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

Characterizing Cardiac Electrophysiology during Radiofrequency Ablation : An Integrative Ex vivo, In silico, and In vivo Approach

Catheter ablation is a major treatment for atrial tachycardias. Hereby, the precise monitoring of the lesion formation is an important success factor. This book presents computational, wet-lab, and clinical studies with the aim of evaluating the signal characteristics of the intracardiac electrograms (IEGMs) recorded around ablation lesions from different perspectives. The detailed analysis of the IEGMs can optimize the description of durable and complex lesions during the ablation procedure

High-Density Mapping Analysis of Electrical Spatiotemporal Behaviour in Atrial Fibrillation

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas), 2022, Universidade de Lisboa, Faculdade de CiênciasDoenças cardiovasculares, tais como arritmias, são a principal causa de morte no mundo, especialmente no Sul e no Este da Ásia, e nos Estados Unidos da América [1]. As arritmas são caracterizadas pela alteração no ritmo sinusal normal do coração. Em particular, a fibrilhação auricular (FA) é a arritmia cardíaca mais comum na prática clínica, contribuindo para mais de 200 mil mortes globalmente em 2017 [2]. Caracteriza-se pela contração rápida e dessincronizada das aurículas, e está associada ao aumento da mortalidade e afecta de forma negativa a qualidade de vida dos pacientes. A FA é geralmente tratada através de medicação, porém quando esta falha, a ablação por cateter é indicada, sendo um tratamento de referência para combater esta patologia. A ablação apresenta uma taxa de sucesso de aproximadamente 50% no primeiro procedimento, sendo necessário efectuar vários procedimentos para aumentar a eficácia do tratamento [3]. A detecção desta patologia envolve, numa primeira fase, a realização de um electrocardiograma (ECG) e, posteriormente um estudo electrofisiológico para saber com precisão onde se localiza e o mecanismo subjacente à mesma. Este último implica o registo da actividade eléctrica através de electrogramas (EGM) locais em diferentes pontos das aurículas e dos ventrículos, com o auxílio de sistemas de mapeamento tridimensionais (3D) electroanatómicos, sendo um procedimento invasivo. Existem diversos métodos lineares e não lineares que permitem a análise dos EGMs nos domínios do tempo, frequência, fase, entre outros, com a finalidade de melhor compreender os mecanismos subjacentes à FA e, consequentemente aumentar a taxa de sucesso do processo de ablação e melhorar a sua eficiência. Esta área de estudo progrediu significativamente, tanto a nível de hardware, como de software. Apesar disso, os métodos desenvolvidos não têm nem acrescentado benefícios adicionais, nem melhorado significativamente a taxa de sucesso do processo de ablação. Existem várias razões para tal, e grande parte deve-se ao facto destes métodos de análise estarem incorporados nos sistemas de mapeamento e o seu software ser exclusivo. Isto leva a que não consigamos perceber como é que os algoritmos funcionam nos diferentes sistemas de mapeamento para comparar as suas diferenças e semelhanças. Devido a estes constrangimentos, os investigadores são compelidos a desenvolver os seus próprios métodos de análise e técnicas de mapeamento, o que leva à existência de uma multitude de métodos e técnicas de mapeamento que parecem ser diferentes entre si, resultando em informação ambígua e conflituosa no que diz respeito aos mecanismos da FA, e a conclusões distintas entre estudos. O sucesso do tratamento poderia aumentar se tivéssemos uma melhor compreensão dos métodos de análise e da sua aplicação no contexto da FA; perceber se os métodos apontam para o mesmo fenómeno de fibrilhação, se existe alguma correlação entre os métodos, e se a informação fornecida pelos mesmos é complementar ou redundante. Assim, o objectivo deste trabalho consistiu em implementar diferentes métodos para analisar os EGMs e a estrutura 3D da aurícula esquerda (AE) de doentes com FA, numa tentativa de responder às questões que motivaram a realização deste projecto. Em última análise, ao observar os mapas 3D da AE tendo uma melhor compreensão dos métodos, poderemos identificar com precisão as regiões na AE responsáveis por iniciar a FA, e ter mais conhecimento sobre os mecanismos responsáveis pela mesma. Desta forma, o processo de ablação poderá alcançar o seu potencial. Para este projecto, foram incluídos os mapas 3D electroanatómicos da AE de dez doentes com FA paroxística ou persistente do hospital de Santa Marta, recolhidos com o sistema de mapeamento CARTO 3. Cada ponto electroanatómico dos mapas inclui as 12 derivações do ECG, e os EGMs unipolares e bipolares registados com o cateter de mapeamento Pentaray de 20 pólos. Porém, apenas os EGMs bipolares foram incluídos na análise. Processaram-se os sinais bipolares e, devido a algumas limitações, foi possível apenas a implementação de dois métodos diferentes para os analisar: um no domínio da frequência – Frequência Dominante (FD) –, e outro no domínio da Teoria da Informação – a entropia de Shannon. De seguida, criaram-se três tipos de mapas 3D electroanatómicos da AE para cada doente: um de voltagem, cuja informação foi adquirida com o sistema de mapeamento, um de FD, e outro de entropia. A informação de cada mapa estava organizada segundo um padrão de cores. Observando os diferentes tipos de mapas da AE paralelamente, foi possível comparar os métodos, e perceber que tipo de informação cada um deles fornecia, numa tentativa de melhor compreender os mecanismos da FA. Foi possível observar em algumas regiões da AE, principalmente nos mapas de voltagem e de FD, a presença de “centros de activação” ou “centros de fibrilhação”, que poderão ser os gatilhos responsáveis por desencadear ou manter o mecanismo de fibrilhação. Para confirmar se de facto aquelas regiões eram os gatilhos de fibrilhação, seria necessário submeter os doentes ao processo de ablação e queimar essas zonas; e posteriormente acompanhar os doentes para observar os efeitos do procedimento e confirmar a hipótese. Contudo, dadas as limitações do trabalho e o facto desta área de investigação ser pouco explorada, é fulcral obter um maior número de estudo comparativos entre mais métodos de diferentes domínios e confirmar se apontam ou não para o mesmo fenómeno de fibrilhação. Apesar de terem sido implementados apenas dois métodos de análise dos EGMs, o projecto permitiu a comparação entre os mesmos, uma área de estudo por onde ainda há muito para investigar. Com mais conhecimento sobre os diferentes métodos, a sua aplicação, inter-relação e adequação no estudo dos mecanismos da FA e das propriedades electrofisiológicas desta patologia, é possível desenvolver procedimentos de ablação mais eficientes e selectivos, de forma a diminuir os riscos e aumentar a taxa de sucesso do tratamento.Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in clinical practice and is described by rapid and irregular contractions of the atria. Despite catheter ablation (CA) being a well-established treatment for AF, it is sub-optimal, with a success rate of approximately 50 % after a single procedure, with some patients requiring multiple procedures to achieve long-term freedom from this pathology. This prompted the proposal and development of various quantitative electrogram (EGM)-based methods along with different mapping systems with their respective mapping techniques, to better understand the mechanisms responsible for initiating and maintaining AF, thus improving ablation outcomes. However, this diversification of methods and tools resulted in disperse and inconsistent data regarding the mechanisms of AF. This work consisted of employing two different methods to analyse the electrograms (EGM): dominant frequency (DF) and Shannon entropy (ShEn). From these EGMs, metrics were then extracted and displayed in colour-coded fashion on a 3D mesh of the left atrium (LA) from patients with paroxysmal or persistent AF. The two methods were compared to understand whether or not these indicated different phenomena/mechanisms, and if these could locate sites suspected of triggering and maintaining AF. The results, while not fully conforming to the literature, allowed the comparison between different EGM analysis methods, a field of study that requires further research. Overall, this project highlighted the limited data available within the topic, hindering our understanding of AF mechanisms and development of more effective and selective ablation procedures to avoid unnecessary complications, and ultimately improve the effects of the treatment's outcomes

A novel simplified approach to radiofrequency catheter ablation of idiopathic ventricular outflow tract premature ventricular contractions : from substrate analysis to results

Summary: Premature ventricular contractions (PVCs) are a common finding in the general population. The most common site of PVCs, in patients without structural heart disease, is the right ventricular outflow tract (RVOT) and the left ventricular outflow tract (LVOT). The prognosis associated with frequent PVCs depends on the presence of structural heart disease, so that idiopathic PVCs have been considered benign. Recently however, evidence has emerged that a small percentage of those patients may present with polymorphic ventricular tachycardia or ventricular fibrillation or evolve to left ventricular dysfunction. Catheter ablation is indicated for frequent symptomatic PVCs refractory to medical therapy or in case of patient’s preference. Currently, catheter ablation is based on activation mapping, confirmed by pace mapping match of at least 11/12 ECG leads between the paced beat and the PVC morphology. The acute success rate ranges from 78% to 100% according to the series, and to the location of the PVCs. Remote magnetic navigation presents as a good option for PVC ablation offering a high success rate with better safety profile. Intraprocedural low PVC burden occurs in up to 30% to 48% of cases, resulting in either, cancelation of the ablation procedure in up to 11% of patients, or reduction of the success rate from 85% to 56% when ablation is attempted with pace mapping only. Recently non-invasive mapping systems based on the electrocardiogram analysis (ECGI) have been developed. These systems are capable of mapping an arrhythmia with just one beat, instead of the usual point by point acquisition, being especially useful in the case of rare arrhythmias. EGGI also constitutes a valuable noninvasive tool for studying the mechanisms of arrhythmias. With this system we were able to demonstrate the presence of an electrophysiological substrate in the RVOT of patients with PVCs and apparently normal hearts. It has been accepted for many years that in patients with idiopathic PVCs from the outflow tracts, the RVOT displays normal electroanatomical mapping features and electrophysiological properties. However, we have demonstrated that there is a substrate for idiopathic PVCs in the form of low voltage areas (LVAs) that are not detected by usual image methods including cardiac magnetic resonance (CMR). We described for the first time, the association between the presence of ST-segment elevation in V1-V2 at the 2nd intercostal space (ICS) with LVAs across the RVOT and have proposed it as a non-invasive electrocardiographic marker of LVAs. We also identified the presence of abnormal potentials in intracardiac electrograms at the ablation site during diastole, after the T wave of the surface ECG that became presystolic during the PVC and were called diastolic potentials (DPs). In Chapter V we describe in detail the study that validated those findings and evaluated the feasibility and efficacy of a proposed simplified substrate approach, for catheter ablation in patients with low intraprocedural PVC burden, defined as less than 2 PVCs/min in the first 5 minutes of the procedure. It consists of fast mapping of the RVOT in sinus rhythm looking for LVAs and DPs, identifying the area, and finally performing a restricted activation map of the PVCs at that area. Briefly, it was a prospective single-arm clinical trial at two centers and three groups were studied: a) patients with low intraprocedural PVC burden that underwent ablation with the novel simplified approach method (study group); b) patients with low intraprocedural PVC burden that underwent ablation using the standard activation mapping method between 2016 and 2018 (historical group); and c) patients without PVCs, subjected to catheter ablation of supraventricular tachycardias that agreed to have a voltage map of the RVOT in sinus rhythm performed (validation group). The calculated sample size was 38 patients in each group. The exclusion criteria were as follows: known structural heart disease, history of sustained ventricular arrhythmias, inability to perform CMR, previous ablation and standard 12-Lead ECG with evidence of conduction or electrical disease or abnormal QRS morphology were excluded. Patients in the study and validation groups, had an ECG performed at the 2nd ICS and the RVOT mapped in sinus rhythm to assess the presence of ST-segment elevation, and LVAS and DPs, respectively. The results were compared between both groups. The study group and the historical group were compared regarding the efficacy of the new simplified ablation method in terms of abolishment of the PVCs and improvement of procedure speed and success rate. When available, ECGI was performed in the study group to evaluate the accuracy of the method to identify the site of origin of the PVCs. The ECGI was performed with two systems, the Amycard (EP Solutions SA, Switzerland) and the VIVO (Catheter Precision, NJ USA). The prevalence of LVAs and DPs was significantly higher in the study group in comparison with the validation group, respectively, 71% vs 11%, p<0.0001 and 87% vs 8%, p<0.0001. The ST-segment elevation was a good predictor of LVAS with a sensitivity of 87%, specificity of 96%, positive predictor value of 93% and negative predictor value of 91%. The novel simplified approach abolished the PVCs in 90% of the patients as opposed to 47% of patients in the historical group, p<0.0001. Only 74% patients underwent ablation in the historical group versus 100% in the study group. In patients that underwent ablation, the procedure time was significantly lower in the study group when comparing to the historical group, 130 (100-164) vs 183 (160-203) min, p<0.0001 and the success rate was significantly higher, 90% vs 64%, p=0.013. The recurrence rate in patients with a successful ablation after a median follow-up time of 1060 (574-1807) days, was not significantly different between both groups, Log-Rank=0.125 ECGI before ablation was performed in 17 patients in the study group. In 6 patients the ECGI was performed just with the Amycard system, in two just with the VIVO system and in 9 patients both systems were used. We found a good agreement between the ECGI and the invasive mapping, with the predicted site of origin being in the same or contiguous segment of the ablation site in 14/15 patients (93%) with the Amycard system and in 100% of patients with the VIVO system. When both systems were used simultaneously, the agreement between them was 8/9 (90%). So, in conclusion, the proposed approach partially based on substrate mapping including searching for LVAs and DPs, proved to be feasible, faster, and more efficient than the previous approach based exclusively on activation mapping. ST-segment elevation at the 2nd ICS proved to be a good predictor of LVAs. ECGI was a valuable tool to noninvasively predict the site of origin the arrhythmia

Characterization of Cardiac Electrogram Signals During Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in United States. The most popular treatment for AF is a percutaneous procedure called catheter ablation. Current AF ablation procedures unfortunately have a poor success rate, primarily because the mechanisms involved in AF are incompletely understood even today. Intra-atrial electrograms have previously been shown to provide information on the mechanisms of AF. This thesis focuses on two such mechanisms – AF-sustaining sites known as sustained rotational activities (RotAs), and atrial tissue with unique electrical properties known as myocardial scars. Catheter ablation procedures today construct the 3D electroanatomic map of the left atrium (LA) by maneuvering a conventional Multipolar Diagnostic Catheter (MPDC) along the LA endocardial surface. These procedures are limited to pulmonary vein isolation and other linear ablation performed on various regions of the left atrium (such as roof and mitral isthmus) where the regions are decided based on the atrial anatomy. However, it remains unclear how to utilize the information provided by the MPDC to analyze and characterize the RotAs and scars. Previous electrogram characterization studies mainly use a single bipole rather than MPDCs to characterize the electrograms based on features such as cycle length or dominant frequency from the time or frequency domain. In this thesis we developed novel techniques for investigating the above mentioned mechanisms using signal analysis, mathematical modeling, numerical simulation and clinical experiments, all utilizing MPDC recordings. First, the variations in the total conduction delay (TCD) from MPDC electrograms as the MPDC moves towards a RotA source was investigated. Second, the maximum peak-to-peak amplitudes of MPDC electrograms recorded during AF and NSR were analyzed. This thesis provides insights into methods of characterization of cardiac electrograms and the findings of this thesis could address the current challenges in AF ablation

Personalized Multi-Scale Modeling of the Atria: Heterogeneities, Fiber Architecture, Hemodialysis and Ablation Therapy

This book targets three fields of computational multi-scale cardiac modeling. First, advanced models of the cellular atrial electrophysiology and fiber orientation are introduced. Second, novel methods to create patient-specific models of the atria are described. Third, applications of personalized models in basic research and clinical practice are presented. The results mark an important step towards the patient-specific model-based atrial fibrillation diagnosis, understanding and treatment