Biomarker-guided optimization of transcutaneous vagal stimulation for atrial fibrillation

摘要 心房颤动(房颤)是临床上最常见的显着心律失常，并与 心血管发病率和死亡率。最近的证据表明，自主神经系统在 在房颤发病机制中的中心作用，特别是在早期阶段，以及我们小组和 其他研究表明，迷走神经刺激(VNS)的自主神经调节可以抑制房颤。 实验模型。我们最近完成的随机临床试验获得了令人兴奋的初步数据。 显示在阵发性房颤的门诊患者中，慢性间歇性经皮房颤(TVNS) 与假刺激相比，6个月的房颤负荷显著降低。然而，对此的回应 TVNS在不同患者之间是不同的，强调了TVNS是一种新兴的，有前途的 房颤的治疗方式、剂量和/或患者选择必须优化。因此，迫切需要 开发生物标志物，可以1)确定最佳给药方案，2)选择理想的候选药物 TVNS治疗，从而最佳地指导房颤的治疗。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底物的影响可用于指导和优化治疗。 重要的是，我们最近展示了P波交替(PWA)，这是一种细微的心跳到心跳的变化 在6个月的时间里，与假手术组相比，活动组的P波形态减少，并且 房颤负荷降低与房颤负荷减轻相关。因此，我们假设PWA是一种有用的指导工具 房颤的TVNS治疗。我们最近还发现，房颤负荷的减少与血清水平有关 神经肽Y(NPY)是交感神经活性的替代标记物。因此，我们提议的研究将测试 假设对心搏间期P波形态细微变化的评估 心电图和血清NPY水平可用于首先确定最佳参数和 第二，指导TVNS的治疗。我们的具体目标是：1.确定tVNS对自主神经音调的影响。 阵发性房颤患者的心房基质和神经调质。2.调查以下各项的慢性影响 与假手术相比，TVNS对阵发性房颤患者房颤负荷的影响 3.确定慢性TVNS反应的生理生化标志物。我们期待着 这些研究的结果将首先为tVNS对自主神经张力、房颤底物的影响提供洞察力 和神经调节剂，第二，允许使用PWA，NPY和代谢组生物标记物来优化tVNS 减轻房颤患者的房颤负担。通过引入优化的TVNS治疗方案，结果来自 我们提出的研究有可能颠覆目前治疗房颤的科学范式，并且 因此，这将大大改善卫生保健服务的提供。因为越来越多的患者患有 房颤和现有治疗方案的低成功率和潜在副作用，这是一种替代方法 例如TVNS有可能影响临床实践并改善这些患者的预后。

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.