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

• 批准号: 10339889
• 负责人: Stavros Stavrakis
• 金额: $ 40.05万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 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/10339889
• 关键词: Ablation; Acute; Address; 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 Selection; Patient-Focused Outcomes; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Population; Randomized; Randomized Clinical Trials; Refractory; Regimen; Research Personnel; Role; Sampling; Series; Serum; Surrogate Markers; Testing; Treatment Protocols; Variant; Veins; base; clinical practice; clinically significant; cytokine; experience; health care delivery; heart rate variability; improved outcome; individual patient; insight; metabolomics; mortality; multidisciplinary; neuropeptide Y; novel; patient subsets; placebo group; response; response biomarker; side effect; smart watch; success; tool; treatment optimization; vagus nerve stimulation

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）是最常见的临床心律不齐，与增加有关 心血管发病率和死亡率。最近的证据表明，自主神经系统发挥 在AF的发病机理中的中心作用，尤其是在早期阶段，以及我们小组的几项研究， 其他人则表明，迷走神经刺激（VN）的自主神经调节可以抑制AF 实验模型。我们有来自最近完成的随机临床试验的令人兴奋的初步数据 表明，在阵发性AF的卧床患者中 与假刺激相比，6个月导致AF负担显着减少。但是，回应 到TVNS的个别患者之间是可变的，强调了这样的观念，即TVN是一种新兴而有希望的 必须优化AF的方式，剂量和/或患者选择。因此，迫切需要 开发可能的生物标志物1）确定最佳给药方案，2）选择理想的候选者 TVNS疗法，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对自主语调和心房底物的影响可用于指导和优化治疗。 重要的是，我们最近表明，P-Wave Alternans（PWA）是一种微妙的节拍到束缚的变化 与假手术组在6个月内相比，P波的形态在活动中减少了， 减少与减少AF负担相关。因此，我们假设PWA是指导的有用工具 TVNS治疗AF。我们最近还表明，AF负担的减少与血清水平相关 神经肽Y（NPY）的替代性活性标记。因此，我们提出的研究将测试 假设评估微妙的节拍到脱节变化的p波形态 心电图（ECG）和NPY的血清水平可用于首先，确定最佳参数和 其次，指导电视治疗。我们的具体目的是：1。确定电视对自主语调的影响， 阵发性AF患者的心房底物和神经调节剂。 2。研究 与假相比 刺激和3。确定对慢性TVN反应的生理和生化标志物。我们期待 这些研究的结果将首先提供有关TVN对自主语调的影响的见解 和神经调节剂，其次，允许使用PWA，NPY和代谢组生物标志物优化TVN 减轻患者受苦的患者的AF负担。通过引入优化的TVNS治疗方案，由 我们提出的研究有可能推翻当前的科学范式来治疗AF，并 因此，导致医疗保健提供的重大改善。由于患者数量增加 AF和可用治疗方案的成功和潜在副作用，这是一种替代方法 例如TVNS有可能影响这些患者的临床实践并改善结果。