Myocardial Substrate Driven Mechanistic Insights into Atrial Fibrillation

项目总结/摘要 房颤（AF）仅在美国就影响了300万至500万人。虽然基于导管的程序是常规的 用于治疗AF，高达60%的高复发率仍然是一个挑战。多年来， 已经表明，房颤中的心房心肌与纤维化有关，这种纤维化基质被认为是 然而，大多数消融手术的目标是电隔离 肺静脉这种消融的解剖学方法是基于肺静脉 是阵发性房颤中显示的驱动房颤的异位活动的病灶。 基于靶向肺静脉以外的“病变”区域，特别是针对持续性AF， 不同的结果。这主要是因为（i）没有好的方法来识别这些患病区域，（ii） 对这些纤维化区域在维持AF中所起的作用没有机械的理解。最近， 已经有一些关于转子驱动AF的报道。针对这些转子已经显示出一些有希望的早期结果。 这些转子的结构基础和将其锚定到稳定位置的机制仍然未知。在 犹他州大学的研究人员开发了一种慢性持续性房颤的大型动物模型。我们有 我也率先使用MRI检测心房颤动中的心房壁重构，但缺乏严格的组织学检查 验证。使用不同分辨率和高分辨率的系列电标测组合 在这里提出的体内和离体MRI中，我们将开发一种更机械的方法， 消融导致手术结局显著改善。基于串行高密度 在不同时间点在时域和频域中处理的电描记图的电记录， AF的进展，我们将制定一个详细的机械理解AF。这些翻译研究 将显示是否存在稳定的AF驱动因素及其在不同位置稳定性的机械基础。 这些为AF驱动器提供稳定性的纤维化区域可以是导管消融的基础， 改善结果。为了验证这一假设，我们将利用独特的实验，临床和动物模型 设施以及广泛的专业知识，在电气测绘，计算建模和成像 可在犹他州大学获得。临床结果将减少重复手术的数量， 目前由于心律失常复发而对患者造成巨大的成本和风险。

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.