Myocardial Substrate Driven Mechanistic Insights into Atrial Fibrillation

项目摘要/摘要 仅在美国就有300-500万人患有房颤。尽管基于导管的手术是常规的 用于治疗房颤，高达60%的高复发率仍然是一个挑战。多年来，它已经 已有研究表明，房颤患者的心房心肌与纤维化有关，这种纤维化的底物被认为是 在维持房颤方面发挥重要作用。然而，大多数消融手术的目标是电气隔离 肺静脉。这种消融的解剖学方法是基于这样一种假设：肺静脉 在阵发性房颤中，异位活动是导致房颤的焦点。更机械化的方法 基于对肺静脉以外的“病变”区域的定位，特别是针对持续性房颤 结果各不相同。这主要是因为(I)没有好的方法来识别这些病区和(Ii)有 对这些纤维化区在维持房颤中所起的作用没有机械性的了解。最近，在那里 已经有一些关于转子驾驶房颤的报道。瞄准这些转子已经显示出一些有希望的初步结果。 这些转子的结构基础和将它们锚定到稳定位置的机制仍不清楚。在 犹他州大学，我们已经建立了一个持续性房颤的慢性大动物模型。我们有 我还率先使用MRI检测心房颤动的房壁重构，但缺乏严格的组织学 验证。使用不同分辨率和高分辨率的系列电子地图的组合 在此提出的体内和体外MRI，我们将开发一种更机械的方法，以导管为基础 消融治疗可显著改善手术效果。基于串口高密度 不同时间点在时间域和频率域处理的心电图电记录 关于房颤的进展，我们将对房颤的机制有一个详细的了解。这些翻译研究 将显示房颤是否有稳定的驱动力，以及它们在不同位置稳定的机械基础。 这些为房颤司机提供稳定性的纤维化区域可以成为导管消融的基础，导致 改善了结果。为了验证这一假设，我们将使用独特的实验、临床和动物模型。 设施以及在电气测绘、计算建模和成像方面的广泛专业知识 在犹他大学提供。临床结果将是减少重复手术的次数 目前由于心律失常复发所做的治疗，给患者带来了很大的成本和风险。

Project Summary/Abstract Atrial fibrillation (AF) affects 3-5 million people in the US alone. Although catheter-based procedure is routinely used in treating AF, the high recurrence rate of up to 60 % continues to be a challenge. Over the years it has been shown that the atrial myocardium in AF is associated with fibrosis and this fibrotic substrate is thought to play a major role in sustaining AF. Yet, the goal for most ablation procedures is to electrically isolate the pulmonary veins. This anatomical approach to ablation is based on the assumption that the pulmonary veins are the foci for ectopic activity driving atrial fibrillation shown in paroxysmal AF. More mechanistic approaches based on targeting “diseased” areas beyond the pulmonary veins, specially, for persistent AF has yielded varying results. This is mostly because (i) there is no good way to identify these diseased areas and (ii) there is no mechanistic understanding of the role played by these fibrotic areas in sustaining AF. More recently, there have been some reports of rotors driving AF. Targeting these rotors has shown some promising early results. The structural basis of these rotors and the mechanism anchoring these to stable sites are still unknown. At the University of Utah we have developed a chronic large animal model of persistent atrial fibrillation. We have also pioneered using MRI to detect atrial wall remodeling in atrial fibrillation but it lacks rigorous histological validation. Using a combination of serial electrical mapping at different resolutions and high resolution in-vivo and ex-vivo MRI proposed here we will develop a more mechanistic approach to catheter-based ablation leading to significant improvement in procedural outcomes. Based on serial high density electrical recording of electrograms processed in both time and frequency domains at different time points in the progression of AF we will develop a detailed mechanistic understanding of AF. These translation studies will show if there are stable drivers of AF and the mechanistic basis for their stability at various locations. These areas of fibrosis that provide stability to AF drivers can be the basis of catheter ablation resulting in an improved outcome. To test this hypothesis, we will make use of unique experimental, clinical and animal model facilities as well as the extensive expertise in electrical mapping, computational modeling and imaging available at University of Utah. The clinical consequence will be reduced number of repeat procedures that are currently done due to arrhythmia recurrence at a significant cost and risk to patients.