Selective activation of the vagus nerve as an improved therapy for heart failure

选择性激活迷走神经作为心力衰竭的改进疗法

• 批准号: 8645395
• 负责人: BRETT ROSS DOWDEN
• 金额: $ 22.2万
• 依托单位: BLACKROCK MICROSYSTEMS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-06 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645395
• 关键词: Acute; Acute Pain; Address; Adrenergic Fibers; Adverse effects; Affect; American; Architecture; Area; Arrhythmia; Asthma; Autonomic nervous system; Axon; Bronchoconstriction; Canis familiaris; Cardiac; Cardiac Output; Carotid Arteries; Catecholamines; Chicago; Chronic; Clinical; Clinical Trials; Devices; Dimensions; Education; Electric Stimulation; Electrodes; Equilibrium; Etiology; Fascicle; Fiber; Frequencies; Goals; Gold; Health Care Costs; Healthcare; Heart; Heart Rate; Heart failure; Hour; Hypotension; Implant; Individual; Infection; Inflammation; Inflammatory; Injury; Ischemia; Laryngeal muscle structure; Lead; Location; Longevity; Malignant - descriptor; Maps; Microelectrodes; Morbidity - disease rate; Nerve; Nerve Fibers; Operative Surgical Procedures; Organ; Output; Oxidative Stress; Patients; Perfusion; Peripheral; Persons; Pharmacologic Substance; Phase; Physiologic pulse; Positioning Attribute; Procedures; Public Health; Quality of life; Recurrent Laryngeal Nerve; Research; Rest; Science; Secondary to; Secure; Side; Small Business Technology Transfer Research; Specificity; Stress; Sudden Death; Surgical complication; Sympathetic Nerve Block; Symptoms; System; Technology; Therapeutic; Tissues; Utah; Vagus nerve structure; Ventricular; Ventricular Dysfunction; Viscera; Visceral; Withdrawal; chronotropic; commercialization; cost; data acquisition; design; heart function; implantation; improved; innovation; instrumentation; meetings; microsystems; mortality; public health relevance; relating to nervous system; research study; restoration; simulation; sudden cardiac death; synaptic inhibition; vagus nerve stimulation; vocal cord

DESCRIPTION (provided by applicant): The goal of the proposed project is to alleviate the enormous public health burden of heart failure. Heart failure leads to significant morbidity and mortality, affects almost five million Americans, and results in more than 35 billion dollars in annual healthcare costs. Current pharmacological and surgical treatments are only moderately effective and can have substantial side effects. Regardless of cause, heart failure can lead to sustained, decreased cardiac output resulting in failure of the heart to meet the perfusion demands of peripheral tissue. This decrease in cardiac output is accompanied by an imbalance in input to the heart from the autonomic nervous system. A pathological decrease in parasympathetic activity and increase in sympathetic activity further contribute to heart failure through increased oxidative stress and inflammation and predispose patients to malignant arrhythmias and sudden death. Restoration of autonomic balance would remove stress from the failing heart, and not only improve heart function but would also improve patient comfort and quality of life. The specific aim of this project is to restore autonomic balance to the failing hert through electrical stimulation of the vagus nerve using an implanted microelectrode array. The vagus nerve carries parasympathetic fibers to the heart, but also innervates the viscera and vocal cords. Therefore, electrical stimulation must be highly targeted to avoid unwanted side effects. The key innovation of this project will be to achieve the high degree of specificity required to benefit heart function without producing side effects by stimulating the vagus nerve with the micro-fabricated "Utah" electrode array. The Utah electrode array is comprised of 96 individual microelectrodes designed to penetrate into nerve fascicles, thus placing the conductive tip of each electrode in close proximity to small independent groups of nerve axons. This fine access to the nerve provides the ability to stimulate small groups of axons while allowing the rest of the nerve to function normally. The specific aims of this project include 1) modify the Utah electrode array from its current dimensions to a size specific to the vagus nerve, 2) demonstrate that stimulation delivered via the appropriate electrodes can activate vagus nerve fibers innervating the heart without producing unwanted side effects, and 3) show that this activation will have beneficial effects on the symptoms of heart failure. This Phase I STTR will accomplish the above aims in short-term canine experiments. Deliverables from the successful completion of these aims will be an electrode array optimized for use in the vagus nerve, the surgical strategy for implantation into the vagus nerve, and stimulation parameters optimized for producing beneficial parasympathetic effects on the heart. These outputs will support the successful transition to long- term canine experiments and subsequent clinical trials and commercialization in Phases II and III of the STTR. Because of the large number of people suffering from heart failure and the limitations of current treatments, the successful completion of this project will have a profound positive impact on public health and wellbeing.

描述(申请人提供)：建议项目的目标是减轻心力衰竭带来的巨大公共健康负担。心力衰竭导致严重的发病率和死亡率，影响到近500万美国人，并导致每年超过350亿美元的医疗费用。目前的药物和手术治疗只是中等有效，可能会有很大的副作用。无论原因如何，心力衰竭都可能导致持续的心输出量减少，导致心脏无法满足外周组织的灌流需求。心输出量的减少伴随着自主神经系统对心脏的输入失衡。副交感神经活性的病理性降低和交感神经活性的增加通过增加氧化应激和炎症进一步导致心力衰竭，并使患者容易发生恶性心律失常和猝死。自主神经平衡的恢复将消除衰竭心脏的压力，不仅改善心脏功能，还将改善患者的舒适度和生活质量。这个项目的具体目的是通过使用植入的微电极阵列电刺激迷走神经来恢复衰竭的Hert的自主神经平衡。迷走神经将副交感神经纤维输送到心脏，但也神经支配内脏和声带。因此，电刺激必须具有高度的针对性，以避免不必要的副作用。该项目的关键创新将是通过使用微型制造的“犹他州”电极阵列刺激迷走神经，实现所需的高度特异性，以利于心脏功能，而不会产生副作用。犹他州的电极阵列由96个独立的微电极组成，旨在穿透神经束，从而将每个电极的导电尖端放置在靠近独立的小神经轴突群的地方。这种对神经的良好接触提供了刺激小群轴突的能力，同时允许神经的其余部分正常工作。该项目的具体目标包括1)将犹他州的电极阵列从目前的尺寸修改为迷走神经特有的尺寸；2)证明通过适当的电极提供的刺激可以激活支配心脏的迷走神经纤维，而不会产生不想要的副作用；3)证明这种激活将对心力衰竭的症状产生有益的影响。本研究的第一阶段将在犬的短期实验中实现上述目标。这些目标的成功实现将包括优化用于迷走神经的电极阵列、植入迷走神经的手术策略以及优化对心脏产生有益副交感神经效应的刺激参数。这些成果将支持成功过渡到犬的长期试验和随后的临床试验，并在STTR的第二和第三阶段实现商业化。由于患有心力衰竭的人数众多，加上目前治疗方法的局限性，这一项目的顺利完成将对公众健康和福祉产生深远的积极影响。