Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

心房颤动（AF）是最常见的心律失常，也是中风的主要原因。尽管 发病率迅速上升，目前的治疗方法是次优的。这主要是因为目前的AF治疗， 包括消融术，并不针对AF的基本机制。 复杂的电激活模式难以使用标准激活时间标测来标测。然而， 越来越多的证据表明AF是由心房中的稳定源（例如转子或病灶活动）驱动的。 不幸的是，以前尝试使用AF电描记图来检测这些来源的成功率参差不齐。我们 最近开发了一种电描记图形态复发（EMR）分析， 比先前描述的AF更准确地反映AF的分子和电生理底物 我们最近的研究表明，房颤的高复发区域的形态， 最短周期长度（即，低复发周期长度的区域）可以对应于 增加的副交感神经支配和/或增加的氧化损伤。此外，我们的临床研究 提示在持续性房颤患者中，EMR标测是可行的， 信息.我们对这一建议的总体假设是：“高复发形态的部位， 周期长度（即Δ T）代表增加的自主信号传导和/或增加的氧化损伤的区域， 这对维持持续性房颤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，以及持续性AF患者的CLR引导消融策略。 具体目标1，我们将在AF的犬快速心房起搏模型中评估是否靶向抑制 副交感神经信号传导-通过表达Gαi/o抑制肽（Gαi/o_ct）的质粒， 心房亚区的最低振幅-将逆转电重构和AF。在特定目标2中，我们将评估 在相同的犬模型中，是否靶向抑制氧化损伤的两个主要来源中的一个或多个 在房颤中，通过在心房亚区表达NOX 2 shRNA抑制线粒体过氧化氢酶， 逆转电重构，防止纤维化进展并减少AF。在特定目标3中， 正在接受导管消融术的持续性房颤患者将随机接受经导管消融术指导的消融策略，或 单独肺静脉隔离;我们将确定在这些患者中，超声引导消融策略是否会增加ECG 与单独的PVI相比的优势频率。所有目标的完成将为电子病历的使用提供一条清晰的道路 作为一种新的诊断方法来指导AF的治疗干预。 先前开发和验证EMR以测试治疗AF的几种新型靶向方法。由于AF可能 具有复杂的潜在病理生理学，这些方法中的一种或多种可以是可行的， 治疗，并最终可以组合使用。该提案提供了一个重要的推进平台 房颤的治疗科学。

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.