In silico characterization of atrial electrical activity modulation by the autonomic nervous system for atrial fibrillation management
Cardiovascular diseases are the leading cause of mortality and morbidity in industrialized societies. Among these diseases, atrial fibrillation (AF) stands out as the most common arrhythmia encountered in clinical practice. It is estimated that by 2050, AF will affect 6-12 million people in the USA...
| Autores: | , , |
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| Tipo de recurso: | tesis de maestría |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Zaragoza |
| Repositorio: | Zaguán. Repositorio Digital de la Universidad de Zaragoza |
| OAI Identifier: | oai:zaguan.unizar.es:145318 |
| Acceso en línea: | http://zaguan.unizar.es/record/145318 |
| Access Level: | acceso abierto |
| Palabra clave: | simulación tecnología médica bioelectricidad fisiología cardiovascular |
| Sumario: | Cardiovascular diseases are the leading cause of mortality and morbidity in industrialized societies. Among these diseases, atrial fibrillation (AF) stands out as the most common arrhythmia encountered in clinical practice. It is estimated that by 2050, AF will affect 6-12 million people in the USA and by 2060, 17.9 million people in Europe. AF significantly increases the risk for heart failure, stroke and overall mortality and it negatively impacts the quality of life and healthcare costs. The development of arrhythmias, including AF, involves three key elements: an arrhythmogenic substrate, a trigger and modulating factors. The Autonomic nervous system (ANS) has been proved to be a crucial modulator in this process, with both its parasympathetic and sympathetic ANS branches playing a pivotal role in initiating and sustaining AF. <br />Given the complex relationship between AF and the ANS, the primary objective of this thesis is to improve the understanding of the mechanisms by which the ANS promotes and modulates AF and pave the way for the development of new treatment strategies. <br />To achieve this goal, we developed comprehensive in silico computational models incorporating theoretical descriptions of electrophysiology, cholinergic and ß-adrenergic stimulation and the effects of electrical remodeling resulting from the arrhythmia. These models encompass scales from the cellular to the whole atria level, with the multi-dimensional models also considering structural remodeling and providing a geometrical representation of ANS innervation. <br />By combining theoretical computational research with the analysis of clinical and experimental atrial signals, the research presented in this thesis establishes a foundation for future investigations aimed at guiding the search for more effective anti-arrhythmic therapies targeting the ANS.<br />The first part of this thesis focuses on characterizing the autonomic influence on the modulation of f-waves, i.e. the AF electrical activity reflected on the surface electrocardiogram (ECG). In particular, the f-wave frequency is analyzed as a means to non-invasively assess ANS activity during AF.<br />This research could be the basis for future developments of personalized treatment approaches based on specific ANS dysregulation patterns, with such approaches having the potential to be beneficial in managing AF.<br /> <br />In Chapter 3, we aimed to assess the impact of vagal stimulation on the respiratory modulation of fibrillatory frequency in persistent AF (psAF) patients. The objective was to explore the possibility of using this relationship as a surrogate measure to quantify the vagal input in such patients. <br />To achieve this, we combined the analysis of data obtained from a clinical study involving ECG recordings of psAF patients during controlled respiration with computational modeling and simulation. In these simulations, we mimicked the parasympathetic modulation induced by respiration by introducing cyclic variations in the concentration of acetylcholine (ACh), the parasympathetic neurotransmitter. Both 2D tissue models and 3D biatrial models considering different innervation patterns were employed in this investigation.<br />We found that temporal variations in the fibrillatory frequency followed the simulated temporal ACh(n) pattern in all cases. The temporal mean of the fibrillatory frequency (fm) depended on the fibrillatory pattern, on the percentage of ACh release nodes and on the mean ACh concentration over time. The magnitude of the respiratory modulation of the fibrillatory frequency (¿f) depended on the percentage of ACh release nodes and on the peak-to-peak ACh range ¿ACh. The spatial pattern of ACh release did not have an impact on fm and only a mild impact on ¿f for the highest tested spatial ACh percentage.<br />In Chapter 4 of this thesis, we delved into the correlation between autonomic influences and alterations in the modulation of the fibrillatory frequency during head-up tilt (HUT) and head-down tilt (HDT) tests. These tests are commonly used in medical settings to assess the autonomic function, providing valuable information about the ability of the ANS to regulate blood pressure and heart rate in response to postural changes. <br />Similarly, we sought to assess if the same test could be adopted in AF to evaluate the autonomic modulation of atrial electrical activity.<br />We used computational modeling and simulation to test different combinations of sympathetic and parasympathetic stimulation. The simulation outcomes were then compared to the analysis of clinical ECGs obtained from psAF patients who underwent a tilt test protocol. Collectively, the findings of this study indicate that the increase in the fibrillatory rate following the HUT maneuver and the decrease in the fibrillatory rate following the HDT maneuver can be primarily attributed to enhanced and diminished sympathetic activity, respectively. Furthermore, it appears that parasympathetic stimulation exerts a modulatory effect on the sympathetic effects rather than being the primary driving force behind the observed trends in atrial function.<br />Managing AF is challenging due to its complex and uncertain underlying mechanisms. Rhythm control strategies focus on restoring and maintaining sinus rhythm. This can be achieved through a combination of treatment approaches, including electrical or pharmacological cardioversion, antiarrhythmic drug therapy and catheter ablation. Chapter 5 and Chapter 6 of this thesis focus on AF therapies, particularly addressing signal processing of atrial electrograms (EGMs) to improve cardioneuroablation procedures and theoretically investigating the efficacy of new pharmacological therapies targeting ion channels and neural components.<br />In Chapter 5, we developed a method to locate atrial parasympathetic innervation sites using EGM measurements. <br />The ablation of the intrinsic cardiac autonomic ganglia, called ganglionated plexi (GPs), individually or in combination with pulmonary vein isolation, has been associated with a decreased risk of AF recurrence. However, accurate location of GPs is required for ablation to be effective.<br />We developed computational models to simulate non-AF, paroxysmal AF and psAF tissues. In GPs, predominance of parasympathetic activity has been shown, so parasympathetic effects were incorporated by increasing the concentration of ACh in randomly distributed islands within the tissue. Different sizes of ACh islands and fibrosis geometries were considered, including uniform diffuse and non-uniform diffuse fibrosis. Unipolar EGMs in a 16x16 electrode mesh were generated from the simulation.<br />The study revealed that the amplitude of the atrial EGM repolarization wave reflects the presence or absence of ACh release sites, with larger positive amplitudes indicating that the electrode is placed over an ACh region. Statistical analysis was employed to determine optimal thresholds for identification of ACh sites. The method successfully identified ACh sites in all types of tissues, with higher accuracy in the absence of fibrosis or with uniform diffuse fibrosis. The proposed algorithm proves robust against noise and electrode-to-tissue distance variations.<br />Chapter 6 focuses on the analysis of antiarrhythmic pharmacological therapies in combination with $\beta$-adrenergic signaling to treat cholinergic AF.<br />The parasympathetic neurotransmitter ACh causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry.<br />In this chapter, we used computational modeling and simulation to examine the impact of SK channel block (SKb) and ß-adrenergic stimulation by Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration.<br />The results showed that SKb alone prolongs APD90 and is able to stop sustained rotors in the presence of ACh concentrations up to 0.01 µM. Iso terminates rotors under all tested ACh concentrations, but results in highly-variable steady-state outcomes depending on the baseline AP morphology. Importantly, the combination of SKb and Iso results in greater APD90 prolongation and shows promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility.<br />In conclusion, this thesis develops cardiac computational modeling and simulation techniques to provide insights into the mechanisms of AF under the influence of the ANS and presents innovative methodologies for its treatment. Specifically, this research sheds light on the modulation of fibrillatory frequency by the ANS, enhancing our understanding of the potential underlying mechanisms behind macroscopic observations. Furthermore, it paves the way for the possibility of non-invasively assessing autonomic activity from EGM signals. In addition, from a therapeutic perspective, this thesis develops a method to determine the location and dimensions of GPs from an EGM grid to aid in cardioneuroablation procedures. Finally, it investigates potential pharmacological therapies, identifying the combination of SK channel blockade and Iso as a potential therapy for treating cholinergically-induced AF.<br /> |
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