Biomarker-guided optimization of transcutaneous vagal stimulation for atrial fibrillation

生物标志物引导的房颤经皮迷走神经刺激优化

基本信息

批准号：
10549341
负责人：
Stavros Stavrakis
金额：
$ 39.1万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549341
关键词：
Ablation Acute Arrhythmia Atrial Fibrillation Atropine Autonomic nervous system Biochemical Biochemical Markers Biological Markers Blood specimen Cardiovascular system Chronic Clinical Clinical Trials Coronary sinus structure Crossover Design Data Dose EKG P Wave Electrocardiogram Electrophysiology (science)Experimental Models Frequencies Heart Atrium Hour Human Inflammatory Infusion procedures Isoproterenol Laboratories Lead Measures Modality Monitor Morbidity - disease rate Morphology Myocardial Neuromodulator Pathogenesis Patient Participation Patient Selection Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Physiological Play Population Randomized Refractory Regimen Research Personnel Role Sampling Series Serum Surrogate Markers Testing Treatment Protocols Variant Veins clinical practice clinically significant cytokine experience health care delivery heart rate variability improved improved outcome individual patient insight metabolomics mortality multidisciplinary neuropeptide Y novel patient subsets placebo group randomized, clinical trials response response biomarker side effect smart watch success tool treatment optimization vagus nerve stimulation

项目摘要

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.

抽象的心房颤动 (AF) 是最常见的具有临床意义的心律失常，并且与心律失常的增加有关。心血管发病率和死亡率。最近的证据表明自主神经系统起着在 AF 发病机制中的核心作用，特别是在早期阶段，以及我们小组和其他人已经表明，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研究显示，在阵发性 AF 的门诊患者中，慢性、间歇性经皮 VNS (tVNS) 超过与假刺激相比，6 个月后 AF 负担显着降低。然而，回应 tVNS 的治疗效果在个体患者中存在差异，这凸显了这样一个观点：虽然 tVNS 是一种新兴的、有前途的治疗方法，但 AF 的治疗方式、剂量和/或患者选择必须进行优化。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 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，我们最近证明了 P 波交替 (PWA)，一种微妙的逐搏变化与假手术组相比，在 6 个月的时间内，P 波的形态在活动组中有所减弱，并且减少与房颤负担减轻相关。因此，我们假设 PWA 是一个有用的指导工具 AF 的 tVNS 治疗。我们最近还表明，房颤负担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。因此，我们提出的研究将测试评估 P 波形态中细微的逐搏变化的假设心电图 (ECG) 和 NPY 血清水平可用于首先确定最佳参数和二是指导tVNS治疗。我们的具体目标是： 1. 确定 tVNS 对自主神经张力的影响，阵发性房颤患者的心房基质和神经调节剂。 2. 调查慢性影响与假手术相比，6 个月内阵发性 AF 患者 AF 负担的最佳 tVNS 3. 识别慢性 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深入了解 tVNS 对自主神经张力、房颤底物的影响其次，允许使用 PWA、NPY 和代谢组生物标志物优化 tVNS 减轻 AF 患者的负担。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当前治疗房颤的科学范式，并且因此，导致医疗保健服务的重大改善。由于患者数量不断增加 AF 以及现有治疗方案的不良成功率和潜在副作用，另一种方法诸如 tVNS 之类的技术有可能影响临床实践并改善这些患者的治疗结果。