Assessing the ability of substrate mapping techniques to guide ventricular tachycardia ablation using computational modelling

BACKGROUND: Identification of targets for ablation of post-infarction ventricular tachycardias (VTs) remains challenging, often requiring arrhythmia induction to delineate the reentrant circuit. This carries a risk for the patient and may not be feasible. Substrate mapping has emerged as a safer strategy to uncover arrhythmogenic regions. However, VT recurrence remains common. GOAL: To use computer simulations to assess the ability of different substrate mapping approaches to identify VT exit sites. METHODS: A 3D computational model of the porcine post-infarction heart was constructed to simulate VT and paced rhythm. Electroanatomical maps were constructed based on endocardial electrogram features and the reentry vulnerability index (RVI - a metric combining activation (AT) and repolarization timings to identify tissue susceptibility to reentry). Since scar transmurality in our model was not homogeneous, parameters derived from all signals (including dense scar regions) were used in the analysis. Potential ablation targets obtained from each electroanatomical map during pacing were compared to the exit site detected during VT mapping. RESULTS: Simulation data showed that voltage cut-offs applied to bipolar electrograms could delineate the scar, but not the VT circuit. Electrogram fractionation had the highest correlation with scar transmurality. The RVI identified regions closest to VT exit site but was outperformed by AT gradients combined with voltage cut-offs. The performance of all metrics was affected by pacing location. CONCLUSIONS: Substrate mapping could provide information about the infarct, but the directional dependency on activation should be considered. Activation-repolarization metrics have utility in safely identifying VT targets, even with non-transmural scars

Multiscale computational analysis of the bioelectric consequences of myocardial ischaemia and infarction

[EN] Ischaemic heart disease is considered as the single most frequent cause of death, provoking more than 7 000 000 deaths every year worldwide. A high percentage of patients experience sudden cardiac death, caused in most cases by tachyarrhythmic mechanisms associated to myocardial ischaemia and infarction. These diseases are difficult to study using solely experimental means due to their complex dynamics and unstable nature. In the past decades, integrative computational simulation techniques have become a powerful tool to complement experimental and clinical research when trying to elucidate the intimate mechanisms of ischaemic electrophysiological processes and to aid the clinician in the improvement and optimization of therapeutic procedures. The purpose of this paper is to briefly review some of the multiscale computational models of myocardial ischaemia and infarction developed in the past 20 years, ranging from the cellular level to whole-heart simulations.This work was partially supported by the 'VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica' from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds-ERDF-FEDER), and by the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119).Ferrero De Loma-Osorio, JM.; Trénor Gomis, BA.; Romero Pérez, L. (2014). Multiscale computational analysis of the bioelectric consequences of myocardial ischaemia and infarction. EP-Europace. 16(3):405-415. https://doi.org/10.1093/europace/eut405S40541516

Noninvasive Electrocardiographic Imaging (ECGi) to Guide Catheter Ablation of Scar-related Ventricular Tachycardia

Scar-related VT is caused by local \textit{short circuits} of electrical propagation formed by slow-conducting channels of surviving tissue within a scar. Catheter ablation treats scar-related VT by destroying the critical channel of surviving tissues. Its efficacy heavily relies on how well the channels critical to the formation of VT circuits can be localized. Unfortunately, in current practice, this relies on invasive catheter mapping that falls short in several critical aspects: up to 90$\%$ of the VT circuits are too short-lived to be mapped, the mapping cannot be done non-invasively prior to the ablation procedure, and the mapping is restricted to one heart surface at a time. Electrocardiographic imaging (ECGi) is a noninvasive approach that reconstructs cardiac electrical signals from a very dense body surface electrocardiogram (ECG) in combination with patient-specific geometries of the heart and torso. In this dissertation, we investigate the clinical utility of ECGi in guiding catheter ablation of scar-related VT. Specifically, we investigate two open questions that are not well-understood in the potential of ECGi for mapping VT circuits. First, instead of commonly-used epicardial ECGi, we investigate the validity of simultaneous epicardial and endocardial ECGi mapping of VT circuits, and the possibility of using information from these two surfaces to infer the morphology of 3D circuits. Second, we investigate the integration of ECGi electrical information of VT circuits with magnetic resonance imaging (MRI) of scar analysis for joint electrical and structural delineation of the substrates for VT circuits. These studies were performed on a combination of computer simulation, animal model, and human subject data. Experimental results showed that epi-endo ECGi mapping could reconstruct VT circuits, differentiate 2D versus 3D circuits, and provide information about the location of the VT circuit beneath the surface. They also showed that integrated MRI-ECGi analysis offered a quantitative characterization of the scar substrate that forms a VT circuit. These outcomes showed that simultaneous epi-endo ECGi in the combination of MRI structural scar imaging may provide a viable augmentation to the current practice of invasive catheter mapping. It may help clinicians plan for the ablation prior to the procedure by equipping them with knowledge about a VT circuit\u27s critical components, the surfaces that are involved, and the 3D morphology of the VT circuit

Three-dimensional cardiac computational modelling: methods, features and applications

[EN] The combination of computational models and biophysical simulations can help to interpret an array of experimental data and contribute to the understanding, diagnosis and treatment of complex diseases such as cardiac arrhythmias. For this reason, three-dimensional (3D) cardiac computational modelling is currently a rising field of research. The advance of medical imaging technology over the last decades has allowed the evolution from generic to patient-specific 3D cardiac models that faithfully represent the anatomy and different cardiac features of a given alive subject. Here we analyse sixty representative 3D cardiac computational models developed and published during the last fifty years, describing their information sources, features, development methods and online availability. This paper also reviews the necessary components to build a 3D computational model of the heart aimed at biophysical simulation, paying especial attention to cardiac electrophysiology (EP), and the existing approaches to incorporate those components. We assess the challenges associated to the different steps of the building process, from the processing of raw clinical or biological data to the final application, including image segmentation, inclusion of substructures and meshing among others. We briefly outline the personalisation approaches that are currently available in 3D cardiac computational modelling. Finally, we present examples of several specific applications, mainly related to cardiac EP simulation and model-based image analysis, showing the potential usefulness of 3D cardiac computational modelling into clinical environments as a tool to aid in the prevention, diagnosis and treatment of cardiac diseases.This work was partially supported by the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-C03-01 and TIN2011-28067) and the European Commission (European Regional Development Funds - ERDF - FEDER) and by "eTorso project" (GVA/2013-001404) from the Generalitat Valenciana (Spain). ALP is financially supported by the program "Ayudas para contratos predoctorales para la formacion de doctores" from the Ministerio de Economia y Competitividad of Spain (BES-2013-064089).López Pérez, AD.; Sebastián Aguilar, R.; Ferrero De Loma-Osorio, JM. (2015). 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Cardiac Remodeling Of Conduction, Repolarization and Excitation-Contraction Coupling: From Animal Model to Failing Human Heart

Heart failure is one of the leading causes of death worldwide, with rising impact with the increasing ageing population. This is in sharp contrast with the limited and non-ideal therapies available. Approximately 50% of deaths from heart failure are sudden and unexpected, and presumably the consequence of lethal ventricular arrhythmias. Despite significant reduction of mortality from sudden cardiac death achieved by ICDs and drugs such as beta-blockers, there remains a large room for improving the survivability of heart failure patients by advancing our understanding of arrhythmogenesis from molecular level to multi-cellular tissue level. Another important aspect of heart failure is abnormal excitation-contraction: EC) coupling and calcium handling, functional changes of which exert great impact on both arrhythmia vulnerability and pump failure. Advancing the understanding the remodeling of EC coupling and calcium handling might provide potential molecular and anatomical targets for clinical intervention. In this dissertation, I first developed two optical imaging systems: both hardware and software) for quantifying the conduction, repolarization and excitation-contraction coupling. The first one is the panoramic imaging system for mapping the entire ventricular epicardium of a rabbit heart. The second one is the dual imaging system for simultaneous measurement of action potential and calcium transient. Using the systems I developed, I conducted two rabbit studies to investigate the role electrical instability and structural heterogeneity in the induction and maintenance of arrhythmias. We first identified the importance of both dynamic instability and effective tissue size in the spontaneous termination of arrhythmia in the normal rabbit heart. We then identified novel mechanism of how healed myocardial infarction promotes the induction of ventricular arrhythmia. Finally, guided by the knowledge from the animal studies, I studied the failing human heart with the aim to advance our understanding of cardiac electrophysiology in human heart failure. We first demonstrated the transmural heterogeneity of EC coupling in nonfailing heart and identified potential mechanisms of electrical and mechanical dysfunction by quantifying the remodeling of EC coupling. We then studied the remodeling of conduction and repolarization with the aim to determine of the role of dispersion of repolarization and electrical instability in the induction of arrhythmia in human heart failure

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

Bayesian Inference with Combined Dynamic and Sparsity Models: Application in 3D Electrophysiological Imaging

Data-driven inference is widely encountered in various scientific domains to convert the observed measurements into information that cannot be directly observed about a system. Despite the quickly-developing sensor and imaging technologies, in many domains, data collection remains an expensive endeavor due to financial and physical constraints. To overcome the limits in data and to reduce the demand on expensive data collection, it is important to incorporate prior information in order to place the data-driven inference in a domain-relevant context and to improve its accuracy. Two sources of assumptions have been used successfully in many inverse problem applications. One is the temporal dynamics of the system (dynamic structure). The other is the low-dimensional structure of a system (sparsity structure). In existing work, these two structures have often been explored separately, while in most high-dimensional dynamic system they are commonly co-existing and contain complementary information. In this work, our main focus is to build a robustness inference framework to combine dynamic and sparsity constraints. The driving application in this work is a biomedical inverse problem of electrophysiological (EP) imaging, which noninvasively and quantitatively reconstruct transmural action potentials from body-surface voltage data with the goal to improve cardiac disease prevention, diagnosis, and treatment. The general framework can be extended to a variety of applications that deal with the inference of high-dimensional dynamic systems

Construction of 3D MR image-based computer models of pathologic hearts, augmented with histology and optical fluorescence imaging to characterize action potential propagation

International audienceCardiac computer models can help us understand and predict the propagation of excitation waves (i.e., action potential, AP) in healthy and pathologic hearts. Our broad aim is to develop accurate 3D MR image-based computer models of electrophysiology in large hearts (translatable to clinical applications) and to validate them experimentally. The specific goals of this paper were to match models with maps of the propagation of optical AP on the epicardial surface using large porcine hearts with scars, estimating several parameters relevant to macroscopic reaction-diffusion electrophysiological models. We used voltage-sensitive dyes to image AP in large porcine hearts with scars (3 specimens had chronic myocardial infarct, and 3 had radiofrequency RF acute scars). We first analyzed the main AP waves' characteristics: duration (APD) and propagation under controlled pacing locations and frequencies as recorded from 2D optical images. We further built 3D MR image-based computer models that have information derived from the optical measures, as well as morphologic MRI data (i.e., myocardial anatomy, fiber directions and scar definition). The scar morphology from MR images was validated against corresponding whole-mount histology. We also compared the measured 3D isochronal maps of depolarization to simulated isochrones (the latter replicating precisely the experimental conditions), performing model customization and 3D volumetric adjustments of the local conductivity. Our results demonstrated that mean APD in the border zone (BZ) of the infarct scars was reduced by ~13% (compared to ~318 ms measured in normal zone, NZ), but APD did not change significantly in the thin BZ of the ablation scars. A generic value for velocity ratio (1:2.7) in healthy myocardial tissue was derived from measured values of transverse and longitudinal conduction velocities relative to fibers direction (22cm/s and 60cm/s, respectively). The model customization and 3D volumetric adjustment reduced the differences between measurements and simulations; for example, from one pacing location, the adjustment reduced the absolute error in local depolarization times by a factor of 5 (i.e., from 58 ms to 11 ms) in the infarcted heart, and by a factor of 6 (i.e., from 60 ms to 9 ms) in the heart with the RF scar. Moreover, the sensitivity of adjusted conductivity maps to different pacing locations was tested, and the errors in activation times were found to be of approximately 10-12 ms independent of pacing location used to adjust model parameters, suggesting that any location can be used for model predictions

Personalized Cardiac Computational Models: From Clinical Data to Simulation of Infarct-Related Ventricular Tachycardia

In the chronic stage of myocardial infarction, a significant number of patients develop life-threatening ventricular tachycardias (VT) due to the arrhythmogenic nature of the remodeled myocardium. Radiofrequency ablation (RFA) is a common procedure to isolate reentry pathways across the infarct scar that are responsible for VT. Unfortunately, this strategy show relatively low success rates; up to 50% of patients experience recurrent VT after the procedure. In the last decade, intensive research in the field of computational cardiac electrophysiology (EP) has demonstrated the ability of three-dimensional (3D) cardiac computational models to perform in-silico EP studies. However, the personalization and modeling of certain key components remain challenging, particularly in the case of the infarct border zone (BZ). In this study, we used a clinical dataset from a patient with a history of infarct-related VT to build an image-based 3D ventricular model aimed at computational simulation of cardiac EP, including detailed patient-specific cardiac anatomy and infarct scar geometry. We modeled the BZ in eight different ways by combining the presence or absence of electrical remodeling with four different levels of image-based patchy fibrosis (0, 10, 20, and 30%). A 3D torso model was also constructed to compute the ECG. Patient-specific sinus activation patterns were simulated and validated against the patient's ECG. Subsequently, the pacing protocol used to induce reentrant VTs in the EP laboratory was reproduced in-silico. The clinical VT was induced with different versions of the model and from different pacing points, thus identifying the slow conducting channel responsible for such VT. Finally, the real patient's ECG recorded during VT episodes was used to validate our simulation results and to assess different strategies to model the BZ. Our study showed that reduced conduction velocities and heterogeneity in action potential duration in the BZ are the main factors in promoting reentrant activity. Either electrical remodeling or fibrosis in a degree of at least 30% in the BZ were required to initiate VT. Moreover, this proof-of-concept study confirms the feasibility of developing 3D computational models for cardiac EP able to reproduce cardiac activation in sinus rhythm and during VT, using exclusively non-invasive clinical data

Design and development of optical reflectance spectroscopy and optical coherence tomography catheters for myocardial tissue characterization

Catheter ablation therapy attempts to restore sinus rhythm in arrhythmia patients by producing site-specific tissue modification along regions which cause abnormal electrical activity. This treatment, though widely used, often requires repeat procedures to observe long-term therapeutic benefits. This limitation is driven in part by challenges faced by conventional schemes in validating lesion adequacy at the time of the procedure. Optical techniques are well-suited for the interrogation and characterization of biological tissues. In particular, optical coherence tomography (OCT) relies on coherence gating of singly-scattered light to enable high-resolution structural imaging for tissue diagnostics and procedural guidance. Alternatively, optical reflectance spectroscopy (ORS) is a point measurement technique which makes use of incoherent, multiply-scattered light to probe tissue volumes and derive important data from its optical signature. ORS relies on the fact that light-tissue interactions are regulated by absorption and scattering, which directly relate to the intrinsic tissue biochemistry and cellular organization. In this thesis, we explore the integration of these modalities into ablation catheters for obtaining procedural metrics which could be utilized to guide catheter ablation therapy. We first present the development of an accelerated computational light transport model and its application for guiding ORS catheter design. A custom ORS-integrated ablation catheter is then implemented and tested within porcine specimens in vitro. A model is proposed for real-time estimation of lesion size based on changes in spectral morphology acquired during ablation. We then fabricated custom integrated OCT M-mode RF catheters and present a model for detecting contact status based on deep convolutional neural networks trained on endomyocardial images. Additionally, we demonstrate for the first time, tracking of RF-induced lesion formation employing OCT Doppler micro-velocimetry; this response is shown to be commensurate with the degree of treatment. We further demonstrate for the first time spectroscopic tracking of kinetics related to the heme oxidation cascade during thermal treatment, which are linked to tissue denaturation. The pairing of these modalities into a single RF catheter was also validated for guiding lesion delivery in vitro and within live pigs. Finally, we conclude with a proof-of-concept demonstration of ORS as a mapping tool to guide epicardial ablation in human donor hearts. These results showcase the vast potential of ORS and OCT empowered RF catheters for aiding intraprocedural guidance of catheter ablation procedures which could be utilized alongside current practices