Doctor of Philosophy

dissertationAtrial fibrillation (AF) is the leading cause of ischemic stroke and is the most commonly observed arrhythmia in clinical cardiology. Catheter ablation of AF, in which specific regions of cardiac anatomy associated with AF are intenionally injured to create scar tissue, has been honed over the last 15 years to become a relatively common and safe treatment option. However, the success of these anatomically driven ablation strategies, particularly in hearts that have been exposed to AF for extended periods, remains poor. AF induces changes in the electrical and structural properties of the cardiac tissue that further promotes the permanence of AF. In a process known as electroanatomical (EAM) mapping, clinicians record time signals known as electrograms (EGMs) from the heart and the locations of the recording sites to create geometric representations, or maps, of the electrophysiological properties of the heart. Analysis of the maps and the individual EGM morphologies can indicate regions of abnormal tissue, or substrates that facilitate arrhythmogenesis and AF perpetuation. Despite this progress, limitations in the control of devices currently used for EAM acquisition and reliance on suboptimal metrics of tissue viability appear to be hindering the potential of treatment guided by substrate mapping. In this research, we used computational models of cardiac excitation to evaluate param- eters of EAM that affect the performance of substrate mapping. These models, which have been validated with experimental and clinical studies, have yielded new insights into the limitations of current mapping systems, but more importantly, they guided us to develop new systems and metrics for robust substrate mapping. We report here on the progress in these simulation studies and on novel measurement approaches that have the potential to improve the robustness and precision of EAM in patients with arrhythmias. Appropriate detection of proarrhythmic substrates promises to improve ablation of AF beyond rudimentary destruction of anatomical targets to directed targeting of complicit tissues. Targeted treatment of AF sustaining tissues, based on the substrate mapping approaches described in this dissertation, has the potential to improve upon the efficacy of current AF treatment options

Atrial substrate characterization based on bipolar voltage electrograms acquired with multipolar, focal and mini-electrode catheters.

BACKGROUND Bipolar voltage (BV) electrograms for left atrial (LA) substrate characterization depend on catheter design and electrode configuration. AIMS The aim of the study was to investigate the relationship between the BV amplitude (BVA) using four catheters with different electrode design and to identify their specific LA cutoffs for scar and healthy tissue. METHODS AND RESULTS Consecutive high-resolution electroanatomic mapping was performed using a multipolar-minielectrode Orion catheter (Orion-map), a duo-decapolar circular mapping catheter (Lasso-map), and an irrigated focal ablation catheter with minielectrodes (Mifi-map). Virtual remapping using the Mifi-map was performed with a 4.5 mm tip-size electrode configuration (Nav-map). BVAs were compared in voxels of 3 × 3 × 3 mm3. The equivalent BVA cutoff for every catheter was calculated for established reference cutoff values of 0.1, 0.2, 0.5, 1.0, and 1.5 mV. We analyzed 25 patients (72% men, age 68 ± 15 years). For scar tissue, a 0.5 mV cutoff using the Nav corresponds to a lower cutoff of 0.35 mV for the Orion and of 0.48 mV for the Lasso. Accordingly, a 0.2 mV cutoff corresponds to a cutoff of 0.09 mV for the Orion and of 0.14 mV for the Lasso. For healthy tissue cutoff at 1.5 mV, a larger BVA cutoff for the small electrodes of the Orion and the Lasso was determined of 1.68 and 2.21 mV, respectively. CONCLUSION When measuring LA BVA, significant differences were seen between focal, multielectrode, and minielectrode catheters. Adapted cutoffs for scar and healthy tissue are required for different catheters

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping

Aims : Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. Methods and results: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. Conclusion: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.This work was funded by Abbott Laboratories, St. Paul, MN, USA.S

Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays

[EN] Introduction: The omnipolar electrogram method was recently proposed to try to generate orientation-independent electrograms. It estimates the electric field from the bipolar electrograms of a clique, under the assumption of locally plane and homogeneous propagation. The local electric field evolution over time describes a loop trajectory from which omnipolar signals in the propagation direction, substrate and propagation features, are derived. In this work, we propose substrate and conduction velocity mapping modalities based on a modified version of the omnipolar electrogram method, which aims to reduce orientation-dependent residual components in the standard approach. Methods: A simulated electrical propagation in 2D, with a tissue including a circular patch of diffuse fibrosis, was used for validation. Unipolar electrograms were calculated in a multi-electrode array, also deriving bipolar electrograms along the two main directions of the grid. Simulated bipolar electrograms were also contaminated with real noise, to assess the robustness of the mapping strategies against noise. The performance of the maps in identifying fibrosis and in reproducing unipolar reference voltage maps was evaluated. Bipolar voltage maps were also considered for performance comparison. Results: Results show that the modified omnipolar mapping strategies are more accurate and robust against noise than bipolar and standard omnipolar maps in fibrosis detection (accuracies higher than 85 vs. 80% and 70%, respectively). They present better correlation with unipolar reference voltage maps than bipolar and original omnipolar maps (Pearson's correlations higher than 0.75 vs. 0.60 and 0.70, respectively). Conclusion: The modified omnipolar method improves fibrosis detection, characterization of substrate and propagation, also reducing the residual sensitivity to directionality over the standard approach and improving robustness against noise. Nevertheless, studies with real electrograms will elucidate its impact in catheter ablation interventions.This study has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 766082 (MY-ATRIA project), from projects PID2019-104881RB-I00, and PID2019-105674RB-I00 from MICINN, Spain, from Gobierno de Aragon (BSICoS Group T39-20R) cofunded by FEDER 20142020 Building Europe from Aragon and from Generalitat Valenciana through the fellowship ACIF/2018/174 and the grant PROMETEO/2020/043.Riccio, J.; Alcaine, A.; Rocher-Ventura, S.; Martínez-Mateu, L.; Laranjo, S.; Saiz Rodríguez, FJ.; Laguna, P.... (2021). Characterization of Atrial Propagation Patterns and Fibrotic Substrate With a Modified Omnipolar Electrogram Strategy in Multi-Electrode Arrays. Frontiers in Physiology. 12:1-21. https://doi.org/10.3389/fphys.2021.674223S1211

A 3-Dimensional In Silico Test Bed for Radiofrequency Ablation Catheter Design Evaluation and Optimization

Atrial fibrillation (AF) is the disordered activation of the atrial myocardium, which is a major cause of stroke. Currently, the most effective, minimally traumatic treatment for AF is percutaneous catheter ablation to isolate arrhythmogenic areas from the rest of the atrium. The standard in vitro evaluation of ablation catheters through lesion studies is a resource intensive effort due to tissue variability and visual measurement methods, necessitating large sample sizes and multiple prototype builds. A computational test bed for ablation catheter evaluation was built in SolidWorks® using the morphology and dimensions of the left atrium adjacent structures. From this geometry, the physical model was built in COMSOL Multiphysics®, where a combination of the laminar fluid flow, electrical currents, and bioheat transfer was used to simulate radiofrequency (RF) tissue ablation. Simulations in simplified 3D geometries led to lesions sizes within the reported ranges from an in-vivo ablation study. However, though the ellipsoid lesion morphologies in the full atrial model were consistent with past lesion studies, perpendicularly oriented catheter tips were associated with decreases of -91.3% and -70.0% in lesion depth and maximum diameter. On the other hand, tangentially oriented catheter tips produced lesions that were only off by -28.4% and +7.9% for max depth and max diameter. Preliminary investigation into the causes of the discrepancy were performed for fluid velocities, contact area, and other factors. Finally, suggestions for further investigation are provided to aid in determining the root cause of the discrepancy, such that the test bed may be used for other ablation catheter evaluations

Formation of Intracardiac Electrograms under Physiological and Pathological Conditions

This work presents methods to advance electrophysiological simulations of intracardiac electrograms (IEGM). An experimental setup is introduced, which combines electrical measurements of extracellular potentials with a method for optical acquisition of the transmembrane voltage in-vitro. Thereby, intracardiac electrograms can be recorded under defined conditions. Using experimental and clinical signals, detailed simulations of IEGMs are parametrized, which can support clinical diagnosis

Characterization and modeling of the human left atrium using optical coherence tomography

With current needs to better understand the interaction between atrial tissue microstructure and atrial fibrillation dynamics, micrometer scale imaging with optical coherence tomography has significant potential to provide further insight on arrhythmia mechanisms and improve treatment guidance. However, optical coherence tomography imaging of cardiac tissue in humans is largely unexplored, and the ability of optical coherence tomography to identify the structural substrate of atrial fibrillation has not yet been investigated. Therefore, the objective of this thesis was to develop an optical coherence tomography imaging atlas of the human heart, study the utility of optical coherence tomography in providing useful features of human left atrial tissues, and develop a framework for optical coherence tomography-informed cardiac modeling that could be used to probe dynamics between electrophysiology and tissue structure. Human left atrial tissues were comprehensively imaged by optical coherence tomography for the first time, providing an imaging atlas that can guide identification of left atrial tissue features from optical coherence tomography imaging. Optical coherence tomography image features corresponding to myofiber and collagen fiber orientation, adipose tissue, endocardial thickness and composition, and venous media were established. Varying collagen fiber distributions in the myocardial sleeves were identified within the pulmonary veins. A scheme for mapping optical coherence tomography data of dissected left atrial tissues to a three-dimensional, anatomical model of the human left atrium was also developed, enabling the mapping of distributions of imaged adipose tissue and fiber orientation to the whole left atrial geometry. These results inform future applications of structural substrate mapping in the human left atrium using optical coherence tomography-integrated catheters, as well as potential directions of ex vivo optical coherence tomography atrial imaging studies. Additionally, we developed a workflow for creating optical mapping models of atrial tissue as informed by optical coherence tomography. Tissue geometry, fiber orientation, ablation lesion geometry, and heterogeneous tissue types were extracted from optical coherence tomography images and incorporated into tissue-specific meshes. Electrophysiological propagation was simulated and combined with photon scattering simulations to evaluate the influence of tissue-specific structure on electrical and optical mapping signals. Through tissue-specific modeling of myofiber orientation, ablation lesions, and heterogeneous tissue types, the influence of myofiber orientation on transmural activation, the relationship between fluorescent signals and lesion geometry, and the blurring of optical mapping signals in the presence of heterogeneous tissue types were investigated. By providing a comprehensive optical coherence tomography image database of the human left atrium and a workflow for developing optical coherence tomography-informed cardiac tissue models, this work establishes the foundation for utilizing optical coherence tomography to improve the structural substrate characterization of atrial fibrillation. Future developments include analysis of optical coherence tomography imaged tissue structure with respect to clinical presentation, development of automated processing to better leverage the large amount of imaging data, enhancements and validation of the modeling scheme, and in vivo evaluation of the left atrial structural substrate through optical coherence tomography-integrated catheter

Characterization of Propagation Patterns with Omnipolar EGM in Epicardial Multi-Electrode Arrays

Omnipolar Electrogram (OP-EGM) is a recently proposed technique to characterize myocardial propagation in multi-electrode catheters regardless of the angle between propagation direction and catheter bipolar. This work aims to evaluate the accuracy of atrial propagation parameters obtained with OP-EGM in sinus rhythm (SR) and in different patterns of atrial fibrillation (AF).Real and simulated unipolar electrograms (u-EGMs) were used in this study. For both types of data, conduction velocity was obtained for each clique of 4 neighbour electrodes using OP-EGM. As a reference, conduction velocity was also computed from local activation times (LATs) using a linear propagation model.Analysis of simulated data showed that conduction velocity had good concordance with propagation patterns for both estimations, although the LAT-based errors were lower in most of the cases. When conduction velocity magnitude (CV) was 1 mm/ms, its estimation errors (expressed as mean ± std) calculated with OP-EGM and from LATs were 0.053 ± 0.005 mm/ms and 0.003 ±2.1 ×10-5 mm/ms, respectively, when focus was at 30 mm from the bottom of the tissue slice, while propagation direction angular errors were 6.64 ± 4.3°and 4.35 ± 2.8°. In real data, maps obtained with OP-EGM presented smoother and more coherent patterns than those based on LATs

Multimodal ventricular tachycardia analysis : towards the accurate parametrization of predictive HPC electrophysiological computational models

After a myocardial infarction, the affected areas of the cardiac tissue suffer changes in their electrical and mechanical properties. This post-infarction scar tissue has been related with a particular type of arrhythmia: ventricular tachycardia (VT). A thorough study on the experimental data acquired with clinical tools is presented in this thesis with the objective of defining the limitations of the clinical data towards predictive computational models. Computational models have a large potential as predictive tools for VT, but the verification, validation and uncertain quantification of the numerical results is required before they can be employed as a clinical tool. Swine experimental data from an invasive electrophysiological study and Cardiac Magnetic Resonance imaging is processed to obtain accurate characterizations of the post-infarction scar. Based on the results, the limitation of each technique is described. Furthermore, the volume of the scar is evaluated as marker for post-infarction VT induction mechanisms. A control case from the animal experimental protocol is employed to build a simulation scenario in which biventricular simulations are done using a detailed cell model adapted to the ionic currents present in the swine myocytes. The uncertainty of the model derived from diffusion and fibre orientation is quantified. Finally, the recovery of the model to an extrastimulus is compared to experimental data by computationally reproducing an S1-S2 protocol. Results from the cardiac computational model show that the propagation wave patterns from numerical results match the one described by the experimental activation maps if the DTI fibre orientations are used. The electrophysiological activation is sensitive to fibre orientation. Therefore simulations including the fibre orientations from DTI are able to reproduce a physiological wave propagation pattern. The diffusion coefficients highly determine the conduction velocity. The S1-S2 protocol produced restitution curves that have similar slopes to the experimental curves. This work is a first step forward towards validation of cardiac electrophysiology simulations. Future work will address the limitations about optimal parametrization of the O'Hara-Rudy cell model to fully validate the cardiac computational model for prediction of VT inducibility.Tras un infarto de miocardio, las zonas de tejido cardiaco afectadas sufren cambios en sus propiedades eléctricas y mecánicas. Este substrato miocárdico se ha relacionado con la taquicardia ventricular (TV), un tipo de arritmia. En esta tesis se presenta un estudio exhaustivo de los datos experimentales adquiridos con protocolos clínicos con el objetivo de definir las limitaciones de los datos clínicos antes de avanzar hacia modelos computacionales. Los modelos computacionales tienen un gran potencial como herramientas para la predicción de TV, pero es necesaria su verificación, validación y la cuantificación de la incertidumbre en los resultados numéricos antes de poderlos emplear como herramientas clínicas. La caracterización precisa del sustrato miocárdico, cicatriz, se realiza mediante el procesado de los datos experimentales porcinos obtenidos del estudio electrofisiológico invasivo y la resonancia magnética cardiaca. Como consecuencia, se describen las limitaciones de cada técnica. Ademas, se estudia si el volumen da la cicatriz puede actuar como indicador de la aparición de VT. El escenario de simulación para los modelos computacionales biventriulares se construye a partir de los datos experimentales de un caso control incluido en el protocolo experimental. En el, se realizan simulaciones electrofisiológicas empleando un modelo celular detallado adaptado a las propiedades de las corrientes iónicas en los miocitos de los cerdos. Se cuantifica la incertidumbre del modelo generada por la difusión y la orientación de las fibras. Por ultimo, se compara la recuperación del modelo a un extraestímulo con datas experimentales mediante la simulación de un protocolo S1-S2. Los resultado numéricos obtenidos muestran que los patrones de propagación de la onda de las simulación cardiaca coinciden con los descritos por los mapas de activación experimentales si la fibras incluidas en el modelo corresponden a los datos de DTI. El modelo de activación es sensible a la orientación de fibras impuesta. Las simulaciones incluyendo la orientación de fibras de DTI es capaz de reproducir los patrones fisiológicos de la onda de propagación eléctrica en ambos ventrículos. El velocidad de conducción obtenida es muy dependiente del coeficiente de difusión impuesto. El protocolo S1-S2 protocolo genera curvas de restitución con pendientes simulares a las curvas experimentales. Esta tesis es un primer paso hacia la validación de las simulaciones electrofisiológicas cardiacas. En el futuro, se mejoraran las limitaciones relacionadas con una optima parametrización del modelo celular de O?Hara-Rudy para validar por completo el modelo computacional cardiaco para avanzar hacia la predicción de la predicción de VT.Postprint (published version