The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model

Purpose: Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected. Methods: In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation. Results: We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. Conclusion: This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment

A COMPUTATIONAL STUDY OF PATCH IMPLANTATION AND MITRAL VALVE MECHANICS

Myocardial infarction (i.e., a heart attack) is the most common heart disease in the United States. Mitral valve regurgitation, or the backflow of blood into the atrium from the left ventricle, is one of the complications associated with myocardial infarction. In this dissertation, a validated model of a sheep heart that has suffered myocardial infarction has been employed to study mitral valve regurgitation. The model was rebuilt with the knowledge of geometrical changes captured with MRI technique and is assigned with anisotropic, inhomogeneous, nearly incompressible and highly non-linear material properties. Patch augmentation was performed on its anterior leaflet, using a simplified approach, and its posterior leaflet, using a more realistic approach. In this finite element simulation, we virtually installed an elliptical patch within the central portion of the posterior leaflet. To the best of the author’s knowledge, this type of simulation has not been performed previously. In another simulation, the effect of patch within the anterior leaflet was simulated. The results from the two different surgical simulations show that patch implantation helps the free edges of the leaflets come close to one another, which leads to improved coaptation. Additionally, the changes in chordal force distributions are also reported. Finally, this study answers a few questions regarding mitral valve patch augmentation surgeries and emphasizes the importance of further investigations on the influence of patch positioning and material properties on key outcomes. The ultimate goal is to use the proposed techniques to assess human models that are patient-specific

Electro-mechanical whole-heart digital twins: A fully coupled multi-physics approach

Mathematical models of the human heart are evolving to become a cornerstone of precision medicine and support clinical decision making by providing a powerful tool to understand the mechanisms underlying pathophysiological conditions. In this study, we present a detailed mathematical description of a fully coupled multi-scale model of the human heart, including electrophysiology, mechanics, and a closed-loop model of circulation. State-of-the-art models based on human physiology are used to describe membrane kinetics, excitation-contraction coupling and active tension generation in the atria and the ventricles. Furthermore, we highlight ways to adapt this framework to patient specific measurements to build digital twins. The validity of the model is demonstrated through simulations on a personalized whole heart geometry based on magnetic resonance imaging data of a healthy volunteer. Additionally, the fully coupled model was employed to evaluate the effects of a typical atrial ablation scar on the cardiovascular system. With this work, we provide an adaptable multi-scale model that allows a comprehensive personalization from ion channels to the organ level enabling digital twin modeling

Doctor of Philosophy

dissertationDiffusion tensor MRI (DT-MRI or DTI) has been proven useful for characterizing biological tissue microstructure, with the majority of DTI studies having been performed previously in the brain. Other studies have shown that changes in DTI parameters are detectable in the presence of cardiac pathology, recovery, and development, and provide insight into the microstructural mechanisms of these processes. However, the technical challenges of implementing cardiac DTI in vivo, including prohibitive scan times inherent to DTI and measuring small-scale diffusion in the beating heart, have limited its widespread usage. This research aims to address these technical challenges by: (1) formulating a model-based reconstruction algorithm to accurately estimate DTI parameters directly from fewer MRI measurements and (2) designing novel diffusion encoding MRI pulse sequences that compensate for the higher-order motion of the beating heart. The model-based reconstruction method was tested on undersampled DTI data and its performance was compared against other state-of-the-art reconstruction algorithms. Model-based reconstruction was shown to produce DTI parameter maps with less blurring and noise and to estimate global DTI parameters more accurately than alternative methods. Through numerical simulations and experimental demonstrations in live rats, higher-order motion compensated diffusion-encoding was shown to successfully eliminate signal loss due to motion, which in turn produced data of sufficient quality to accurately estimate DTI parameters, such as fiber helix angle. Ultimately, the model-based reconstruction and higher-order motion compensation methods were combined to characterize changes in the cardiac microstructure in a rat model with inducible arterial hypertension in order to demonstrate the ability of cardiac DTI to detect pathological changes in living myocardium

Personalized Electromechanical Modeling of the Human Heart : Challenges and Opportunities for the Simulation of Pathophysiological Scenarios

Mathematische Modelle des menschlichen Herzens entwickeln sich zu einem Eckpfeiler der personalisierten Medizin. Sie sind ein nützliches Instrument und helfen klinischen Entscheidungsträgern die zugrundeliegenden Mechanismen von Herzkrankheiten zu erforschen und zu verstehen. Aufgrund der Komplexität des Herzens benötigen derartige Modelle allerdings eine detaillierte Beschreibung der physikalischen Prozesse, welche auf verschiedenen räumlichen und zeitlichen Skalen miteinander interagieren. Aus mathematischer Perspektive stellen vor allem die Entwicklung robuster numerischer Methoden für die Lösung des Modells in Raum und Zeit sowie die Identifizierung von Parametern aus patientenspezifischen Messungen eine Herausforderung dar. In dieser Arbeit wird ein detailliertes mathematisches Modell vorgestellt, welches ein vollgekoppeltes Multiskalenmodell des menschlichen Herzens beschreibt. Das Modell beinhaltet unter anderem die Ausbreitung des elektrischen Signals und die mechanische Verformung des Herzmuskels sowie eine Beschreibung des Herz-Kreislauf-Systems. Basierend auf dem neusten Stand der Technik wurden Modelle der Membrankinetik sowie der Entwicklung der aktiven Kraft zu einem einheitlichen Modell einer Herzmuskelzelle zusammengeführt. Dieses beschreibt die elektromechanische Kopplung in Herzmuskelzellen der Vorhöfe und der Herzkammern basierend auf der Physiologie im Menschen und wurde mit Hilfe von experimentellen Daten aus einzelnen Zellen neu parametrisiert. Um das elektromechanisch gekoppelte Modell des menschlichen Herzens lösen zu können, wurde ein gestaffeltes Lösungsverfahren entwickelt, welches auf bereits existierenden Softwarelösungen der Elektrophysiologie und Mechanik aufbaut. Das neue Modell wurde verwendet, um den Einfluss elektromechanischer Rückkopplungseffekte auf das Herz im Sinusrhythmus zu untersuchen. Die Simulationsergebnisse zeigten, dass elektromechanische Rückkopplungseffekte auf zellulärer Ebene einen wesentlichen Einfluss auf das mechanische Verhalten des Herzens haben. Dahingegen hatte die Verformung des Herzens nur einen geringen Einfluss auf den Diffusionskoeffizienten des elektrischen Signals. Um die verschiedenen Komponenten der Simulationssoftware zu verifizieren, wurden spezielle Probleme definiert, welche die wichtigsten Aspekte der Elektrophysiologie und der Mechanik abdecken. Zusätzlich wurden diese Probleme dazu verwendet, den Einfluss von räumlicher und zeitlicher Diskretisierung auf die numerische Lösung zu bewerten. Die Ergebnisse zeigten, dass Raum- und Zeitdiskretisierung vor allem für das elektrophysiologische Problem die limitierenden Faktoren sind, während die Mechanik hauptsächlich anfällig für volumenversteifende Effekte ist. Weiterhin wurde das Modell verwendet, um zu untersuchen, wie sich eine Verteilung der Faserspannung auf den gesamten Herzmuskel auf die Funktion der linken Herzkammer auswirkt. Hierzu wurde zusätzlich eine Spannung in die Normalenrichtungen der Fasern einer idealisierten linken Herzkammer angewandt. Es zeigte sich, dass insbesondere eine Spannung senkrecht zu den Faserschichten zu einer physiologischeren Kontraktion der Kammer führte. Allerdings konnten diese Ergebnisse auf einem ganzen Herzen nicht vollständig bestätigt werden. In einem zweiten Projekt wurde mit Hilfe eines Modells der linken Herzkammer untersucht, wie sich das Rotationsmuster der Kammer unter Modifikation der lokalen elektromechanischen Eigenschaften verändert. Hierzu wurden in vivo Daten elektromechanischer Parameter von 30 Patienten mit Herzversagen und Linksschenkelblock in das Modell integriert, simuliert und ausgewertet. Die Ergebnisse konnten die klinisch aufgestellte Hypothese nicht bestätigen und es zeigte sich keine Korrelation zwischen den elektromechanischen Parametern und dem Rotationsverhalten. Die Auswirkungen von standardisierten Ablationsstrategien zur Behandlung von Vorhofflimmern in Bezug auf die kardiovaskuläre Leistung wurde in einem Modell des ganzen Herzens untersucht. Aufgrund der Narben im linken Vorhof wurde die elektrische Aktivierung und die Steifigkeit des Herzmuskels verändert. Dies führte zu einem reduzierten Auswurfvolumen, welches in direktem Zusammenhang mit dem inaktiven Gewebe steht. Abhängig von der Steifigkeit der Narben hat sich zusätzlich der Druck im linken Vorhof erhöht. Die linke Herzkammer war nur wenig beeinflusst. Zu guter Letzt wurden schrittweise pathologische Mechanismen in das Herzmodell integriert, welche in Zusammenhang mit Herzversagen stehen und in Patienten mit dilatativer Kardiomyopathie zu beobachten sind. Die Simulationen zeigten, dass vor allem zelluläre Veränderungen bezüglich der elektrophysiologischen Eigenschaften für die schlechte mechanische Aktivtät des Herzens verantwortlich sind. Weiterhin zeigte sich, dass strukturelle Veränderungen der Anatomie und die erhöhte Steifigkeit des Herzmuskels und die damit einhergehenden Anpassungen des Herz-Kreislauf-Systems nötig sind, um in vivo Messungen zu reproduzieren. In dieser Arbeit wurde eine Simulationsumgebung vorgestellt, welche die Berechnung der elektromechanischen Aktivität des Herzens und des Herz-Kreislauf-Systems ermöglicht. Die Simulationsumgebung wurde mit Hilfe von einfachen Beispielen verifiziert und unter Einbeziehung von Daten aus der Magnetresonanztomographie validiert. Zu guter Letzt wurde die Simulationsumgebung genutzt, um klinische Fragen zu beantworten, welche andernfalls im Dunkeln blieben

Impact of uncertainties in cardiac mechanics simulations

Modeling the mechanics of the heart have led to considerable insights, but it still representes a complex and demanding computational problem, especially in a strongly coupled electromechanical setting. Passive cardiac tissue is commonly modeled as a hyperelastic, near-incompressible and orthotropic material, which are properties very challenging for the numerical solution of the model. In particular, near-incompressibility is known to cause numerical issues. In this work, some improvements were done in a cardiac mechanics simulator in order to be more efficient in the treatment of these numerical issues. With the improved solver for cardiac mechanics, it was possible to run problems with higher computational cost, such as sensitivity and uncertainty quantification analyses. This type of analysis has been a topic of scientific interest to assess the possibility of translating patient-specific simulations to clinical applications. However, personalized simulations are still challenging problems, because of the wide biological variability among patients, the uncertainties in experimental measurements and in the geometric representation of the heart. Due to these uncertainties in model inputs, it is difficult to define a reliable model that can be translated to clinical applications. Recent studies have focused on quantifying uncertainties for cardiac models in order to investigate how they can influence simulation results and, consequently, how we can make the models more reliable. Then, the present work also quantifies how uncertainties in the geometry can impact in quantities of interest from cardiac mechanics. The polynomial chaos approach was used to quantify uncertainties in geometries of the left ventricle during cardiac mechanics simulations. Initially, we performed some studies using simplified geometries during ventricular filling phase simulations and, after, we quantify uncertainties in more realistic geometries during the full cardiac cycle.A modelagem da mecânica cardíaca tem levado a descobertas interessantes, porém este continua sendo um problema complexo e de alta demanda computacional, especialmente em modelos eletromecânicos fortemente acoplados. O tecido cardíaco é geralmente considerado como um material hiperelástico, quase incompressível e ortotrópico, fatores que dificultam a solução numérica do modelo. Neste trabalho, melhorias foram realizadas em um simulador da mecânica cardíaca para tratar tais problemas numéricos de forma mais eficiente. Com este simulador mais eficiente foi possível tratar problemas que demandam de um maior esfoço computacional, como as análises de sensibilidade e quantificação de incertezas, onde várias simulações precisam ser realizadas. Este tipo de análise tem sido tópico de interesse científico para avaliar a possibilidade de usar simulações personalizadas por paciente em aplicações clínicas. Porém, estas simulações ainda são problemas desafiadores, por causa da grande variabilidade biológica entre pacientes e das incertezas em medidas experimentais e em representações geométricas do coração. Devido a estas incertezas em entradas do modelo, é difícil definir um modelo confiável que possa ser usado em aplicações clínicas. Estudos recentes têm se voltado à investigação de como estas incertezas podem influenciar no resultado de simulações e, consequentemente, descobrir como tornar os modelos mais confiáveis. Então, o presente trabalho quantifica incertezas nas geometrias usadas nas simulações para investigar como quantidades de interesse da mecânica cardíaca podem ser afetadas. A abordagem do polinômio caos é utilizada para a quantificação de incertezas em geometrias do ventrículo esquerdo submetidas a simulações da mecânica cardíaca. Inicialmente, as análises foram realizadas usando geometrias simplificadas em simulações da fase de preenchimento ventricular e, posteriormente, análises de quantificação de incertezas em geometrias mais realísticas submetidas a simulações do ciclo cardíaco completo são realizadas.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-chamber Heart Model

Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the hemodynamic performance of the heart has not been investigated thoroughly. In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scar affect atrial as well as ventricular contraction and relaxation. We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4% and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular pumping function. Our results have the potential to help tailoring ablation strategies towards minimal global hemodynamic impairment

Ablation of Cardiac Tissue with Nanosecond Pulsed Electric Fields: Experiments and Numerical Simulations

Cardiac ablation for the treatment of cardiac arrhythmia is usually performed by heating tissue with radio-frequency (RF) electrical currents to create conduction-blocking lesions in order to stop the propagation of electrical waves. Problems associated with RF ablation are recurrence of arrhythmias after successful treatments, tissue loss beyond the targeted tissue, long duration of the ablation procedure, and thermal side effects including thrombus formation that may lead to stroke. Here, we propose a new, non-thermal ablation method using nanosecond pulsed electric fields (nsPEFs) with better-controlled ablation volume, shorter procedure time, and no thermal side effects. We demonstrate that we can create non-conductive transmural lesions using different electrode configurations. We also develop a numerical model of nsPEF ablation, which allows us to estimate the critical electric field which leads in cardiac tissue and helps to provide a guideline for clinical tissue ablation. Our experimental model is a Langendorff-perfused rabbit heart. The heart is placed in a life-support system, and optical mapping is performed to study its electrical activity. We further developed the capability to apply short sequences of nanosecond pulses to tissue through pairs of customized electrodes. In order to characterize the 3D geometry of an ablated volume, we have adopted propidium iodide and TTC staining in conjunction with tissue sectioning. Our results obtained by optical mapping data and PI/TTC stained tissue show that fully transmural lesions can be obtained faster and with better control over the ablated volume than in conventional (RF) ablation, in the absence of thermal side effects. In order to aid nsPEF ablation planning, we used the COMSOL finite element software to create a model of the electric field distribution in cardiac tissue, which has a complex anisotropic architecture, for different electrode configurations. The experimental and numerical results are consistent and suggest a critical electric field strength of 3kV/cm for the death of cardiac tissue. This threshold obtained by the numerical model can function as a guideline for future clinical nsPEF treatment of atrial fibrillation. In summary, we have developed nsPEF ablation for the treatment of cardiac arrhythmia to provide better control over the ablated volume than conventional (RF) ablation, to reduce procedure time, and to avoid thermal side effects. Our ultimate goal is to bring this technology to the clinical practice