Simulation du remodelage structurel des oreillettes : dissociation endo-épicardique, optimisation multi-paramètre des conductivités et morphologie des potentiels extracellulaires

La fibrillation auriculaire (FA) est le type d’arythmie cardiaque le plus fréquent. Cependant, ses mécanismes sont encore mal compris et le développement de stratégies thérapeutiques efficaces reste un défi. Des recherches ont montré que les mécanismes de remodelage structurel, notamment la dissociation électrique endocardique-épicardique, jouent un rôle potentiellement important dans l'initiation, la complexité et le maintien de la FA. En ce sens, les potentiels extracellulaires sont des outils non invasifs largement utilisés dans le diagnostic et la compréhension de cette arythmie ainsi que dans le guidage des interventions par cathéter. L'objectif principal de cette thèse était de développer des modèles informatiques des oreillettes et d’étudier dans ces modèles comment les potentiels extracellulaires et les cartes d'activation à haute résolution peuvent être exploités pour caractériser les mécanismes de dissociation endocardique-épicardique en tant que substrat de la FA. Dans un premier temps, en utilisant un modèle de tissu auriculaire, nous avons montré que la dissociation endo-épicardique (délai endo-épicardique et couplage transmural) affecte l'asymétrie des électrogrammes unipolaires à travers l'orientation des sources de courant dipolaire dans le tissu auriculaire. Ce résultat a été par la suite confirmé par l’analyse morphologique des composantes de l’onde P dans un modèle anatomique des oreillettes. Nous avons en outre montré que l’épaisseur de la paroi auriculaire ainsi que le couplage transmural étaient des déterminants importants de ce délai, et que ce dernier peut induire des altérations significatives de la morphologie l’onde P même lorsque les cartes d’activation sont similaires et que les ondes P ont la même durée. Dans un second temps, nous avons exploré les effets tridimensionnels de la dissociation endo-épicardique et validé une technique de détection de percée d’ondes (breakthroughs) basée sur l’analyse des cartes d'activation à haute résolution et le suivi des ondes, en utilisant un modèle électro-anatomique de découplage endo-épicardique local. Nous avons utilisé cet outil pour la caractérisation de la dissociation endo-épicardique. Un critère de validité en a été dérivé, ce qui faciliterait la comparaison des taux de percée avec les données cliniques et la validation des outils d'analyse des signaux cartographiques lors de la caractérisation de la dissociation endo-épicardique. Enfin, nous avons développé un outil d'optimisation multi-paramètre qui rend possible l’étude des limites des modèles continus homogénéisés dans l'étude des mécanismes de dissociation endo-épicardique et aide dans le choix des modèles (continu homogénéisé ou discret détaillé). L’outil permet d’estimer le profil régulier de conductivité qui reproduit le mieux les propriétés de conduction cardiaque d'un modèle discret donné. Les résultats ont montré l'efficacité de cet outil pour reproduire des cartes d'activation dans le modèle homogénéisé même en présence de fibrose sévère. Ultimement, ce travail pose les bases du développement de nouveaux modèles informatiques pouvant aider à l’interprétation des signaux électriques dans des tissus cardiaques remodelés où la présence de micro-hétérogénéités exhibe les limites des modèles homogénéisés.Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. However, its mechanisms are still poorly understood and the development of effective therapeutic strategies remains a challenge. Research studies have shown that the mechanisms of structural remodeling, including endocardial-epicardial electrical dissociation, play a potentially important role in the initiation, complexity, and maintenance of AF. In this sense, extracellular potentials are non-invasive tools widely used in the diagnosis and understanding of this arrhythmia as well as in the guidance of catheter interventions. The main objective of this thesis was to develop computer models of the atria and to study in these models how extracellular potentials and high resolution activation maps can be exploited to characterize the mechanisms of endocardial-epicardial dissociation as substrate of AF. First, using an atrial tissue model, we showed that endo-epicardial dissociation (endo-epicardial delay and transmural coupling) alters the asymmetry of unipolar electrograms through the orientation of dipolar current sources in the atrial tissue. This result was later confirmed by morphological analysis of the P-wave components in an anatomical model of the atria. We further showed that atrial wall thickness as well as transmural coupling were important determinants of this delay, and that the latter can induce significant alterations in P-wave morphology even when activation maps are similar and P-waves have the same duration. Secondly, we explored the three-dimensional effects of endo-epicardial dissociation and validated a breakthrough wave detection technique based on the analysis of high-resolution activation maps and wave tracking, using an electro-anatomical model of local endo-epicardial decoupling. We used this tool for the characterization of endo-epicardial dissociation. A validity criterion was derived, which would facilitate the comparison of breakthrough rates with clinical data and the validation of mapping signals analysis tools for characterizing endo-epicardial dissociation. Finally, we developed a multi-parameter optimization tool that makes it possible to study the limits of homogenized continuous models in the study of endo-epicardial dissociation mechanisms and to help in the choice of models (homogenized continuous or detailed discrete). The tool enabled the estimation of the regular conductivity profile that best reproduces the cardiac conduction properties of a given discrete model. The results showed the effectiveness of this tool in reproducing activation maps in the homogenized model even in the presence of severe fibrosis. Ultimately, this work lays the foundations for the development of new computer models that can help in the interpretation of electrical signals in remodeled heart tissues where the presence of micro-heterogeneities exhibits the limits of homogenized models

Clinical Application of Electrocardiographic Imaging in Patients with Ischemic Cardiomyopathy, Early Repolarization Syndrome and Brugada Syndrome

Electrocardiographic Imaging (ECGI) is a noninvasive modality for human application in both research and clinical settings. It is an important tool for investigation of abnormal electrophysiological (EP) substrates and arrhythmias in patients. Multi-channel body surface potential recordings and the patient-specific heart-torso geometry from ECG gated computed tomography are processed by ECGI algorithms to reconstruct epicardial potentials, electrograms and patterns of activation and repolarization. ECGI is able to continuously generate high-resolution, panoramic EP maps of the entire heart on a beat-by-beat basis, which cannot be achieved with invasive catheter mapping. ECGI was applied in ischemic cardiomyopathy patients to characterize the abnormal EP substrate associated with myocardial infarction. In patients who developed ventricular tachycardia during the study, the arrhythmia activation pattern and site of origin were correlated with the EP substrate to identify components of the reentry circuit. The study subjects included patients with and without a history of clinical ventricular arrhythmias. The properties of scar EP substrate were compared between the two groups to determine whether substantial differences exist. This differentiating capability of ECGI was examined as a potential tool for arrhythmic risk stratification in this population. In a separate clinical study, ECGI was applied in a group of patients with early repolarization syndrome, which has been recently shown to be associated with an increased risk of ventricular fibrillation. The ventricular activation and repolarization patterns during sinus rhythm were characterized and compared with data from normal controls. This study aimed to provide insights into the mechanisms of the early repolarization ECG pattern and the related arrhythmogenesis. ECGI was also applied in patients with Brugada syndrome to image the EP substrate and to study the underlying mechanisms of the Brugada ECG pattern and abnormal epicardial electrograms. Heart rate change protocol in selected patients helped unmask the coexistence of abnormal conduction and abnormal repolarization in the EP substrate. Brugada syndrome patients were also compared with patients with right bundle branch block (generally considered benign) to determine whether the substrate was specific to Brugada syndrome, and whether ECGI can differentiate between these two pathologies with similar ECG patterns. The above studies demonstrated the feasibility and clinical importance of ECGI for noninvasive diagnosis, pre-procedural guidance and arrhythmic risk stratification in human subjects

The contact electrogram and its architectural determinants in atrial fibrillation

The electrogram is the sine qua non of excitable tissues, yet classification in atrial fibrillation (AF) remains poorly related to substrate factors. The objective of this thesis was to establish the relationship between electrograms and two commonly implicated substrate factors, connexin 43 and fibrosis in AF. The substrates and methods chosen to achieve this ranged from human acutely induced AF using open chest surgical mapping (Chapter 6), ex vivo whole heart Langendorff (Chapter 7) with in vivo telemetry confirming spontaneous AF in a new species of rat, the Brown Norway and finally isolated atrial preparations from an older cohort of rats using orthogonal pacing and novel co-localisation methods at sub-millimetre resolution and in some atria, optical mapping (Chapter 8). In rodents, electrode size and spacing was varied (Chapters 5, 10) to study its effects on structure function correlations (Chapter 9). Novel indices of AF organisation and automated electrogram morphology were used to quantify function (Chapter 4). Key results include the discoveries that humans without any history of prior AF have sinus rhythm electrograms with high spectral frequency content, that wavefront propagation velocities correlated with fibrosis and connexin phosphorylation ratios, that AF heterogeneity of conduction correlates to fibrosis and that orthogonal pacing in heavily fibrosed atria causes anisotropy in electrogram-fibrosis correlations. Furthermore, fibrosis and connexin 43 have differing and distinct spatial resolutions in their relationship with AF organisational indices. In conclusion a new model of AF has been found, and structure function correlations shown on an unprecedented scale, but with caveats of electrode size and direction dependence. These findings impact structure function methods and prove the effect of substrate on AF organisation.Open Acces

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

2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias

2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias

Cardiac development in relation to clinical supraventricular arrhythmias : focus on structure-function relations

Supraventricular tachycardias (SVTs) are amongst the most commonly encountered cardiac arrhythmias in clinical practice in both children and adults. The causative mechanisms underlying the appearance of most of these SVTs have however still remained as intriguing as they are unexplained. In this thesis, cardiac development is analyzed in relation to the etiology of clinical supraventricular arrhythmias with a special focus on structure-function relations. Firstly, in PART I of this thesis, both the (patho) physiological development of the annulus fibrosus cordis and the etiological origin of clinical accessory AV pathway (AP) mediated AVRT in children and adults is analyzed in experimental animal models and human sections. Secondly, in PART II of this thesis a review of the different ontogenic theories on the embryonic development of the AV Node (AVN) in literature is followed by an experimental study postulating a new concept on the developmental origin of the AVN in relation to the etiology of AV Nodal Reentrant Tachycardia (AVNRT). As a general introduction to both these basic research (I & II) and the clinical (III) parts of this thesis, structural cardiac development in avians (with references to equivalent mouse and human developmental timelines) (Figure 1) will first be described since the development of the cardiac conduction system (CCS) and structural cardiogenesis are intimately related. Next, the developmental transitions in impulse propagation and the construction of the individual components of the specialized CCS and the AVN in particular will be shortly outlined. Following a description of the changes in electrocardiograms (ECGs) during cardiogenesis, current concepts on the transitions in ventricular activation sequences during embryogenesis will be discussed. Thereafter, contemporary knowledge on the development of the isolating annulus fibrosis, the key structure involved in AP persistence, in relation to general CCS development will be reviewed. Subsequently, relevant genera l characteristics of the different animal models and the immunohistochemical markers used in this thesis are briefly discussed. Following the description of the structural basics of cardiogenesis, attention will be focused on current knowledge of clinical SVTs in neonates and children and the treatment of these arrhythmias. These therapeutic clinical issues will be further outlined in PART III of this thesis.UBL - phd migration 201

Bioelectric Signal Analysis to Expose Nervous Control of the Human Heart

This thesis describes the development of new methods to infer the nature of nervous control of the human heart using recordings of its electrical behaviour. Malfunctions of this control system are a leading cause of death, and can be triggered by a diverse range of influences including basic physiological factors and one’s emotional state. However, the mechanisms of failure remain poorly understood, partly due to a lack of relevant human data. The principal purpose of the work described in this thesis is to improve the availability of such data. A literature review was conducted, covering the current understanding of electrical activity in the heart and its control by the nervous system, as well as the techniques available to observe that behaviour. A variety of novel techniques were developed and implemented experimentally to demonstrate their utility. Specialised methods for the filtering and subsequent spectral analysis of electrocardiograph (ECG) signals were used to expose differences between psychologically distinct groups in terms of their response to emotional stimuli. Algorithms were developed to automatically process unipolar electrogram recordings with minimal human intervention, enabling the analysis of heterogeneous electrophysiological dynamics, which requires datasets of a size that would otherwise make in-depth analyses intractable. New indices were developed for measuring the timing of localised electrical activation and recovery from unipolar electrograms, in order to overcome the fact that conventional indices are not well suited to dynamic analyses. Experiments using these tools demonstrated that respiration induces heart-rate independent modulation of the ventricles’ electrophysiological behaviour via the autonomic nervous system. By improving the accessibility of human in situ data, the developed tools enable new research methodologies to study interactions between the heart and the nervous system, which may ultimately contribute to the development of new treatments to prevent thousands of deaths in the UK alone each year