Biomarker-guided optimization of transcutaneous vagal stimulation for atrial fibrillation

摘要 心房颤动（AF）是最常见的临床上显著的心律失常， 心血管疾病发病率和死亡率。最近的证据表明，自主神经系统发挥作用， 在房颤发病机制中的核心作用，特别是在早期阶段，我们小组的几项研究和 其他人已经表明，迷走神经刺激（VNS）的自主调节可以抑制AF， 实验模型我们从最近完成的随机临床试验中获得了令人兴奋的初步数据 显示在阵发性房颤的非卧床患者中，慢性、间歇性经皮VNS（tVNS）超过 与假刺激相比，6个月导致AF负荷显著降低。然而，回应 tVNS在个体患者中是可变的，强调了虽然tVNS是一种新兴的，有前途的 在AF的治疗模式中，必须优化给药和/或患者选择。因此，迫切需要 开发生物标志物，可以1）确定最佳给药方案和2）选择理想的候选人， tVNS治疗，从而最佳地指导AF管理。我们提出的研究将检验总体假设 tVNS对自主神经张力和心房基质的影响可用于指导和优化治疗。 重要的是，我们最近已经表明，P波交替（PWA），一个微妙的心跳到心跳的变化，在 与假手术组相比，在6个月的时间内， 降低与AF负担减轻相关。因此，我们假设PWA是一个有用的工具， tVNS治疗AF。我们最近也表明AF负荷的减少与血清水平相关， 神经肽Y（NPY），交感神经活动的替代标记物。因此，我们提出的研究将测试 该假设认为，评估心脏的P波形态中的细微搏动间变化， 心电图（ECG）和血清NPY水平可用于首先确定最佳参数， 二是指导tVNS治疗。我们的具体目标是：1.为了确定tVNS对自主神经张力的影响， 阵发性房颤患者心房基质和神经调质的变化。为了研究 与假手术相比，阵发性AF患者6个月期间AF负荷的最佳tVNS 刺激，3。确定慢性tVNS反应的生理和生化标志物。我们预计 这些研究的结果将首先提供对tVNS对自主神经张力、AF底物 第二，允许使用PWA、NPY和代谢组学生物标志物优化tVNS 减轻患者的房颤负担。通过引入优化的tVNS治疗方案， 我们提出的研究有可能推翻目前治疗房颤的科学范式， 从而导致保健服务的重大改善。由于越来越多的患者 房颤和不良成功率和潜在的副作用的可用治疗方案，一种替代方法 例如tVNS有可能影响临床实践并改善这些患者的结局。

Abstract Atrial fibrillation (AF) is the most common clinically significant arrhythmia and is associated with increased cardiovascular morbidity and mortality. Recent evidence suggests that the autonomic nervous system plays a central role in the pathogenesis of AF, especially in the early stages and several studies from our group and others have shown that autonomic modulation with vagus nerve stimulation (VNS) can suppress AF in experimental models. We have exciting preliminary data from our recently completed randomized clinical trial showing that in ambulatory patients with paroxysmal AF, chronic, intermittent transcutaneous VNS (tVNS) over 6 months resulted in a significant decrease in AF burden compared to sham stimulation. However, the response to tVNS was variable among individual patients, highlighting the notion that while tVNS is an emerging, promising modality for AF, the dosing and/or patient selection have to be optimized. Therefore, there is an urgent need to develop biomarkers that could 1) determine the optimal dosing regimen and 2) select the ideal candidates for tVNS therapy, and thus optimally guide AF management. Our proposed studies will test the overall hypothesis that the effects of tVNS on autonomic tone and atrial substrate can be used to guide and optimize therapy. Importantly, we have recently shown that P-wave alternans (PWA), a subtle beat-to-beat variation in the morphology of the P-wave, diminished in the active, compared to the sham group over a 6-month period and the decrease correlated with AF burden reduction. Therefore, we hypothesize that PWA is a useful tool for guiding tVNS therapy for AF. We have also recently shown that the decrease in AF burden correlated with serum levels of neuropeptide Y (NPY), a surrogate marker of sympathetic activity. Therefore, our proposed studies will test the hypothesis that assessment of subtle beat-to-beat variations in the P-wave morphology of the electrocardiogram (ECG) and serum levels of NPY can be used to first, determine the optimal parameters and second, guide tVNS treatment. Our specific aims are: 1. To determine the effects of tVNS on autonomic tone, atrial substrate and neuromodulators in patients with paroxysmal AF. 2. To investigate the chronic effects of optimal tVNS on AF burden in patients with paroxysmal AF over a 6-month period, compared with sham stimulation and 3. To identify physiological and biochemical markers of response to chronic tVNS. We anticipate that the results of these studies will first, provide insights into the effects of tVNS on autonomic tone, AF substrate and neuromodulators, and second, permit optimization of tVNS using PWA, NPY and metabolomic biomarkers to reduce AF burden of afflicted patients. By introducing an optimized tVNS treatment protocol, results from our proposed studies have the potential to overturn the current scientific paradigm for treatment of AF, and thus, lead to major improvements in health care delivery. Because of the increasing number of patients with AF and the poor success and potential side effects of the available treatment options, an alternative approach such as tVNS has the potential to impact clinical practice and improve outcomes for these patients.