Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

心房颤动(房颤)是最常见的心律失常，也是中风的主要原因。尽管它的 发病率迅速上升，目前的治疗方法并不理想。这在很大程度上是因为目前的房颤疗法， 包括消融，并不针对房颤的基本机制。AF的特点是 使用标准激活时间映射难以映射的复杂电激活模式。然而， 越来越多的证据表明，房颤是由心房内的稳定来源驱动的，例如转子或局部活动。 不幸的是，以前使用房颤电信号检测这些震源的尝试有成功也有成功。我们 最近开发了一种电信号形态复发(EMR)分析，似乎比 比之前描述的房颤更准确地反映了房颤的分子和电生理底物 房颤的心电图测量。我们最近的研究表明，具有高复发率的区域 最短循环长度(即，低循环循环长度的区域-CLR)可以对应于 副交感神经支配增加和/或氧化损伤增加。此外，我们的临床研究 提示在持续性房颤患者中，EMR标测既是可行的，又提供了重要的生理功能 信息。我们对这一提议的总体假设是：具有最短复发率的部位 周期长度(即CLR)代表自主神经信号增强和/或氧化损伤增加的区域， 这对维持持久的急性呼吸综合征至关重要。为了验证这一假设，我们将使用新的基因疗法。 我们实验室开发的方法，以及CLR指导下的持续性房颤患者的消融策略。在……里面 具体目标1，我们将评估在犬快速心房起搏模型中是否靶向抑制房颤 副交感神经信号转导--表达G-αI/O抑制肽(G-αI/o_ct)的表达 CLR最低的房亚区--将逆转电重构和房颤。在具体目标2中，我们将评估 在同一犬模型中，靶向抑制是氧化损伤的两个主要来源之一还是多个 房颤时CLR-Will最低的房室亚区NOX2shRNA线粒体过氧化氢酶的表达 逆转电重构，防止纤维化进展，减少房颤。在特定目标3中，患有 正在接受导管消融的持续性房颤患者将随机接受CLR引导的消融策略或 我们将确定在这些患者中，CLR引导的消融策略是否会增加心电图 与单独的PVI相比，主要频率。完成所有目标将为使用电子病历提供一条清晰的途径 标测作为一种新的诊断方法指导房颤的治疗干预。这项提议充分利用了 预先开发和验证EMR，以测试几种治疗房颤的新的靶向方法。因为房颤可能 有复杂的潜在病理生理学，这些方法中的一个或多个可能是可行的 治疗作用，并最终可用于联合使用。这项提议提供了一个关键的平台来推进 治疗房颤的科学。

Atrial fibrillation (AF) is the most common heart rhythm disorder and is a major cause of stroke. Despite its rapidly rising incidence, current therapies are suboptimal. This is largely because current AF therapies, including ablation, are not targeted to the fundamental mechanisms underlying AF. AF is characterized by complex electrical activation patterns that are difficult to map using standard activation time mapping. Yet, there is growing evidence that AF is driven by stable sources in the atria, such as rotors or focal activity. Unfortunately, previous attempts to use AF electrograms to detect these sources have had mixed success. We have recently developed an electrogram morphology recurrence (EMR) analysis that appears to more accurately reflect molecular and electrophysiological substrate for AF than previously described AF electrogram measures of AF. Our recent studies suggest that regions of high recurrence morphology with the shortest cycle lengths (i.e. regions of low recurrence cycle length - CLR) may correspond to regions of increased parasympathetic innervation and/or increased oxidative injury. Furthermore, our clinical studies suggest that in patients with persistent AF, EMR mapping is both feasible and provides important physiologic information. Our overall hypothesis for this proposal is: ‘sites of high recurrence morphology with the shortest cycle length (i.e. CLR) represent regions of increased autonomic signaling and/or increased oxidative injury, which are critical to the maintenance of persistent AF.’ To test this hypothesis, we will use novel gene therapy approaches developed in our lab, as well as a CLR-guided ablation strategy in patients with persistent AF. In Specific Aim 1, we will assess in a canine rapid atrial pacing model of AF whether targeted inhibition of parasympathetic signaling – by expression of plasmids expressing Gαi/o inhibitory peptides (Gαi/o_ct) at the atrial sub-region with lowest CLR – will reverse electrical remodeling and AF. In Specific Aim 2, we will assess in the same canine model whether targeted inhibition one or more of the two major sources of oxidative injury in AF - by expression of NOX2 shRNA  mitochondrial catalase at the atrial sub-region with lowest CLR – will reverse electrical remodeling, prevent progression of fibrosis and decrease AF. In Specific Aim 3, patients with persistent AF who are undergoing catheter ablation will be randomized to a CLR guided ablation strategy or PVI alone; we will determine whether in these patients a CLR guided ablation strategy will increase ECG dominant frequency compared to PVI alone. Completion of all the aims will provide a clear path to using EMR mapping as a new diagnostic method to guide therapeutic intervention for AF. This proposal leverages the prior development and validation of EMR to test several novel targeted approaches for treating AF. As AF may have complex underlying pathophysiology, it is feasible that one or more of these approaches could be therapeutic and could ultimately be used in combination. This proposal provides a critical platform to advance the science of curative therapy for AF.