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.

自主调节部分电神经阻滞的研究 美国每年有超过 60 万人死于心脏病。心源性猝死 常因冠心病 (CHD) 和/或患者的室性快速心律失常 (VT) 而发生 心力衰竭（HF）。心脏病后的自主神经失调对于心力衰竭的发生至关重要 和VT。现有的干预措施缺乏响应时间、可逆性和随时间的适应性。因此，一个 主要未满足的需求是使用有针对性的、快速的、 可逆且可分级的方式，对自主神经来说是安全的，并且最终可以长期部署。 在过去的十年中，电神经阻滞领域的进步已显示出实现这一期望的希望 治疗方式。周围电神经阻滞起效快、可逆且可分级。之前 神经阻滞已用于完全阻滞神经。这是第一项探索部分价值的研究 阻塞神经。部分电神经阻滞可以减轻自主神经反射而不消除它们。 然而，目前尚不清楚该块在任何所需水平上的稳定性和可控性。理解 部分阻止的特征将对自主系统的控制产生深远的贡献。 心功能闭环控制的可行性高度依赖于实时信息的可用性 自主参数的反馈。现有的监控技术缺乏响应能力和 敏感性。直接记录自主神经功能，提供实时控制源 使用心脏间质和血管儿茶酚胺的实时测量。这个假设的中心假设 建议可以下调自主神经系统并维持对心脏的交感神经驱动 使用 DC 阻滞达到临床相关的较低设定点。将自主系统维持在不同状态的能力 根据心功能的变化和心脏应激指数（例如，VT 负荷、心率）指定设定点 将允许对患者进行高度特定的疾病干预。具体来说，该提案的目标是规范 心脏的功能性交感神经控制并维持给定的设定点 30 分钟。目标 1：识别并 使用以下参数表征在给定设定点维持神经阻滞所需的部分神经阻滞参数 迷走（自主）神经的急性啮齿动物模型。目标 2：识别心脏中的神经阻滞目标 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， 特别是对块功效和恢复的影响。目标 3：评估部分阻滞对局部心脏的影响 去甲肾上腺素使用释放快速扫描循环伏安法与高密度评估相配合 局部心电功能。目标 4：使用神经递质生物传感器，开发一种控制范式 确定何时启动阻止以及确定阻止级别。