Catheter ablation in patients with atrial fibrillation : mapping refinements, outcome prediction and effect on quality of life

PhD ThesisChapter 1 presents a literature review, focused primarily on the pathophysiology and management of atrial fibrillation (AF). Chapter 2 examines correlations between the dominant frequency of AF - calculated using principal component analysis from a modified surface 12-lead ECG (which included posterior leads), a standard 12-lead ECG and intracardiac recordings from both atria. The inclusion of posterior leads did not improve correlation with left atrial activity because of the dominance of lead V1 in both ECG configurations. Chapter 3 explores whether acute and 12-month outcome following catheter ablation for AF can be predicted beforehand from clinical and surface AF waveform parameters. Multivariate risk scores combining these parameters can predict arrhythmia outcome following ablation, and could therefore be used to identify those most likely to benefit from this therapy. Chapter 4 examines the effect of catheter ablation on AF symptoms and quality of life (QoL). AF symptom and QoL scores improved significantly in patients who maintained sinus rhythm after ablation but did not change in those with recurrent AF. AF-specific QoL scales are more responsive to change and correlate better with ablation outcome. Chapter 5 examines inter-atrial frequency gradients in patients with persistent AF using multipolar contact mapping. A right-to-left atrial frequency gradient was found in a quarter of the patients studied, implying that their arrhythmia was being maintained by high frequency sources in the right rather than the left atrium. Chapter 6 examines whether targeting high frequency and highly repetitive complex fractionated atrial electrogram sites, identified using multipolar contact mapping during persistent AF, resulted in arrhythmia termination and maintenance of sinus rhythm long-term. The utility of administering flecainide to distinguish critical from bystander AF sites was also investigated. Flecainide did not help refine ablation targets and 12-month outcome after targeting these sites was not superior to other ablation strategies

Studies on the dynamics of chaotic multi-wavelet reentrant propagation using a hybrid cellular automaton model of excitable tissue

There is a compelling body of evidence implicating continuous propagation (reentry) sustained by multiple meandering wavelets in the pathology of advanced human atrial fibrillation (AF). This forms the basis for many current therapies such as the Cox MAZE procedure and its derivatives, which aim to create non-conducting lesions in order to "transect" these circuits before they form. Nevertheless, our ability to successfully treat persistent and permanent AF using catheter ablation remains inadequate due to current limitations of clinical mapping technology as well as an incomplete understanding of how to place lesions in order to maximize circuit transection and, more importantly, minimize AF burden. Here, we used a hybrid cellular automaton model to study the dynamics of chaotic, multi-wavelet reentry (MWR) in excitable tissue. First, we used reentry as an exemplar to investigate a hysteretic disease mechanism in a multistable nonlinear system. We found that certain interactions with the environment can cause persistent changes to system behavior without altering its structure or properties, thus leading to a disconnect between clinical symptoms and the underlying state of disease. Second, we developed a novel analytical method to characterize the spatiotemporal dynamics of MWR. We identified a heterogeneous spatial distribution of reentrant pathways that correlated with the spatial distribution of cell activation frequencies. Third, we investigated the impact of topological and geometrical substrate alterations on the dynamics of MWR. We demonstrated a multi-phasic relationship between obstacle size and the fate of individual episodes. Notably, for a narrow range of sizes, obstacles appeared to play an active role in rapidly converting MWR to stable structural reentry. Our studies indicate that reentrant-pathway distributions are non-uniform in heterogeneous media (such as the atrial myocardium) and suggest a clinically measurable correlate for identifying regions of high circuit density, supporting the feasibility of patient-specific targeted ablation. Moreover, we have elucidated the key mechanisms of interaction between focal obstacles and MWR, which has implications for the use of spot ablation to treat AF as some recent studies have suggested

A Mechanistically Guided Approach to Treatment of Multi-Wavelet Reentry: Experiments in a Computational Model of Cardiac Propagation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States today. However, treatment options remain limited despite the enormous magnitude of both AF prevalence and the associated economic cost. Of those treatment options that are available, ablation-based interventional methods have demonstrated the highest rates of long-term cure. Unfortunately, these methods have substantially lower efficacy in patients with heavier burdens of disease, thus leaving the most affected individuals with the least hope for successful treatment. The focus of this research is to develop a mechanistically guided approach towards the treatment of multi-wavelet reentry (MWR), one of the primary drivers of AF. For this purpose, we use a computational model of electrical propagation in cardiac tissue to simulate both episodes of fibrillatory activity and the ablative treatment thereof. We demonstrate that the probability of forming the reentrant circuits necessary for continuous electrical activity is a function of the shape and size of a tissue as well as its underlying cellular properties. Ablation at tissue sites with high probability of circuit formation more efficiently reduces the overall duration of fibrillatory episodes than ablation at sites with low probability. We then propose and validate in silico a parameter-based metric for predicting the propensity of an individual tissue to support fibrillation, which we term the fibrillogenicity index. Using this metric, we develop an algorithm for prospectively determining optimized, tissue-specific ablation patterns. Finally, we examine the relationship between multi-wavelet reentry and focal drivers, and demonstrate that MWR and fibrillatory conduction exist along a continuum. We examine the complex interplay between functional and structural substrates within fibrillating tissue and define the mechanisms by which they promote the perpetuation of AF. These findings present a novel theoretical framework for understanding treatment of multi-wavelet reentry driven AF and provide a set of testable predictions that can serve to guide the design of future experimental studies aimed at advancing the rational design of patient-specific ablation sets for treating AF

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

An investigation into therapies for atrial arrythmias using a biophysical model of the human atria

The most common type of sustained arrhythmia is atrial fibrillation (AF), affecting about 2% of the general population and 8% to 11% of the elderly, more than 65 years of age. The treatment of atrial arrythmia is still based on empirical considerations and is usually evaluated in clinical studies or in animal experiments. The main drawbacks of animal experiments lie in the difficulty of technically accessing the whole atria and in the differences between animal and human anatomy. In the last years, ever-increasing computer power has permitted the development of biophysical models of the human atria. It has become possible to simulate cellular electrical propagation in the whole human heart. Compared to clinical and animal studies, an in silico approach has the advantages of repeatability and reproducibility under controlled conditions. In this thesis, a biophysical model of the human atria has been used to investigate therapies of atrial arrhythmias: surgical ablation and therapeutic pacing. First, a brief review of the concepts of biophysical modeling of human atria developed until now is presented, as well as a brief description of several types of arrhythmia that can be simulated with the biophysical model. Second, measures of organization are considered to quantify and classify the different types of AF. With these measures, AF organization is evaluated at the electrogram signals level as well as at the cellular level. Four types of atrial arrhythmia are differentiated with the use of the biophysical model: atrial flutter, chronic AF, meandering AF and cholinergic AF. Finally, simulations of atrial therapies are investigated. The biophysical model has been used to test the efficacy of ablation lines. The surgical Maze-III procedure has proven to be highly effective in treating chronic AF. However, due to the technical difficulty and the risk of the procedure, less invasive ablation techniques have been investigated. The results confirm the superiority of aggressive surgical procedures in the termination of AF, as described in the clinical studies. Furthermore, an ideal ablation pattern has been proposed using the biophysical model. The ideal pattern should be able to prevent AF with a limited number of ablation lines of minimal length, while allowing for the maintenance or recovery of mechanical activity of both atria during sinus rhythm. The second therapeutic approach investigated is that of pacing. An algorithm of pacing and different pacing sites are investigated during this research. Antitachycardia pacing on different types of AF are carried out. The simulations showed that more organized arrhythmia such as atrial flutter can be pace-terminated. On the other hand, only local capture is possible on more complex AF. The results obtained with the biophysical model are in agreement with the clinical studies. The results of the present research prove that atrial therapies can be approached by means of a biophysical model of the human atria. This tool can be used to investigate further therapeutic techniques and thus, improve the quality of life of patients

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

Mechanisms of Atrial Arrhythmia: Investigations of the Neuro-Myogenic Interface in the Mouse

Arrhythmia mechanisms rely on multiple factors including structural (myogenic), nervous (neurogenic), and interrelated (the neuro-myogenic interface) factors. I hypothesized that due to this neuro-myogenic interface, the intrinsic cardiac autonomic nervous system (ICANS) is involved in most atrial arrhythmias. This thesis also provides a Threshold Model as a tool to assess the role of different physiological factors influencing arrhythmia. This model allows relative comparison and interpretation of the role of various factors influencing arrhythmogenesis. The mouse allows relatively simple manipulation of genes to determine their role in arrhythmia. This thesis determined what atrial arrhythmias are inducible in the mouse (in vivo) and how to systematically study those arrhythmias. I found that atrial tachycardia/fibrillation (AT/F) and junctional tachycardia (JT) are inducible in the mouse. AF and JT pose significant clinical challenges as many patients do not respond well to current interventions. Neurogenic AF relies on acetylcholine, while myogenic AF relies, in part on gap junctions formed by connexins (Cxs). The atria has muscarinic M2 and M3 receptors. The duration of M2R/M3R G protein signalling is regulated by GTP hydrolysis, a process accelerated by the regulators of G protein signalling (RGS). RGS2 deficient (RGS2-/-) mice had reduced refractory periods that were normalized with a selective M3R blocker (Darifenacin) and increased susceptibility to AT/F induction compared to littermates. For the first time, this showed a role of M3 and RGS in atrial arrhythmia. Cx40 deficient (Cx40-/-) mice were protected from carbachol induced AT/F, while Cx43 G60S mutant (Cx43G60S/+) mice, with an 80% reduction in phospho-Cx43 in the atria were highly susceptible to AT/F that was terminated by darifenacin. This shows a novel neurogenic component to what was previously described as myogenic arrhythmia. Another novel finding was that JT has a neurogenic component, resulting from inappropriate AV nodal pacemaker activation initiated by autonomics. Ivabradine hydrochloride, a selective pacemaker channel blocker, prevented JT and may be useful in patients with JT. In conclusion, this thesis has provided novel findings of the vital role of the neuro-myogenic interface in atrial arrhythmias and has provided the basis for future investigations of potential therapeutic options for patients

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