Investigation of Partial Electrical Nerve Block for Autonomic Regulation

自主调节部分电神经阻滞的研究

• 批准号: 10323259
• 负责人: Tina Louise Vrabec
• 金额: $ 46.06万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-06 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323259
• 关键词: Abdomen; Acute; Area; Arrhythmia; Autonomic Nerve Block; Axon; Bilateral; Biosensor; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiovascular Diseases; Catecholamines; Characteristics; Chest; Chronic; Coronary heart disease; Data; Decentralization; Development; Disease; Down-Regulation; Effectiveness; Elements; Evaluation; Excision; Feedback; Ganglia; Goals; Heart; Heart Diseases; Heart Rate; Heart failure; Hyperalgesia; Hyperhidrosis disorder; Implantable Defibrillators; Individual; Intervention; Investigation; Ischemia; Laboratories; Lead; Manuals; Modality; Monitor; Myocardial dysfunction; Nerve; Nerve Block; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Outcome; Pathology; Pathway interactions; Patients; Periodicity; Peripheral; Persons; Pharmaceutical Preparations; Property; Reaction Time; Reading; Recovery; Reflex action; Regulation; Rodent Model; Scanning; Source; Specific qualifier value; Stress; Sympathetic Nerve Block; System; Tachyarrhythmias; Techniques; Therapeutic; Time; Tissues; United States; Ventricular; Work; autonomic nerve; autonomic reflex; base; cardiogenesis; clinically relevant; conventional therapy; density; effective therapy; electric field; heart function; indexing; innovation; interstitial; neuroregulation; novel; porcine model; response; side effect; sudden cardiac death; technique development; temporal measurement

Investigation of Partial Electrical Nerve Block for Autonomic Regulation More than 600,000 people die of heart disease in the United States every year. Sudden cardiac death often occurs as a result of ventricular tachyarrhythmias (VT) in patients with coronary heart disease (CHD) and/or heart failure (HF). Autonomic dysregulation following cardiac pathology is essential to the development of HF and VT. Existing interventions are lacking in response time, reversibility, and adaptability over time. Thus, a major unmet need is to impact/regulate sympathetic neural control of cardiac function using a targeted, rapid, reversible, and gradable modality that is safe for autonomic nerves and, ultimately, can be deployed chronically. Over the last decade, advances in the field of electrical nerve block, has shown promise to be this desired therapeutic modality. Peripheral electrical nerve block has a rapid onset, is reversible and gradable. Previously nerve block has been used to completely block a nerve. This is the first study to explore the value of partially blocking a nerve. Partial electrical nerve block can mitigate autonomic reflexes without extinguishing them. However, the stability and controllability of the block at any desired level are currently unknown. Understanding the characteristics of partial block would result in far reaching contributions to the control of autonomic systems. The feasibility of closed loop control of cardiac function is highly dependent on the availability of real time feedback of autonomic parameters. Existing monitoring techniques are lacking in both responsiveness and sensitivity. To provide a real-time control source, direct recording of autonomic nerve function will be performed using real-time measurements of cardiac interstitial and vascular catecholamines. The central hypothesis of this proposal is that the autonomic system can be down regulated and the sympathetic drive to the heart maintained at a clinically relevant lower set point using DC block. The ability to maintain the autonomic system at varying specified set points based on changing cardiac function and indices of cardiac stress (e.g VT burden, heart rate) would allow for highly patient specific disease interventions. Specifically, for this proposal, the goal is to regulate functional sympathetic control of the heart and maintain a given set point for 30 minutes. Aim 1: Identify and characterize the parameters of partial nerve block needed to maintain nerve block at a given set point using an acute rodent model on the vagus (autonomic) nerve. Aim 2: Identify nerve block targets in the cardiac sympathetic pathway and characterize the effect of partial block on evoked sympathetic reflex responses, in particular the effect on block efficacy and recovery. Aim 3: Evaluate the effect of partial block on regional cardiac norepinephrine using release fast scanning cyclic voltammetry in coordination with high density assessments of regional cardiac electrical function. Aim 4: Using the neurotransmitter biosensor, develop a control paradigm to determine both when to initiate block as well as determining the block level.

部分电神经阻滞用于植物神经调节的研究 美国每年有60多万人死于心脏病。心源性猝死 冠心病（CHD）患者经常因室性快速性心律失常（VT）和/或 心力衰竭（HF）。心脏病理后的自主神经功能失调对心力衰竭的发展至关重要 和VT。现有的干预措施缺乏反应时间、可逆性和长期适应性。因此 主要未满足的需求是使用靶向的，快速的， 可逆的和可分级的形式，其对自主神经是安全的，并且最终可以长期部署。 在过去的十年里，电神经阻滞领域的进展已经显示出希望达到这一目的。 治疗方式周围电阻滞起效快，可逆，可分级。先前 神经阻滞已被用于完全阻滞神经。这是第一个研究探讨部分价值 阻塞了神经部分电神经阻滞可以减轻自主神经反射而不熄灭它们。 然而，在任何期望的水平块的稳定性和可控性目前是未知的。理解 部分阻塞的特性将导致对自主系统的控制的深远贡献。 心脏功能的闭环控制的可行性高度依赖于真实的时间的可用性 自主参数的反馈。现有的监测技术缺乏反应能力， 灵敏度为了提供实时控制源，将执行自主神经功能的直接记录 使用心脏间质和血管儿茶酚胺的实时测量。这个问题的核心假设是 一种建议是，自主神经系统可以下调，而对心脏的交感神经驱动可以维持 在临床相关的较低设定点使用DC块。维持自主系统在不同的 基于心脏功能和心脏负荷指数（例如VT负荷、心率）变化的指定设定点 将允许高度患者特异性的疾病干预。具体来说，对于这项提案，目标是规范 心脏的功能性交感神经控制，并保持给定的设定点30分钟。目标1：确定和 特征化部分神经阻滞的参数，所述部分神经阻滞的参数需要使用 迷走（自主）神经的急性啮齿动物模型。目的2：确定心脏中的神经阻滞靶点 交感神经通路，并表征部分阻滞对诱发交感神经反射反应的影响， 特别是对阻滞效果和恢复的影响。目的3：评价部分阻滞对局部心脏的影响 去甲肾上腺素释放快速扫描循环伏安法与高密度评价相结合 局部心脏电功能目的4：使用神经递质生物传感器，开发控制范例， 确定何时启动阻塞以及确定阻塞级别。