Literatura académica sobre el tema "Atrial fibrillation substrate"

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Studies in animal modelshave provided important insights into arrhythmia mechanisms. However, to date, we do not dispose ofanimal models of spontaneous atrial arrhythmia.Thus, we aimed to develop a model of spontaneous atrial arrhythmia in rats and to assesspathophysiological mechanisms of these arrhythmias by using a multidisciplinary approach. We alsoaimed to assess the presence and the extent of inflammation and endothelial dysfunction, incriminatedin atrial fibrillation-related complications such as stroke, in atrial fibrillation patients.The animal study describes the first animal model of spontaneous atrial arrhythmias. We alsoprovide evidence that multiple mechanisms participate in arrhythmia occurrence in this model,particularly autonomic imbalance with relative vagal hyperactivity, left atrial endocardial fibrosis, anddecreased left atrial expression of the Pitx2 gene. In our clinical study, we found high levels ofvascular endothelial growth factor and von Willebrand factor in atrial fibrillation patients compared tosinus rhythm controls. These results suggest specific thromboembolic risk patterns according to theclinical form of arrhythmia and highlight a parallel evolution of atrial fibrillation and endothelialdysfunction. These results add new insights into the understanding of atrial arrhythmias. This new animalmodel could facilitate studies of pathophysiological mechanisms involved in atrial arrhythmias andallow assessment of efficacy and toxicity of therapeutic agents in a setting that faithfully reproducesthe clinical presentation of the arrhythmia

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects an estimated 33.5 million people worldwide. Despite its prevalence and economic burden, treatments remain relatively ineffective. Interventional treatments using catheter ablation have shown more success in cure rates than pharmacologic methods for AF. However, success rates diminish drastically in patients with more advanced forms of the disease. The focus of this research is to develop a mapping strategy to improve the success of ablation. To achieve this goal, I used a computational model of excitation in order to simulate atrial fibrillation and evaluate mapping strategies that could guide ablation. I first propose a substrate guided mapping strategy to allow patient-specific treatment rather than a one size fits all approach. Ablation guided by this method reduced AF episode durations compared to baseline durations and an equal amount of random ablation in computational simulations. Because the accuracy of electrogram mapping is dependent upon catheter-tissue contact, I then provide a method to identify the distance between the electrode recording sites and the tissue surface using only the electrogram signal. The algorithm was validated both in silico and in vivo. Finally, I develop a classification algorithm for the identification of activation patterns using simultaneous, multi-site electrode recordings to aid in the development of an appropriate ablation strategy during AF. These findings provide a framework for future mapping and ablation studies in humans and assist in the development of individualized ablation strategies for patients with higher disease burden.

Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and a frequent cause of hospitalization. Moreover, it represents one of the most frequent complication following cardiac surgery with an incidence of around 30% and an important predictor of patient morbidity. The exact pathophysiological mechanisms responsible for the onset and perpetuation of AF are not completely understood. However, clinical and experimental insights on the factors causing AF have suggested that atrial fibrillation is a multi-factorial phenomenon. Atrial fibrillation is characterized by a highly complex and irregular electrical activation of the atrial tissue, which is the manifestation of diverse abnormalities (electrical, structural, metabolic, neurohormonal, and/or molecular alterations) in diverse pathological conditions. In particular, it has been shown that fibrosis, a phenomenon in which extracellular matrix (ECM) components, mainly fibrillar collagen, accumulate between cardiomyocytes, leads to the inhomogeneous atrial electrical conduction typical of fibrillation. Recent studies have suggested that the deregulation of gene expression may act as a molecular mechanism of arrhythmogenesis. In particular, miRNAs, a new class of non-coding RNAs have rapidly emerged as one of the key players in the gene expression regulatory network, so variations in their expression levels may constitute a pathway for the arrhythmia-induced atrial remodeling. The present study aims to investigate the structural and molecular features of atrial tissue, with particular attention to fibrosis, which may be involved in the formation of a pro-arrhythmic substrate. By using both histological and advanced microscopy techniques, intramural fibrotic content and 3D collagen network properties were determined in atrial samples, collected during cardiac surgery in patients who developed or not AF. The quantitative analysis indicated a general decrease of collagen content from the outer (the epicardium) to the inner (the endocardium) myocardial wall, in the overall patient population. However, AF patients presented higher fibrotic values compared to sinus rhythm (SR) patients in the deeper myocardial layers, thus supporting the hypothesis that an accumulation of fibrotic tissue within the myocardial wall may represent an important structural contributor in the pathophysiology of AF. In addition to a quantitative assessment, collagen properties such as fibers orientation (degree and anisotropy) and scale dimension, were determined by non-linear optical microscopy techniques. The analysis revealed that in SR patients collagen network showed a fine architecture characterized by thin fibrils with changing angles and directions compared to AF, where fibers tended to pack-up in larger bundles of defined directions. A quantitative analysis of the 3D collagen network features, throughout the atrial wall, revealed that fibers orientation and scale dimension changed along tissue depth in both SR and AF patients, with larger values of orientation and fiber changes in AF tissues. These results highlight the spatial rearrangement and thickening of the 3D collagen network in AF patients, suggesting its possible role in the maintenance of the arrhythmia. Numerous evidence indicated that also an altered regulation of gene expression may play an important role in the mechanisms of atrial remodeling which underlie AF. In this perspective, the expression pattern of some miRNAs known to target different genes involved in diverse mechanisms that underlie AF was evaluated. A panel of miRNAs (miR-1, miR-133a/b, miR-30c, miR-29a/b, miR-208a/b, miR-328, miR-499, miR-590 and miR-21), principally involved in the formation of a pro-arrhythmic substrate, was selected after an accurate review of the literature and analyzed by RT-qPCR, in AF patients versus SR individuals. To accurately determine the levels of analyzed miRNAs, their expression data are usually normalized relatively to endogenous and/or exogenous reference genes. To date, no general agreement between different normalization strategies has been found, in particular in cardiac tissue, for the study of AF. For these reasons, a preliminary study aiming to establish the best endogenous reference genes for miRNAs data normalization was performed. Specifically, different well-established analysis tools such as NormFinder, GeNorm, BestKeeper and ∆Ct method, were applied on five commonly used endogenous reference transcripts such as 5S, U6, SNORD48, SNORD44 and miR-16. The suitable reference gene obtained, SNORD48, was applied for miRNAs data normalization. Our findings revealed that miRNAs expression levels were different in AF compared to SR patients. MiR-208a and miR-208b displayed statistically significant differences between the two populations. To investigate possible relationships between miRNAs expression levels and the fibrotic content a correlation measurement was also performed. Our analysis revealed that miR-21 and miR-208b were close to a significant correlation with fibrosis. In conclusion, this work introduced new techniques and implemented new methods of analysis for the study of the substrate of AF. In particular, the results obtained with this multiscale approach, from structural to molecular level, exacerbated the role of fibrosis as a critical contributor in the formation of a pro-arrhythmic substrate. Nonetheless, further studies are needed for a better understanding of the ways in which structural, molecular and also cellular remodeling may alter the impulse propagation in the myocardium.

The understanding of the underlying mechanisms of the persistence of atrial fibrillation remains poor. Key to this is the relationship between structure - myocardial architecture, and function - electrical activity, and how these can be measured, interpreted and correlated clinically. We sought to address the hypothesis that the local electrogram morphology is determined by local atrial myocardial activation patterns, which are in turn determined by local atrial myocardial architecture. In addressing this hypothesis, we utilised improved techniques of atrial segmentation and detection of wall enhancements to more accurately delineate underlying de novo atrial myocardial fibrosis, with late-gadolinium enhanced cardiac magnetic resonance imaging (LGE- CMRI). Here, we demonstrated a predilection of native structural remodelling on the posterior left atrial wall. The electrophysiological changes underlying late-gadolinium enhancements were interrogated with high-density electroanatomic 3D mapping using a Kernel as a unit of measure, in the varying rhythms of AF, sinus and pacing, with drop in tissue voltages and conduction velocities in regions of fibrosis, but counter-intuitively, a higher extent of electrogram fractionation in healthy myocardium. We observed the rate and wavefront-activation dependency of voltage, emphasizing the importance of voltage maps being interpreted in the context of its rhythm. We have also described a novel technique of AF voltage mapping, with the metric of mean AF voltage sampled over 8 secs correlating well with LGE-CMRI defined fibrosis, and surprisingly better than that of sinus rhythm voltage suggesting that this metric may be more representative of the underlying atrial substrate. Lastly, reverse translational cell monolayer experiments in novel co-cultured neonatal ventricular rat myocytes and fibroblasts were carried out to corroborate clinical in vivo observations under the control of the basic science laboratory. These emphasized the contributions of the structural and functional changes to electrogram morphology (voltage and fractionation). The contact electrogram is the result of a complex dynamic functional electrophysiology, and its interactions with the underlying atrial myocardium. This increased understanding of structure and function (electroarchitecture) provides mechanistic insights essential if we are to progress beyond the current empiricism of catheter ablation strategies of persistent AF.

The mechanisms responsible for maintenance of AF remain poorly understood. This thesis examines the frequency domain characteristics of AF in order to gain further insights into this arrhythmia. Through a series of studies involving patients undergoing catheter ablation for atrial fibrillation, intra-cardiac electrograms of AF were collected and analysed using Fast Fourier Transform to derive frequency domain parameters of dominant frequency (DF) and organization index (OI). It was found that intravenous flecainide reduced DF of AF, but only an associated increase in OI was predictive of successful return to sinus rhythm. In another study of patients having catheter ablation for persistent AF, a higher OI post-ablation was found to be associated with medium-term freedom of AF, suggesting that OI may be a useful guide to determine the extent of radiofrequency ablation needed. The effects of vagal blockade with atropine were also studied and compared with that of catheter ablation using a stepwise strategy of isolating the pulmonary veins, linear ablation and complex fractionated electrogram ablation, without deliberately targeting ganglionated plexi. This showed that atropine reduced DF and increased OI of AF electrograms, while decreasing mean RR intervals, standard deviation of RR intervals and 5th percentile of RR intervals. The directional changes of all the above parameters mirrored that of catheter ablation, suggesting that vagal blockade and catheter ablation not deliberately aimed at autonomic tissue can have similar effects on the frequency spectrum of AF, probably mediated through modulation of the autonomic tone. The relationship of regional DF and electrogram complexity as assessed by automated measurement of complex fractionated electrogram – mean (CFE-mean) were also compared, pre and post-ablation of the left atrium. There appeared to be only a modest correlation between the two and this was further weakened following ablation, suggesting that these are possibly separate substrate entities.