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

描述（由申请人提供）：拟议项目的目标是减轻心力衰竭的巨大公共卫生负担。心力衰竭导致显著的发病率和死亡率，影响近500万美国人，并导致每年超过350亿美元的医疗保健费用。目前的药理学和手术治疗只有适度的有效性，并可能有很大的副作用。无论原因如何，心力衰竭可导致持续的心输出量减少，从而导致心脏无法满足外周组织的灌注需求。这种心输出量的减少伴随着从自主神经系统到心脏的输入的不平衡。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的氧化应激和炎症进一步导致心力衰竭，并使患者易患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，而且还将改善患者的舒适度和生活质量。本研究的目的是通过植入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。迷走神经携带副交感神经纤维到心脏，但也支配内脏和声带。因此，电刺激必须高度针对性，以避免不必要的副作用。该项目的关键创新将是通过用微制造的“犹他州”电极阵列刺激迷走神经，实现有利于心脏功能而不产生副作用所需的高度特异性。犹他州电极阵列由96个单独的微电极组成，这些微电极被设计为穿透神经束，从而将每个电极的导电尖端放置在非常接近小的独立神经轴突组的位置。这种对神经的精细访问提供了刺激小轴突群的能力，同时允许神经的其余部分正常发挥功能。本项目的具体目的包括：1）将犹他州电极阵列从其当前尺寸修改为迷走神经特定尺寸，2）证明通过适当电极输送的刺激可以激活支配心脏的迷走神经纤维，而不会产生不必要的副作用，3）证明这种激活将对心力衰竭症状产生有益影响。本阶段I STTR将在短期犬实验中实现上述目标。成功完成这些目标的可交付成果将是针对迷走神经使用进行优化的电极阵列、植入迷走神经的手术策略以及针对对心脏产生有益副交感神经作用进行优化的刺激参数。这些产出将支持成功过渡到长期犬实验以及随后的临床试验和STTR第II和III阶段的商业化。由于患有心力衰竭的人数众多以及目前治疗方法的局限性，该项目的成功完成将对公众健康和福祉产生深远的积极影响。

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.