Stroke. The study presents a XAI model using AtheroEdge TM 4.0 to determine the risk of CVD/Stroke in the pharmaceutical framework using the radiogenomics biomarkers. Conclusions: Our observations suggest that the composite CVD risk biomarkers using radiogenomics provide a new dimension to CVD/Stroke risk assessment. The proposed review suggests a unique, unbiased, and XAI model based on AtheroEdge TM 4.0 that can predict the composite risk of CVD/Stroke using radiogenomics in the pharmaceutical paradigm

A Pharmaceutical Paradigm for Cardiovascular Composite Risk Assessment Using Novel Radiogenomics Risk Predictors in Precision Explainable Artificial Intelligence Framework: Clinical Trial Tool

Cardiovascular disease (CVD) is challenging to diagnose and treat since symptoms appear late during the progression of atherosclerosis. Conventional risk factors alone are not always sufficient to properly categorize at-risk patients, and clinical risk scores are inadequate in predicting cardiac events. Integrating genomic-based biomarkers (GBBM) found in plasma/serum samples with novel non-invasive radiomics-based biomarkers (RBBM) such as plaque area, plaque burden, and maximum plaque height can improve composite CVD risk prediction in the pharmaceutical paradigm. These biomarkers consider several pathways involved in the pathophysiology of atherosclerosis disease leading to CVD.This review proposes two hypotheses: (i) The composite biomarkers are strongly correlated and can be used to detect the severity of CVD/Stroke precisely, and (ii) an explainable artificial intelligence (XAI)-based composite risk CVD/Stroke model with survival analysis using deep learning (DL) can predict in preventive, precision, and personalized (aiP3) framework benefiting the pharmaceutical paradigm.The PRISMA search technique resulted in 214 studies assessing composite biomarkers using radiogenomics for CVD/Stroke. The study presents a XAI model using AtheroEdgeTM 4.0 to determine the risk of CVD/Stroke in the pharmaceutical framework using the radiogenomics biomarkers.Our observations suggest that the composite CVD risk biomarkers using radiogenomics provide a new dimension to CVD/Stroke risk assessment. The proposed review suggests a unique, unbiased, and XAI model based on AtheroEdgeTM 4.0 that can predict the composite risk of CVD/Stroke using radiogenomics in the pharmaceutical paradigm

Artificial Intelligence in Cardiac Magnetic Resonance Imaging to Predict Prognosis and Treatment Response

Background Pulmonary arterial hypertension (PAH) is a serious disease of the heart and lungs. Its impact on patients can be severe, including limitation of day-to-day activities and high mortality. The diagnosis, treatment and monitoring of PAH are challenging and there is a need for tools that can aid clinical decision-making to optimise patient outcomes. Cardiac MRI (CMR) provides both qualitative and quantitative information about cardiac function and is an important method for evaluating the severity of PAH. The application of machine learning (ML) tools is of growing interest in medical imaging. ML has the potential to automate complex and repetitive tasks, including the rapid segmentation of anatomical structures on images and extraction of clinically useful information. Aims This thesis proposes the combination of CMR with two different ML tools to predict prognosis and treatment response in PAH. The first ML tool involves the automated measurement of different cardiac parameters and assesses their utility in predicting prognosis and treatment response. The second ML tool involves the extraction of imaging features directly without the need for segmentation to predict the risk of mortality. My Contribution The ML models in this thesis were developed at the University of Sheffield in collaboration with Leiden University. Sheffield is a centre of excellence in PAH treatment thanks to the Sheffield Pulmonary Vascular Disease Unit, which is one of the largest internationally. Each year, more than 700 PAH patients undergo CMR for diagnosis and monitoring. Additionally, each newly diagnosed patient has accompanying in-depth clinical phenotypic data, including right heart catheterisation, exercise and pulmonary function tests, and quality of life assessment. During my research, I created and curated a dataset combining imaging and time-matched clinical data. I identified eligible CMR scans, landmarked and contoured cardiac chambers on multiple sequences and organised the collaboration with computer scientists at Leiden and Sheffield. I arranged image anonymisation, storage and transfer and advised computer scientists on the clinical relevance of CMR images. I performed quality control on ML analyses, collated their results, and analysed the data within clinical context. I have written all chapters in this thesis and clarified the roles of my co-authors at the end of each chapter. Thesis Outline Chapter 1 provided an overview of the growing role of CMR in the diagnosis and evaluation of PAH. Chapter 2 summarised the prognostic value of CMR measurements in the prediction of clinical worsening and mortality in PAH patients. Chapter 3 illustrated the rapid expansion of research using AI approaches to automate CMR measurements. The quality of the existing literature was reviewed, significant shortcomings in the transparency of studies were identified and solutions were recommended. Chapter 4 showed our experience in developing, validating and testing a fully automatic CMR segmentation tool. Our tool was developed in one of the largest multi-vendor, multi-centre and multi-pathology reported datasets, and included a large group of patients with right heart disease. We implemented the lessons learned in Chapter 3 and provided extensive descriptions of our datasets, ML model and performance. Our model showed excellent reliability, generalisability, agreement with CMR experts and correlation with invasive haemodynamics. Chapter 5 demonstrated that the automatic CMR measurements allowed assessment of patient-orientated outcomes and prediction of mortality. Thresholds of changes in CMR metrics were identified that could inform clinical decisions in the monitoring of PAH patients. Chapter 6 showed promising results of an ML tool to extrapolate prognostic CMR features with incremental value compared to clinical risk scores and volumetric CMR measurements. Finally, Chapter 7 showed that myocardial T1 mapping could potentially add diagnostic and prognostic value in PAH. Impact and Future Direction In addition to the known advantages of ML for providing rapid results with minimal human involvement, the ML tools developed in this thesis allow visualisation of outcomes and are transparent to the human assessor. ML applications to automate the measurement of CMR metrics and extract prognostic imaging features have potential to add clinical value by (i) streamlining prognostication, (ii) informing treatment selection, (iii) assisting the monitoring of treatment response and (iv) ultimately improving clinical decision-making and patient outcomes. Additionally, these tools could point to new CMR end-points for clinical trials, accelerating the development of new treatments for PAH. ML will likely elevate the role of CMR as a powerful prognostic modality in the years to come. Looking ahead, I hope to combine multi-source clinical, imaging and patient-orientated data from several ML tools into a single package to facilitate the assessment of cardiovascular disease

Automated deep phenotyping of the cardiovascular system using magnetic resonance imaging

Across a lifetime, the cardiovascular system must adapt to a great range of demands from the body. The individual changes in the cardiovascular system that occur in response to loading conditions are influenced by genetic susceptibility, and the pattern and extent of these changes have prognostic value. Brachial blood pressure (BP) and left ventricular ejection fraction (LVEF) are important biomarkers that capture this response, and their measurements are made at high resolution. Relatively, clinical analysis is crude, and may result in lost information and the introduction of noise. Digital information storage enables efficient extraction of information from a dataset, and this strategy may provide more precise and deeper measures to breakdown current phenotypes into their component parts. The aim of this thesis was to develop automated analysis of cardiovascular magnetic resonance (CMR) imaging for more detailed phenotyping, and apply these techniques for new biological insights into the cardiovascular response to different loading conditions. I therefore tested the feasibility and clinical utility of computational approaches for image and waveform analysis, recruiting and acquiring additional patient cohorts where necessary, and then applied these approaches prospectively to participants before and after six-months of exercise training for a first-time marathon. First, a multi-centre, multi-vendor, multi-field strength, multi-disease CMR resource of 110 patients undergoing repeat imaging in a short time-frame was assembled. The resource was used to assess whether automated analysis of LV structure and function is feasible on real-world data, and if it can improve upon human precision. This showed that clinicians can be confident in detecting a 9% change in EF or a 20g change in LV mass. This will be difficult to improve by clinicians because the greatest source of human error was attributable to the observer rather than modifiable factors. Having understood these errors, a convolutional neural network was trained on separate multi-centre data for automated analysis and was successfully generalizable to the real-world CMR data. Precision was similar to human analysis, and performance was 186 times faster. This real-world benchmarking resource has been made freely available (thevolumesresource.com). Precise automated segmentations were then used as a platform to delve further into the LV phenotype. Global LVEFs measured from CMR imaging in 116 patients with severe aortic stenosis were broken down into ~10 million regional measurements of structure and function, represented by computational three-dimensional LV models for each individual. A cardiac atlas approach was used to compile, label, segment and represent these data. Models were compared with healthy matched controls, and co-registered with follow-up one year after aortic valve replacement (AVR). This showed that there is a tendency to asymmetric septal hypertrophy in all patients with severe aortic stenosis (AS), rather than a characteristic specific to predisposed patients. This response to AS was more unfavourable in males than females (associated with higher NT-proBNP, and lower blood pressure), but was more modifiable with AVR. This was not detected using conventional analysis. Because cardiac function is coupled with the vasculature, a novel integrated assessment of the cardiovascular system was developed. Wave intensity theory was used to combine central blood pressure and CMR aortic blood flow-velocity waveforms to represent the interaction of the heart with the vessels in terms of traveling energy waves. This was performed and then validated in 206 individuals (the largest cohort to date), demonstrating inefficient ventriculo-arterial coupling in female sex and healthy ageing. CMR imaging was performed in 236 individuals before training for a first-time marathon and 138 individuals were followed-up after marathon completion. After training, systolic/diastolic blood pressure reduced by 4/3mmHg, descending aortic stiffness decreased by 16%, and ventriculo-arterial coupling improved by 14%. LV mass increased slightly, with a tendency to more symmetrical hypertrophy. The reduction in aortic stiffness was equivalent to a 4-year reduction in estimated biological aortic age, and the benefit was greater in older, male, and slower individuals. In conclusion, this thesis demonstrates that automating analysis of clinical cardiovascular phenotypes is precise with significant time-saving. Complex data that is usually discarded can be used efficiently to identify new biology. Deeper phenotypes developed in this work inform risk reduction behaviour in healthy individuals, and demonstrably deliver a more sensitive marker of LV remodelling, potentially enhancing risk prediction in severe aortic stenosis

Computational modelling of the human heart and multiscale simulation of its electrophysiological activity aimed at the treatment of cardiac arrhythmias related to ischaemia and Infarction

[ES] Las enfermedades cardiovasculares constituyen la principal causa de morbilidad y mortalidad a nivel mundial, causando en torno a 18 millones de muertes cada año. De entre ellas, la más común es la enfermedad isquémica cardíaca, habitualmente denominada como infarto de miocardio (IM). Tras superar un IM, un considerable número de pacientes desarrollan taquicardias ventriculares (TV) potencialmente mortales durante la fase crónica del IM, es decir, semanas, meses o incluso años después la fase aguda inicial. Este tipo concreto de TV normalmente se origina por una reentrada a través de canales de conducción (CC), filamentos de miocardio superviviente que atraviesan la cicatriz del infarto fibrosa y no conductora. Cuando los fármacos anti-arrítmicos resultan incapaces de evitar episodios recurrentes de TV, la ablación por radiofrecuencia (ARF), un procedimiento mínimamente invasivo realizado mediante cateterismo en el laboratorio de electrofisiología (EF), se usa habitualmente para interrumpir de manera permanente la propagación eléctrica a través de los CCs responsables de la TV. Sin embargo, además de ser invasivo, arriesgado y requerir mucho tiempo, en casos de TVs relacionadas con IM crónico, hasta un 50% de los pacientes continúa padeciendo episodios recurrentes de TV tras el procedimiento de ARF. Por tanto, existe la necesidad de desarrollar nuevas estrategias pre-procedimiento para mejorar la planificación de la ARF y, de ese modo, aumentar esta tasa de éxito relativamente baja. En primer lugar, realizamos una revisión exhaustiva de la literatura referente a los modelos cardiacos 3D existentes, con el fin de obtener un profundo conocimiento de sus principales características y los métodos usados en su construcción, con especial atención sobre los modelos orientados a simulación de EF cardíaca. Luego, usando datos clínicos de un paciente con historial de TV relacionada con infarto, diseñamos e implementamos una serie de estrategias y metodologías para (1) generar modelos computacionales 3D específicos de paciente de ventrículos infartados que puedan usarse para realizar simulaciones de EF cardíaca a nivel de órgano, incluyendo la cicatriz del infarto y la región circundante conocida como zona de borde (ZB); (2) construir modelos 3D de torso que permitan la obtención del ECG simulado; y (3) llevar a cabo estudios in-silico de EF personalizados y pre-procedimiento, tratando de replicar los verdaderos estudios de EF realizados en el laboratorio de EF antes de la ablación. La finalidad de estas metodologías es la de localizar los CCs en el modelo ventricular 3D para ayudar a definir los objetivos de ablación óptimos para el procedimiento de ARF. Por último, realizamos el estudio retrospectivo por simulación de un caso, en el que logramos inducir la TV reentrante relacionada con el infarto usando diferentes configuraciones de modelado para la ZB. Validamos nuestros resultados mediante la reproducción, con una precisión razonable, del ECG del paciente en TV, así como en ritmo sinusal a partir de los mapas de activación endocárdica obtenidos invasivamente mediante sistemas de mapeado electroanatómico en este último caso. Esto permitió encontrar la ubicación y analizar las características del CC responsable de la TV clínica. Cabe destacar que dicho estudio in-silico de EF podría haberse efectuado antes del procedimiento de ARF, puesto que nuestro planteamiento está completamente basado en datos clínicos no invasivos adquiridos antes de la intervención real. Estos resultados confirman la viabilidad de la realización de estudios in-silico de EF personalizados y pre-procedimiento de utilidad, así como el potencial del abordaje propuesto para llegar a ser en un futuro una herramienta de apoyo para la planificación de la ARF en casos de TVs reentrantes relacionadas con infarto. No obstante, la metodología propuesta requiere de notables mejoras y validación por medio de es[CA] Les malalties cardiovasculars constitueixen la principal causa de morbiditat i mortalitat a nivell mundial, causant entorn a 18 milions de morts cada any. De elles, la més comuna és la malaltia isquèmica cardíaca, habitualment denominada infart de miocardi (IM). Després de superar un IM, un considerable nombre de pacients desenvolupen taquicàrdies ventriculars (TV) potencialment mortals durant la fase crònica de l'IM, és a dir, setmanes, mesos i fins i tot anys després de la fase aguda inicial. Aquest tipus concret de TV normalment s'origina per una reentrada a través dels canals de conducció (CC), filaments de miocardi supervivent que travessen la cicatriu de l'infart fibrosa i no conductora. Quan els fàrmacs anti-arítmics resulten incapaços d'evitar episodis recurrents de TV, l'ablació per radiofreqüència (ARF), un procediment mínimament invasiu realitzat mitjançant cateterisme en el laboratori de electrofisiologia (EF), s'usa habitualment per a interrompre de manera permanent la propagació elèctrica a través dels CCs responsables de la TV. No obstant això, a més de ser invasiu, arriscat i requerir molt de temps, en casos de TVs relacionades amb IM crònic fins a un 50% dels pacients continua patint episodis recurrents de TV després del procediment d'ARF. Per tant, existeix la necessitat de desenvolupar noves estratègies pre-procediment per a millorar la planificació de l'ARF i, d'aquesta manera, augmentar la taxa d'èxit, que es relativament baixa. En primer lloc, realitzem una revisió exhaustiva de la literatura referent als models cardíacs 3D existents, amb la finalitat d'obtindre un profund coneixement de les seues principals característiques i els mètodes usats en la seua construcció, amb especial atenció sobre els models orientats a simulació de EF cardíaca. Posteriorment, usant dades clíniques d'un pacient amb historial de TV relacionada amb infart, dissenyem i implementem una sèrie d'estratègies i metodologies per a (1) generar models computacionals 3D específics de pacient de ventricles infartats capaços de realitzar simulacions de EF cardíaca a nivell d'òrgan, incloent la cicatriu de l'infart i la regió circumdant coneguda com a zona de vora (ZV); (2) construir models 3D de tors que permeten l'obtenció del ECG simulat; i (3) dur a terme estudis in-silico de EF personalitzats i pre-procediment, tractant de replicar els vertaders estudis de EF realitzats en el laboratori de EF abans de l'ablació. La finalitat d'aquestes metodologies és la de localitzar els CCs en el model ventricular 3D per a ajudar a definir els objectius d'ablació òptims per al procediment d'ARF. Finalment, a manera de prova de concepte, realitzem l'estudi retrospectiu per simulació d'un cas, en el qual aconseguim induir la TV reentrant relacionada amb l'infart usant diferents configuracions de modelatge per a la ZV. Validem els nostres resultats mitjançant la reproducció, amb una precisió raonable, del ECG del pacient en TV, així com en ritme sinusal a partir dels mapes d'activació endocardíac obtinguts invasivament mitjançant sistemes de mapatge electro-anatòmic en aquest últim cas. Això va permetre trobar la ubicació i analitzar les característiques del CC responsable de la TV clínica. Cal destacar que aquest estudi in-silico de EF podria haver-se efectuat abans del procediment d'ARF, ja que el nostre plantejament està completament basat en dades clíniques no invasius adquirits abans de la intervenció real. Aquests resultats confirmen la viabilitat de la realització d'estudis in-silico de EF personalitzats i pre-procediment d'utilitat, així com el potencial de l'abordatge proposat per a arribar a ser en un futur una eina de suport per a la planificació de l'ARF en casos de TVs reentrants relacionades amb infart. No obstant això, la metodologia proposada requereix de notables millores i validació per mitjà d'estudis de simulació amb grans cohorts de pacients.[EN] Cardiovascular diseases represent the main cause of morbidity and mortality worldwide, causing around 18 million deaths every year. Among these diseases, the most common one is the ischaemic heart disease, usually referred to as myocardial infarction (MI). After surviving to a MI, a considerable number of patients develop life-threatening ventricular tachycardias (VT) during the chronic stage of the MI, that is, weeks, months or even years after the initial acute phase. This particular type of VT is typically sustained by reentry through slow conducting channels (CC), which are filaments of surviving myocardium that cross the non-conducting fibrotic infarct scar. When anti-arrhythmic drugs are unable to prevent recurrent VT episodes, radiofrequency ablation (RFA), a minimally invasive procedure performed by catheterization in the electrophysiology (EP) laboratory, is commonly used to interrupt the electrical conduction through the CCs responsible for the VT permanently. However, besides being invasive, risky and time-consuming, in the cases of VTs related to chronic MI, up to 50% of patients continue suffering from recurrent VT episodes after the RFA procedure. Therefore, there exists a need to develop novel pre-procedural strategies to improve RFA planning and, thereby, increase this relatively low success rate. First, we conducted an exhaustive review of the literature associated with the existing 3D cardiac models in order to gain a deep knowledge about their main features and the methods used for their construction, with special focus on those models oriented to simulation of cardiac EP. Later, using a clinical dataset of a chronically infarcted patient with a history of infarct-related VT, we designed and implemented a number of strategies and methodologies to (1) build patient-specific 3D computational models of infarcted ventricles that can be used to perform simulations of cardiac EP at the organ level, including the infarct scar and the surrounding region known as border zone (BZ); (2) construct 3D torso models that enable to compute the simulated ECG; and (3) carry out pre-procedural personalized in-silico EP studies, trying to replicate the actual EP studies conducted in the EP laboratory prior to the ablation. The goal of these methodologies is to allow locating the CCs into the 3D ventricular model in order to help in defining the optimal ablation targets for the RFA procedure. Lastly, as a proof-of-concept, we performed a retrospective simulation case study, in which we were able to induce an infarct-related reentrant VT using different modelling configurations for the BZ. We validated our results by reproducing with a reasonable accuracy the patient's ECG during VT, as well as in sinus rhythm from the endocardial activation maps invasively recorded via electroanatomical mapping systems in this latter case. This allowed us to find the location and analyse the features of the CC responsible for the clinical VT. Importantly, such in-silico EP study might have been conducted prior to the RFA procedure, since our approach is completely based on non-invasive clinical data acquired before the real intervention. These results confirm the feasibility of performing useful pre-procedural personalized in-silico EP studies, as well as the potential of the proposed approach to become a helpful tool for RFA planning in cases of infarct-related reentrant VTs in the future. Nevertheless, the developed methodology requires further improvements and validation by means of simulation studies including large cohorts of patients.During the carrying out of this doctoral thesis, the author Alejandro Daniel López Pérez was financially supported by the Ministerio de Economía, Industria y Competitividad of Spain through the program Ayudas para contratos predoctorales para la formación de doctores, with the grant number BES-2013-064089.López Pérez, AD. (2019). Computational modelling of the human heart and multiscale simulation of its electrophysiological activity aimed at the treatment of cardiac arrhythmias related to ischaemia and Infarction [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/124973TESI

A Computational Based Approach for Non-invasive Localization of Atrial ectopic foci

Las arritmias auriculares son las arritmias cardı́acas más comunes, afectan a seis millones de personas en Europa e imponen una enorme carga sanitaria en la sociedad. Las nuevas tecnologı́as médicas están ayudando a los electrofisiólogos a adaptar el tratamiento a cada paciente de diferentes maneras. Por ejemplo, la resonancia magnética (MRI) permite evaluar la distribución espacial de la fibrosis auricular; los mapas electroanatómicos (EAM) permiten obtener una caracterización eléctrica de los tejidos en tiempo real; Las imágenes electrocardiográficas (ECGI) permiten estudiar la actividad eléctrica cardı́aca de forma no invasiva; y la ablación por radiofrecuencia (RFA), permite eliminar el tejido patológico en el corazón que desencadena o mantiene una arritmia. A pesar del acceso a tecnologı́as avanzadas y de la existencia de guı́as clı́nicas bien desarrolladas para el tratamiento de las arritmias auriculares, las tasas de éxito del tratamiento a largo plazo siguen siendo bajas, debido a la complejidad de la enfermedad. Por lo tanto, existe una necesidad imperiosa de mejorar los resultados clı́nicos en beneficio de los pacientes y el sistema de salud. Se podrı́an emplear modelos biofı́sicos detallados de las aurı́culas y el torso para integrar todos los datos del paciente en un solo modelo 3D de referencia capaz de reproducir los complejos patrones de activación eléctrica observados en experimentos y la clı́nica. Sin embargo, existen algunas limitaciones relacionadas con la dificultad de construir tales modelos para cada paciente o realizar un número considerable de simulaciones para planificar la terapia óptima de RFA. Teniendo en cuenta todas esas limitaciones, proponemos utilizar modelos biofı́sicos detallados y simulaciones como una herramienta para entrenar sistemas de aprendizaje automático, para lo cual dispondrı́amos de todos los datos y variables del problema, que serı́an imposibles de obtener en un entorno clı́nico real. Por lo tanto, podemos realizar cientos de simulaciones electrofisiológicas, considerando una variedad de escenarios y patologı́as comunes, y entrenar un sistema que deberı́a ser capaz de reconocerlos a partir de un conjunto limitado de datos no invasivos del paciente, como un electrocardiograma (ECG), o mapa de potencial de superficie corporal (BSPM).Abstract Atrial arrhythmias are the most common cardiac arrhythmia, affecting six million people in Europe and imposing a huge healthcare bur- den on society. New technologies are helping electrophysiologists to tailor the treatment to each patient in different ways. For instance, magnetic resonance imaging (MRI) allows to assess the spatial distribution of atrial fibrosis; electro-anatomical maps (EAM) permit to obtain an electrical char- acterization of tissue in real-time; electrocardiographic imaging (ECGI) al- lows to study cardiac electrical activity non-invasively; and radiofrequency ablation (RFA), allows to eliminate pathological tissue in the heart that is triggering or sustaining an arrhythmia. Despite the access to advanced technologies and well-developed clinical guidelines for the management of atrial arrhythmia, long-term treatment success rates remain low, due to the complexity of the disease. Therefore, there is a compelling need to improve clinical outcomes for the benefit of patients and the healthcare system. Detailed biophysical models of the atria and torso could be employed to integrate all the patient data into a single reference 3D model able to re- produce the complex electrical activation patterns observed in experiments and clinics. However, there are some limitations related to the difficulty of building such models for each patient, or performing a substantial number of simulations to plan the optimal RFA therapy. Considering all those lim- itations, we propose to use detailed biophysical models and simulations as a tool to train machine learning systems, for which we have all the ground- truth data which would be impossible to obtain in a real clinical setting. Therefore, we can perform hundreds of electrophysiology simulations, con- sidering a variety of common scenarios and pathologies, and train a system that should be able to recognize them from a limited set of non-invasive pa- tient data, such as an electrocardiogram (ECG), or a body surface potential map (BSPM)