Influence of cardiac tissue anisotropy on re-entrant activation in computational models of ventricular fibrillation

The aim of this study was to establish the role played by anisotropic diffusion in (i) the number of filaments and epicardial phase singularities that sustain ventricular fibrillation in the heart, (ii) the lifetimes of filaments and phase singularities, and (iii) the creation and annihilation dynamics of filaments and phase singularities. A simplified monodomain model of cardiac tissue was used, with membrane excitation described by a simplified 3-variable model. The model was configured so that a single re-entrant wave was unstable, and fragmented into multiple re-entrant waves. Re-entry was then initiated in tissue slabs with varying anisotropy ratio. The main findings of this computational study are: (i) anisotropy ratio influenced the number of filaments Sustaining simulated ventricular fibrillation, with more filaments present in simulations with smaller values of transverse diffusion coefficient, (ii) each re-entrant filament was associated with around 0.9 phase singularities on the surface of the slab geometry, (iii) phase singularities were longer lived than filaments, and (iv) the creation and annihilation of filaments and phase singularities were linear functions of the number of filaments and phase singularities, and these relationships were independent of the anisotropy ratio. This study underscores the important role played by tissue anisotropy in cardiac ventricular fibrillation

Computational modeling of nanodrug-induced effects on cardiac electromechanics

This work generally aims to promote the use of computational models for predicting side effects of nanodrugs under development, as a means to speed up the cycle of drug development, with potential savings on testing, and reduction in the need for animal or human testing. The specific objective of this thesis has been to accurately model a single ventricular contraction-relaxation cycle, and monitor the effects induced by nanodrugs on the electro-mechano-physiology of the left and right ventricles. Nanodrug interaction with ion channels located on cardiac cell membranes, such as those for sodium, potassium and calcium, can distort an electrical wave propagating through the tissue and can affect cardiac macroscale functions. In this study, a material model after Holzapfel and Ogden was developed to account for the anisotropic hyperelastic behavior of cardiac tissue, which was implemented on the open source software library Chaste. A coupled drug-electro-mechano-physiological system was then set up, also on Chaste, where a nanodrug effect was introduced into the cellular structure (nanoscale) as an ion channel inhibitor, and its influence then solved for, with respect to resulting electro-mechanical ventricular behaviors. Using quantifiable biomarkers, these effects were compared to the literature and clinical data. In this work we identified the following main results. Nanodrugs causing sodium channel blockage were found to produce the anticipated delays in electro-mechanics. Our study further predicted additional effects on LV twisting and LV & RV strain. On the other hand, nanodrugs causing potassium and calcium channel blockage revealed that cardiac mechanics is less responsive to mild alterations in electrophysiology, than electrophysiology is to ionic changes. Nonetheless, it is important to quantify these changes, as even a very small deviation from normal could accumulate over multiple cardiac cycles, and lead to adverse consequences on cardiac health in the long term

Automatic identification of ischemia using lightweight attention network in PET cardiac perfusion imaging

Ischemic disease, caused by inadequate blood supply to organs or tissues, poses a significant global health challenge. Early detection of ischemia is crucial for timely intervention and improved patient outcomes. Myocardial perfusion imaging with positron-emission tomography (PET) is a non-invasive technique used to identify ischemia. However, accurately interpreting PET images can be challenging, necessitating the development of reliable classification methods. In this study, we propose a novel approach using MS-DenseNet, a lightweight attention network, for the detection and classification of ischemia from myocardial polar maps. Our model incorporates the squeeze and excitation modules to emphasize relevant feature channels and suppress unnecessary ones. By effectively utilizing channel interdependencies, we achieve optimum reuse of interchannel interactions, enhancing the model's performance. To evaluate the efficacy and accuracy of our proposed model, we compare it with transfer learning models commonly used in medical image analysis. We conducted experiments using a dataset of 138 polar maps (JPEG) obtained from 15O_H2O stress perfusion studies, comprising patients with ischemic and non-ischemic condition. Our results demonstrate that MS-DenseNet outperforms the transfer learning models, highlighting its potential for accurate ischemia detection and classification. This research contributes to the field of ischemia diagnosis by introducing a lightweight attention network that effectively captures the relevant features from myocardial polar maps. The integration of the squeeze and excitation modules further enhances the model's discriminative capabilities. The proposed MS-DenseNet offers a promising solution for accurate and efficient ischemia detection, potentially improving the speed and accuracy of diagnosis and leading to better patient outcomes

Regional Mechanical Properties and Microstructure of Ovine Heart Chambers

Mechanical properties of cardiac tissue play an important role in the normal heart function. As a baseline for understanding of physiology and pathophysiology of the heart, and for development and validation of new therapies, it is crucial to first understand the mechanical behavior of the normal heart tissue. Although heart chambers have the same embryonic origin, differences in the development of mechanical properties are expected to manifest over time during the adulthood period. Therefore, the goal of this study was to determine the passive mechanical properties of all heart chambers through a paired comparison study in an ovine model. Ovine heart was used due its physiological and anatomical similarities to human heart. A total of 189 specimens from anterior and posterior portions of the left and right ventricles, atria, and appendages underwent biaxial mechanical testing. A Fung-type strain energy function was used to fit the experimental data. Tissue behavior was quantified based on the magnitude of strain energy, as an indicator of tissue stiffness, at equibiaxial strains of 0.10, 0.15, and 0.20. Statistical analysis revealed no significant difference in strain energy storage between anterior and posterior portions of each chamber, except for the right ventricle where strain energy storage in the posterior specimens were higher than the anterior specimens. Additionally, all chambers from the left side of the heart had significantly higher strain energy storage than the corresponding chambers on the right side. Furthermore, the highest to lowest stored strain energy were associated with ventricles, appendages, and atria, respectively. Microstructure of tissue specimens from different chambers was also compared using histology. The average surface area ratio of collagen to myocyte was found to be highest for the atria and lowest for the ventricles. This fact could explain the underlying basis for the differences in tissue stiffness between the regions

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

Three-dimensional Multiscale Modelling and Simulation of Atria and Torso Electrophysiology

A better understanding of the electrical activity of the heart under physiological and pathological conditions has always been key for clinicians and researchers. Over the last years, the information in the P-wave signals has been extensively analysed to un-cover the mechanisms underlying atrial arrhythmias by localizing ectopic foci or high-frequency rotors. However, the relationship between the activation of the different areas of the atria and the characteristics of the P-wave signals or body surface poten-tial maps are still far from being completely understood. Multiscale anatomical and functional models of the heart are a new technological framework that can enable the investigation of the heart as a complex system. This thesis is centred in the construction of a multiscale framework that allows the realistic simulation of atrial and torso electrophysiology and integrates all the anatom-ical and functional descriptions described in the literature. The construction of such model involves the development of heterogeneous cellular and tissue electrophysiolo-gy models fitted to empirical data. It also requires an accurate 3D representation of the atrial anatomy, including tissue fibre arrangement, and preferential conduction axes. This multiscale model aims to reproduce faithfully the activation of the atria under physiological and pathological conditions. We use the model for two main applica-tions. First, to study the relationship between atrial activation and surface signals in sinus rhythm. This study should reveal the best places for recording P-waves signals in the torso, and which are the regions of the atria that make the most significant contri-bution to the body surface potential maps and determine the main P-wave characteris-tics. Second, to spatially cluster and classify ectopic atrial foci into clearly differenti-ated atrial regions by using the body surface P-wave integral map (BSPiM) as a bi-omarker. We develop a machine-learning pipeline trained from simulations obtained from the atria-torso model aiming to validate whether ectopic foci with similar BSPiM naturally cluster into differentiated non-intersected atrial regions, and whether new BSPiM could be correctly classified with high accuracy.En la actualidad, una mejor compresión de la actividad eléctrica del corazón en condi-ciones fisiológicas y patológicas es clave para médicos e investigadores. A lo largo de los últimos años, la información derivada de la onda P se ha utilizado para intentar descubrir los mecanismos subyacentes a las arritmias auriculares mediante la localiza-ción de focos ectópicos y rotores de alta frecuencia. Sin embargo, la relación entre la activación de distintas regiones auriculares y las características tanto de las ondas P como de la distribución de potencial en la superficie del torso está lejos de entenderse completamente. Los modelos cardíacos funcionales y anatómicos son una nueva he-rramienta que puede facilitar la investigación relativa al corazón entendido como sis-tema complejo. La presente tesis se centra en la construcción de un modelo multiescala para la simula-ción realista de la electrofisiología cardíaca tanto a nivel auricular como de torso, integrando toda la información anatómica y funcional disponible en la literatura. La construcción de este modelo implica el desarrollo, en base a datos experimentales, de modelos electrofisiológicos heterogéneos tanto celulares como tisulares. Así mismo, es imprescindible una representación tridimensional precisa de la anatomía auricular, incluyendo la dirección de fibras y los haces de conducción preferentes. Este modelo multiescala busca reproducir fielmente la activación auricular en condiciones fisiológi-cas y patológicas. Su uso se ha centrado fundamentalmente en dos aplicaciones. En primer lugar, estudiar la relación entre la activación auricular en ritmo sinusal y las señales en la superficie del torso. Este estudio busca definir la mejor ubicación para el registro de las ondas P en el torso así como determinar aquellas regiones auriculares que contribuyen fundamentalmente a la formación y distribución de potenciales super-ficiales así como a las características de las ondas P. En segundo lugar, agrupar y cla-sificar espacialmente los focos ectópicos en regiones auriculares claramente diferen-ciables empleando como biomarcador los mapas superficiales de integral de la onda P (BSPiM). Se ha desarrollado para ello una metodología de aprendizaje automático en la que las simulaciones obtenidas con el modelo multiescala aurícula-torso sirven de entrenamiento, permitiendo validar si los focos ectópicos cuyos BSPiMs son similares se agrupan de forma natural en regiones auriculares no intersectadas y si BSPiMs nue-vos podrían ser clasificados prospectivamente con gran precisión.Avui en dia, una millor comprenssió de l'activitat elèctrica del cor en condicions fisio-lògiques i patològiques és clau per a metges i investigadors. Al llarg dels últims anys, la informació derivada de l'ona P s'ha utilitzat per intentar descobrir els mecanismes subjacents a les arítmies auriculars mitjançant la localització de focus ectòpics i rotors d'alta freqüència. No obstant això, la relació entre l'activació de diferents regions auri-culars i les característiques tant de les ones P com de la distribució de potencial en la superfície del tors està lluny d'entendre's completament. Els models cardíacs funcionals i anatòmics són una nova eina que pot facilitar la recerca relativa al cor entès com a sistema complex. La present tesi es centra en la construcció d'un model multiescala per a la simulació realista de la electrofisiologia cardíaca tant a nivell auricular com de tors, integrant tota la informació anatòmica i funcional disponible en la literatura. La construcció d'aquest model implica el desenvolupament, sobre la base de dades experimentals, de models electrofisiològics heterogenis, tant cel·lulars com tissulars. Així mateix, és imprescindible una representació tridimensional precisa de l'anatomia auricular, in-cloent la direcció de fibres i els feixos de conducció preferents. Aquest model multies-cala busca reproduir fidelment l'activació auricular en condicions fisiològiques i pa-tològiques. El seu ús s'ha centrat fonamentalment en dues aplicacions. En primer lloc, estudiar la relació entre l'activació auricular en ritme sinusal i els senyals en la superfí-cie del tors. A més a més, amb aquest estudi també es busca definir la millor ubicació per al registre de les ones P en el tors, així com, determinar aquelles regions auriculars que contribueixen fonamentalment a la formació i distribució de potencials superfi-cials a l'hora que es caracteritzen les ones P. En segon lloc, agrupar i classificar espa-cialment els focus ectòpics en regions auriculars clarament diferenciables emprant com a biomarcador els mapes superficials d'integral de l'ona P (BSPiM). És per això que s'ha desenvolupat una metodologia d'aprenentatge automàtic en la qual les simulacions obtingudes amb el model multiescala aurícula-tors serveixen d'entrenament, la qual cosa permet validar si els focus ectòpics, llurs BSPiMs són similars, s'agrupen de for-ma natural en regions auriculars no intersectades i si BSPiMs nous podrien ser classifi-cats de manera prospectiva amb precisió.Ferrer Albero, A. (2017). Three-dimensional Multiscale Modelling and Simulation of Atria and Torso Electrophysiology [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/88402TESI

Load-dependent electrophysiological and structural cardiac remodelling studied in ultrathin myocardial slices.

Introduction: Myocardial slices are becoming an established system to study cardiac electrophysiology and pharmacological research and development. Unlike other preparations, cardiac slices are a multicellular preparation that has an intermediate, adequate complexity required for this research. Previous studies have successfully obtained slices from human biopsies and animal models, where the electrical and structural parameters could be maintained for several hours – a process which is comparable to other preparation types. Therefore, we aimed to use left ventricular myocardial slices obtained from rat models of mechanical unloading (HAHLT) and from two models of overload (TAC and SHR), to investigate electrophysiological and structural alterations in these models. Methods: Mechanical unloading was achieved by heterotopic abdominal heart and lung transplantation (HAHLT, 8 weeks) and overload was induced by thoracic aortic constriction (TAC, 10 and 20 weeks) in male Lewis rats. Spontaneous hypertensive rats (SHR) were also used as a second model of overload and were primarily induced by hypertension (3, 12 and 20 months). Brown Norway and Wistar Kyoto rats were used as the control groups for SHR. Myocardial slices from the left ventricle (LV) free wall were cut (300-350 µm thick) tangentially to the epicardial surface using a high-precision slow-advancing Vibratome and were point-stimulated using a multi-electrode array system (MEA), therefore, acquiring field potentials (FPs). Field potential duration (FPD) and conduction velocity (CV) were analysed locally and transmurally across the LV free wall. In addition, FPD heterogeneity within each slice was calculated. For the SHR group, the same slices used for the MEA recording were preserved and used subsequently to measure Cx43, Nav1.5 protein levels and fibrosis. Results: Slices obtained from normal rat hearts that are chronically unloaded were found to develop atrophy at a whole heart level. They showed an increase in FPD and its heterogeneity with preserved conduction properties when compared to controls. In TACs, an in vivo whole heart function assessment confirmed hypertrophy with no signs of cardiac dysfunction. Slices from TAC rats showed an increase in FPD at both 10 and 20 weeks after banding. FPD heterogeneity was increased at 10 weeks but normalised at 20 weeks. Changes in CV properties were observed in this group, showing a faster CV and longitudinal conduction velocity (CVL) at 10 weeks and no change at 20 weeks. Transverse conduction velocity (CVT) was unchanged in the TAC group. In SHRs, however, hypertrophy was confirmed and signs of dysfunction in the aged group (20 months) were observed due to the decrease in EF by 18%, especially when compared to the 12 months group. FPD and its heterogeneity was unchanged in SHR when compared to controls. Disease and age-related abnormalities in CV properties were observed in SHR and these were associated with changes in Cx43, Nav1.5 protein level and fibrosis. Conclusion: Myocardial slices are a suitable multicellular preparation to study electrophysiological remodelling obtained from different rat models of cardiovascular disease. In addition, it was possible to investigate the changes in CV and FPD transmurally in rats using this type of preparation method. Thus, this study supports the use of this multicellular preparation in understanding the mechanisms of cardiac disease and the testing of new treatments and therapeutic targets.Open Acces

MR imaging of left-ventricular function : novel image acquisition and analysis techniques.

Many cardiac diseases, such as myocardial ischemia, secondary to coronary artery disease, may be identified and localized through the analysis of cardiac deformations. Early efforts for quantifying ventricular wall motion used surgical implantation and tracking of radiopaque markers with X-ray imaging in canine hearts [1]. Such techniques are invasive and affect the regional motion pattern of the ventricular wall during the marker tracking process and, clearly are not feasible clinically. Noninvasive imaging techniques are vital and have been widely applied to the clinic. MRI is a noninvasive imaging technique with the capability to monitor and assess the progression of cardiovascular diseases (CVD) so that effective procedures for the care and treatment of patients can be developed by physicians and researchers. It is capable of providing 3D analysis of global and regional cardiac function with great accuracy and reproducibility. In the past few years, numerous efforts have been devoted to cardiac motion recovery and deformation analysis from MR imaging sequences. In order to assess cardiac function, there are two categories of indices that are used: global and regional indices. Global indices include ejection fraction, cavity volume, and myocardial mass [2]. They are important indices for cardiac disease diagnosis. However, these global indices are not specific for regional analysis. A quantitative assessment of regional parameters may prove beneficial for the diagnosis of disease and evaluation of severity and the quantification of treatment [3]. Local measures, such as wall deformation and strain in all regions of the heart, can provide objective regional quantification of ventricular wall function and relate to the location and extent of ischemic injury. This dissertation is concerned with the development of novel MR imaging techniques and image postprocessing algorithms to analyze left ventricular deformations. A novel pulse sequence, termed Orthogonal CSPAMM (OCSPAMM), has been proposed which results in the same acquisition time as SPAMM for 2D deformation estimation while keeping the main advantages of CSPAMM [4,5]: i.e., maintaining tag contrast through-out the ECG cycle. Different from CSPAMM, in OCSPAMM the second tagging pulse orientation is rotated 90 degrees relative to the first one so that motion information can be obtained simultaneously in two directions. This reduces the acquisition time by a factor of two as compared to the traditional CSPAMM, in which two separate imaging sequences are applied per acquisition. With the application of OCSPAMM, the effect of tag fading encountered in SPAMM tagging due to Tl relaxation is mitigated and tag deformations can be visualized for the entire cardiac cycle, including diastolic phases. A multilevel B-spline fitting method (MBS) has been proposed which incorporates phase-based displacement information for accurate calculation of 2D motion and strain from tagged MRI [6, 7]. The proposed method combines the advantages of continuity and smoothness of MBS, and makes use of phase information derived from tagged MR images. Compared to previous 2D B-spline-based deformation analysis methods, MBS has the following advantages: 1) It can simultaneously achieve a smooth deformation while accurately approximating the given data set; 2) Computationally, it is very fast; and 3) It can produce more accurate deformation results. Since the tag intersections (intersections between two tag lines) can be extracted accurately and are more or less distributed evenly over the myocardium, MBS has proven effective for 2D cardiac motion tracking. To derive phase-based displacements, 2D HARP and SinMod analysis techniques [8,9] were employed. By producing virtual tags from HARP /SinMod and calculating intersections of virtual tag lines, more data points are obtained. In the reference frame, virtual tag lines are the isoparametric curves of an undeformed 2D B-spline model. In subsequent frames, the locations of intersections of virtual tag lines over the myocardium are updated with phase-based displacement. The advantage of the technique is that in acquiring denser myocardial displacements, it uses both real and virtual tag line intersections. It is fast and more accurate than 2D HARP and SinMod tracking. A novel 3D sine wave modeling (3D SinMod) approach for automatic analysis of 3D cardiac deformations has been proposed [10]. An accelerated 3D complementary spatial modulation of magnetization (CSPAMM) tagging technique [11] was used to acquire complete 3D+t tagged MR data sets of the whole heart (3 dynamic CSPAMM tagged MRI volume with tags in different orientations), in-vivo, in 54 heart beats and within 3 breath-holds. In 3D SinMod, the intensity distribution around each pixel is modeled as a cosine wave front. The principle behind 3D SinMod tracking is that both phase and frequency for each voxel are determined directly from the frequency analysis and the displacement is calculated from the quotient of phase difference and local frequency. The deformation fields clearly demonstrate longitudinal shortening during systole. The contraction of the LV base towards the apex as well as the torsional motion between basal and apical slices is clearly observable from the displacements. 3D SinMod can automatically process the image data to derive measures of motion, deformations, and strains between consecutive pair of tagged volumes in 17 seconds. Therefore, comprehensive 4D imaging and postprocessing for determination of ventricular function is now possible in under 10 minutes. For validation of 3D SinMod, 7 3D+t CSPAMM data sets of healthy subjects have been processed. Comparison of mid-wall contour deformations and circumferential shortening results by 3D SinMod showed good agreement with those by 3D HARP. Tag lines tracked by the proposed technique were also compared with manually delineated ones. The average errors calculated for the systolic phase of the cardiac cycles were in the sub-pixel range

Numerical Simulation

Nowadays mathematical modeling and numerical simulations play an important role in life and natural science. Numerous researchers are working in developing different methods and techniques to help understand the behavior of very complex systems, from the brain activity with real importance in medicine to the turbulent flows with important applications in physics and engineering. This book presents an overview of some models, methods, and numerical computations that are useful for the applied research scientists and mathematicians, fluid tech engineers, and postgraduate students