Submillimeter diffusion tensor imaging and late gadolinium enhancement cardiovascular magnetic resonance of chronic myocardial infarction.

BackgroundKnowledge of the three-dimensional (3D) infarct structure and fiber orientation remodeling is essential for complete understanding of infarct pathophysiology and post-infarction electromechanical functioning of the heart. Accurate imaging of infarct microstructure necessitates imaging techniques that produce high image spatial resolution and high signal-to-noise ratio (SNR). The aim of this study is to provide detailed reconstruction of 3D chronic infarcts in order to characterize the infarct microstructural remodeling in porcine and human hearts.MethodsWe employed a customized diffusion tensor imaging (DTI) technique in conjunction with late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) on a 3T clinical scanner to image, at submillimeter resolution, myofiber orientation and scar structure in eight chronically infarcted porcine hearts ex vivo. Systematic quantification of local microstructure was performed and the chronic infarct remodeling was characterized at different levels of wall thickness and scar transmurality. Further, a human heart with myocardial infarction was imaged using the same DTI sequence.ResultsThe SNR of non-diffusion-weighted images was >100 in the infarcted and control hearts. Mean diffusivity and fractional anisotropy (FA) demonstrated a 43% increase, and a 35% decrease respectively, inside the scar tissue. Despite this, the majority of the scar showed anisotropic structure with FA higher than an isotropic liquid. The analysis revealed that the primary eigenvector orientation at the infarcted wall on average followed the pattern of original fiber orientation (imbrication angle mean: 1.96 ± 11.03° vs. 0.84 ± 1.47°, p = 0.61, and inclination angle range: 111.0 ± 10.7° vs. 112.5 ± 6.8°, p = 0.61, infarcted/control wall), but at a higher transmural gradient of inclination angle that increased with scar transmurality (r = 0.36) and the inverse of wall thickness (r = 0.59). Further, the infarcted wall exhibited a significant increase in both the proportion of left-handed epicardial eigenvectors, and in the angle incoherency. The infarcted human heart demonstrated preservation of primary eigenvector orientation at the thinned region of infarct, consistent with the findings in the porcine hearts.ConclusionsThe application of high-resolution DTI and LGE-CMR revealed the detailed organization of anisotropic infarct structure at a chronic state. This information enhances our understanding of chronic post-infarction remodeling in large animal and human hearts

Development and Application of Gadolinium Free Cardiac Magnetic Resonance Fibrosis Imaging for Multiscale Study of Heart Failure in Patients with End Stage Renal Disease

Cardiac magnetic resonance (CMR) is a powerful tool to noninvasively image ventricular fibrosis. Late gadolinium enhancement (LGE) CMR identifies focal and, with T1 mapping, diffuse fibrosis. Despite prevalent cardiac fibrosis and heart failure, patients with end stage renal disease (ESRD) are excluded from LGE. Absence of a suitable diagnostic has limited the understanding of heart failure and obstructed development of therapies in the setting of ESRD. A quantitative, gadolinium free fibrosis detection method could overcome this critical barrier, propelling the advancement of diagnostic, monitoring, and therapy options. This project describes the development of a gadolinium free CMR technique and application for cardiac fibrosis measurement in patients with ESRD. Magnetization transfer (MT) occurs during standard cine balanced steady state free precession (bSSFP) CMR, where extracellular matrix protons exchange magnetization with water molecules. Extracellular water volume expansion, concomitant with fibrosis, reduces MT and subtly elevates signal intensity. Our technique, 2-pt bSSFP, extracts endogenous contrast sensitive to tissue fibrosis by obtaining pairs of high and low MT-weighted images and calculating normalized signal differences, denoted by ΔS/So. We tested 2-pt bSSFP in patients referred for CMR and found excellent agreement spatially with LGE and quantitatively with extracellular volume fraction. Diagnostic and clinical application of 2-pt bSSFP was comparable to LGE. We applied 2-pt bSSFP to patients with ESRD for multiscale comparison with correlates of fibrosis ranging from blood biomarkers to whole organ function. Patients with ESRD displayed hypertrophy with reduced contraction, but elevated ΔS/So and fibrosis. Some biomarkers correlated with both hypertrophy and fibrosis, highlighting the need to distinguish between hypertrophic and fibrotic remodeling. We monitored fibrosis over 1 year using 2-pt bSSFP in a cohort of patients with ESRD. ΔS/So and fibrotic burden increased substantially, despite minor changes in structure and function. Collectively these studies validate and apply 2-pt bSSFP for gadolinium free fibrosis CMR in patients with ESRD. While ventricular structure and function are commensurate with progression toward heart failure, it is now possible to specifically describe global and focal patterns of cardiac fibrosis in ESRD, along with comparisons to blood biomarkers which may lead to improved diagnostics and molecular treatment targets

Comparison of T1-maps and late gadolinium enhancement images in the detection of Myocardial Fibrosis in Hypertrophic Cardiomyopathy

Tese de Mestrado Integrado, Engenharia Biomédica e Biofísica, 2021, Universidade de Lisboa, Faculdade de CiênciasHypertrophic Cardiomyopathy (HCM) is characterized as an abnormal and heterogeneous thickening of the Left Ventricle (LV) wall. HCM is the leading cause of sudden cardiac death in children and young people, with an estimated prevalence of 1:500 in the general population. Myocardial fibrosis is the key histopathological hallmark in HCM and is presented in different patterns: interstitial diffuse fibrosis which, if not treated, evolves to replacement fibrosis. Cardiac Magnetic Resonance (CMR) imaging has been used for the detection and quantification of myocardial fibrosis. The Late Gadolinium Enhancement (LGE) technique is the primary tool for non-invasive tissue characterization, particularly for replacement fibrosis. Conversely, T1 mapping is commonly used for the detection of diffuse interstitial fibrosis, frequently missed using LGE. The clear disadvantage of LGE relies on the need to inject contrast agents that, despite being considered safe, may accumulate in the body for years and potentially cause nephrogenic systemic fibrosis in end-stage chronic kidney disease patients. The capability of native T1 mapping identifying not only diffuse interstitial but also replacement fibrosis would play a pivotal role in HCM diagnosis. The potential of native T1 mapping for a cheaper and non-contrast HCM assessment needs to be further studied. A database of 15 HCM patients, without and with fibrosis, was acquired at Hospital da Luz, Lisboa. In this project, (1) an extensive image preprocessing pipeline was applied to aim for the best possible spatial alignment of the myocardium between the two modalities (native T1 mapping and LGE); (2) the mean native T1 values of individuals without and with the presence of scarred tissue were examined; (3) a pixel-by-pixel analysis was performed to investigate if there is a correlation between fibrotic tissue in LGE and hyperintense regions in native T1 mapping; (4) a Texture Analysis (TA) was performed to study if texture information of native T1 mapping could provide differential diagnosis or prognostic information beyond mean T1 values. The first step was the most longstanding and challenging process. The registration of T1 and LGE images is difficult due to the different intensity profiles. The registration of the myocardial masks using a model with rigid, affine, and free-form deformation transformations revealed to be the best methodology. Mean native T1 values were not increased in patients with scarred tissue. Regarding the third aim, no clear intensity correlation between techniques was observed, which suggests the need for the TA. Seven features (in a total of 350) were selected to distinguish between cardiac segments without and with fibrotic tissue using a ML (Machine Learning) algorithm that finds the features that most contribute to distinguish the two groups. Four first-order features distinguish the cohorts due to the presence of scarred tissue - hyperintense zones - and three texture features suggest that the fibrotic remodeling in the myocardium of HCM patients might be associated with a more heterogeneous tissue texture. A Receiver Operating Characteristics (ROC) analysis was performed and revealed that the Cluster Prominence is the feature that best distinguishes sections without and with fibrotic tissue (accuracy of 70%) but with low sensitivity (65%) and low specifity (64%). A model with the 90th Percentile feature revealed an accuracy of 64%, sensitivity of 71% and specificity of 57%. Studying the Variance feature, the achieved accuracy was 63%, with 66% of sensitivity and 60% of specificity. The remaining features yielded lower accuracy values than the ones previously mentioned, but all of them higher than 50%. The low sensitivity and specificity of the best three models suggest that analysing these values considering these features may help cardiologists to identify focal fibrosis regions and avoid contrast injection methods but may not provide an accurate diagnosis of the presence of fibrotic tissue alone. Further research on the correlation of native T1 mapping and LGE cardiac images is highly recommended to develop a contrast-agent-free technology to replace LGE.A Cardiomiopatia Hipertrófica (do inglês, HCM) é descrita por um espessamento anormal e heterogéneo da parede do ventrículo esquerdo (do inglês, LV). A HCM é a principal causa de morte súbita cardíaca em crianças e jovens, com uma prevalência estimada de 1:500 na população em geral. Esta doença é, na sua maioria, hereditária, e causada por variantes nos genes da proteína do sarcómero (predominantemente MYH7 e MYBPC3). A fibrose do miocárdio é a principal marca histopatológica da HCM e apresenta-se em diferentes padrões: fibrose intersticial difusa que, se não tratada, evolui para fibrose focal. A fibrose é caracterizada por um aumento da deposição de colagénio, que afeta a viabilidade do miocárdio. A imagem de Ressonância Magnética Cardíaca (do inglês, CMR) tem sido usada para a deteção e quantificação de fibrose do miocárdio. A técnica de Realce Tardio (do inglês, LGE) é a principal ferramenta para caracterização não invasiva de tecidos, particularmente de fibrose focal. Em contrapartida, o mapeamento T1 é a técnica mais utilizada para deteção de fibrose intersticial difusa, frequentemente não detetada usando LGE. A clara desvantagem do LGE reside na necessidade de injeção de agentes de contraste. Apesar destes agentes serem considerados seguros, frequentemente causam alergias, podem-se acumular no corpo, por anos, e podem causar fibrose sistémica nefrogénica em pacientes com doença renal crónica terminal. A capacidade do mapeamento T1 nativo identificar, não só a fibrose intersticial difusa mas também a fibrose focal, desempenharia um papel fundamental no diagnóstico da HCM. Consequentemente, é de extrema importância estudar o potencial do mapeamento T1 nativo para uma avaliação desta patologia sem contraste e, desta forma, eliminar os riscos associados à injeção de contraste e reduzir os custos e tempo de preparação associados à utilização de gadolínio. Uma base de dados de 15 pacientes com HCM, com e sem fibrose, previamente adquirida no Hospital da Luz, Lisboa, foi analisada. Neste projeto, (1) aplicou-se um extenso conjunto de passos de pré-processamento de imagem para alcançar a melhor técnica possível de alinhamento espacial do miocárdio entre as duas modalidades (mapeamento T1 nativo e Realce Tardio); (2) após a divisão do miocárdio em 6 secções, como sugerido pela American Heart Association, examinaram-se os valores médios de T1, para cada secção, de indivíduos sem e com presença de tecido cicatricial; (3) realizou-se uma análise pixel a pixel para investigar se existe uma correlação entre o tecido fibrótico em LGE e as regiões hiperintensas no mapeamento T1 nativo; (4) realizou-se uma análise de textura para estudar se a informação de textura do mapeamento T1 nativo poderia fornecer um diagnóstico diferencial ou informação prognóstica além dos valores médios de T1 nativo. A primeira etapa revelou ser o processo mais demorado e desafiante. O batimento cardíaco e o ciclo respiratório representam dois desafios no registo de imagens cardíacas. Para além dos comuns desafios em alinhamento de imagens cardíacas da mesma modalidade, alinhar imagens de diferentes modalidades torna-se um processo mais complexo. Em primeiro lugar, o registo de imagens T1 e de LGE é dificultado pelos distintos perfis de intensidade das duas modalidades. Em segundo lugar, a aquisição de imagens de Realce Tardio ocorre cerca de 7 minutos após a aquisição do mapeamento T1, e o movimento dos pacientes durante este intervalo de tempo é uma fonte adicional de erro. Diferentes softwares foram utilizados, e uma imagem sintética ponderada em T1 foi criada, com o intuito de apresentar intensidades mais similares à imagem a ser alinhada (imagem de LGE). O registo das máscaras miocárdicas por meio de um modelo com transformações rígida, afim e deformações livres mostrou ser a melhor metodologia a aplicar. Os valores médios de T1 nativo não aumentaram significativamente em pacientes com tecido cicatricial, apesar de haver um aumento dos valores de T1 nativo em determinadas secções, em cortes basais e intermédios. Relativamente ao terceiro objetivo abordado, não foi observada uma clara correlação de intensidades entre as técnicas, o que reforçou a necessidade de uma análise de textura (do inglês, TA). Esta análise revelou as sete melhores características (num total de 350) que distinguem segmentos cardíacos sem e com tecido fibrótico, aplicando um método de Machine Learning (do inglês, ML) que identificou, sequencialmente, as features que adicionavam mais informação ao modelo que distinguia os dois grupos de segmentos. Quatro características de primeira ordem distinguem os segmentos devido à presença de tecido cicatricial - zonas hiperintensas - e três características de textura sugerem que a remodelação fibrótica no miocárdio de pacientes com HCM pode estar associada a uma textura mais heterogénea. Foi implementada uma análise ao desempenho de modelos com as features selecionadas, que revelou que a Cluster Prominence é a característica que melhor distingue secções sem e com tecido fibrótico, apesar de com baixa sensibilidade (65%) e baixa especificidade (64%). Um modelo que analisa o Percentil 90 revelou uma precisão de 64%, sensibilidade de 71% e especificidade de 57%. No estudo da Variância, a precisão foi de 63%, a sensibilidade 66% e a especificidade 60%. As restantes features apresentaram valores de precisão inferiores aos mencionados mas acima de 50%. Um modelo com a combinação das sete features selecionadas não melhorou a performance do modelo (precisão de 62%, sensibilidade de 75% e 49% de especificidade). A baixa sensibilidade e especificidade sugerem que a análise desses valores nessas características pode ajudar os cardiologistas a identificar regiões focais de fibrose e evitar métodos de injeção de contraste, mas pode não fornecer um diagnóstico preciso da presença de tecido fibrótico por si só. Em futuras aquisições, encontrar valores semelhantes nas features acima mencionadas, principalmente na Cluster Prominence, em novos dados, poderia ajudar os cardiologistas a identificar regiões de fibrose focal. Desta forma, não seria necessário analisar imagens de Realce Tardio, o que se traduziria na eliminação de injeção de agentes de contraste. Pesquisas adicionais focadas na correlação do mapeamento T1 nativo e imagens cardíacas de LGE são de extrema importância para desenvolver uma tecnologia independente da injeção de agentes de contraste, que substitua o Realce Tardio

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

On motion in dynamic magnetic resonance imaging: Applications in cardiac function and abdominal diffusion

La imagen por resonancia magnética (MRI), hoy en día, representa una potente herramienta para el diagnóstico clínico debido a su flexibilidad y sensibilidad a un amplio rango de propiedades del tejido. Sus principales ventajas son su sobresaliente versatilidad y su capacidad para proporcionar alto contraste entre tejidos blandos. Gracias a esa versatilidad, la MRI se puede emplear para observar diferentes fenómenos físicos dentro del cuerpo humano combinando distintos tipos de pulsos dentro de la secuencia. Esto ha permitido crear distintas modalidades con múltiples aplicaciones tanto biológicas como clínicas. La adquisición de MR es, sin embargo, un proceso lento, lo que conlleva una solución de compromiso entre resolución y tiempo de adquisición (Lima da Cruz, 2016; Royuela-del Val, 2017). Debido a esto, la presencia de movimiento fisiológico durante la adquisición puede conllevar una grave degradación de la calidad de imagen, así como un incremento del tiempo de adquisición, aumentando así tambien la incomodidad del paciente. Esta limitación práctica representa un gran obstáculo para la viabilidad clínica de la MRI. En esta Tesis Doctoral se abordan dos problemas de interés en el campo de la MRI en los que el movimiento fisiológico tiene un papel protagonista. Éstos son, por un lado, la estimación robusta de parámetros de rotación y esfuerzo miocárdico a partir de imágenes de MR-Tagging dinámica para el diagnóstico y clasificación de cardiomiopatías y, por otro, la reconstrucción de mapas del coeficiente de difusión aparente (ADC) a alta resolución y con alta relación señal a ruido (SNR) a partir de adquisiciones de imagen ponderada en difusión (DWI) multiparamétrica en el hígado.Departamento de Teoría de la Señal y Comunicaciones e Ingeniería TelemáticaDoctorado en Tecnologías de la Información y las Telecomunicacione

Unravelling the role of the left and right ventricles in pulmonary arterial hypertension: patient and small animal cardiac MRI studies

The definite hemodynamic diagnosis of pulmonary hypertension (PH) requires direct measurement of the pulmonary artery pressure by right heart catheterisation. As right heart catheterisation is an invasive test with a small risk of associated morbidity and mortality, diagnostic algorithms have been devised that combines clinical history and examination, cardio- respiratory assessment by non-imaging techniques and subsequently imaging techniques in patients suspected of having PH. The aim of these initial investigations is to establish a tentative diagnosis of PH, help identify the underlying aetiology and to provide information regarding disease severity and determine response to treatment. Although PH is a disease of the pulmonary vasculature, it is the subsequent right ventricular (RV) failure that is the main cause of morbidity and mortality in PH patient. Thus, RV is the most widely studied of the chambers in PH, however focus has started to move to the left ventricle (LV). Although a disease of the pulmonary circulation and the RV, there is now evidence demonstrating LV abnormalities in PH. Further to this, the atrial chambers offer valuable information when measuring cardiac function as well as in identifying the aetiology of PH. Small animal (rodent) models are increasingly used to identify pathophysiology as well as therapies for PH with the intention of translating the findings to humans. Accurate monitoring of disease in rodents with emphasis on ventricular function and the ability to monitor the disease state without killing the animal is needed

Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model

Rationale Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals

Auxetic cardiac patches with tunable mechanical and conductive properties toward treating myocardial infarction

An auxetic conductive cardiac patch (AuxCP) for the treatment of myocardial infarction (MI) is introduced. The auxetic design gives the patch a negative Poisson's ratio, providing it with the ability to conform to the demanding mechanics of the heart. The conductivity allows the patch to interface with electroresponsive tissues such as the heart. Excimer laser microablation is used to micropattern a re-entrant honeycomb (bow-tie) design into a chitosan-polyaniline composite. It is shown that the bow-tie design can produce patches with a wide range in mechanical strength and anisotropy, which can be tuned to match native heart tissue. Further, the auxetic patches are conductive and cytocompatible with murine neonatal cardiomyocytes in vitro. Ex vivo studies demonstrate that the auxetic patches have no detrimental effect on the electrophysiology of both healthy and MI rat hearts and conform better to native heart movements than unpatterned patches of the same material. Finally, the AuxCP applied in a rat MI model results in no detrimental effect on cardiac function and negligible fibrotic response after two weeks in vivo. This approach represents a versatile and robust platform for cardiac biomaterial design and could therefore lead to a promising treatment for MI