Subcutaneous nerve stimulation for arrhythmia control.

本研究项目的具体目标是检验Medtronic InterStim II 与3889 SNS电极导线耦合的神经刺激器可用于皮下神经刺激（SCNS）， 在犬模型中实现心房颤动（AF）的节律和速率控制。如果犬类研究成功， 我们将进行试点临床试验，以促进房颤和快速心室反应患者的心率控制。 最终目标是激励Medtronic Inc.为FDA批准SCNS进行额外的临床研究 作为管理AF的标签适应症。本研究响应RFA-RM-16-027，因为它将利用 现有的市场认可技术用于新的市场适应症。房颤是最常见的心律失常 在发达国家，这与死亡率和发病率的显著增加有关。用药 AF的频率和节律控制并不是一致成功的，并且可能与显著的副作用有关。 房室（AV）结导管消融是药物难治性心律失常患者心率控制的一种选择。 AF和快速心室反应。然而，房室结消融使患者起搏器依赖。是 非常需要开发一种用于AF控制而不使用药物或消融程序的替代方法。 组织学研究表明皮肤受交感神经支配。在狗中， 颈部和胸部的交感神经纤维主要来自星状神经节（SG）。我们的初步 研究表明，来自胸部不同部位的皮下神经刺激（SCNS）可损伤SG 减少SG神经活动（SGNA）。这些发现提出了一个令人兴奋的可能性， 可以降低SGNA以提供AF的速率和节律控制。拥有一批 FDA批准的用于疼痛和排尿控制的神经刺激器。本研究的目的是测试 假设InterStim II神经刺激器和3889 SNS电极导线可有效用于SCNS 如果结果令人鼓舞，有可能促使美敦力申办试点临床研究。 并将这些发现应用到人类患者身上。我们提出以下具体目标： 在各种输出下执行SCNS，以测试输出的大小在以下方面很重要的假设： 确定神经调节的效果。具体而言，高输出刺激导致SG损伤， 降低交感神经张力，而极低输出量的SCNS可引起SG和心神经出芽， 增加了交感神经张力。具体目标2：检验SCNS在高输出下有效的假设 在很低输出时AF的频率和节律控制是有帮助的。如果SG损坏是 SCNS的抗肿瘤作用的机制，那么它遵循高输出SCNS是必要的， 并足以产生抗肿瘤作用。另一方面，如果非常低的输出SCNS导致神经 发芽并增加交感神经张力，那么低输出刺激应该是预防性的。我们将使用一个 犬模型的阵发性和持续性房颤，以测试这些假设。

The specific goal of this research project is to test the hypothesis that the Medtronic InterStim II Neurostimulator coupled with 3889 SNS Leads can be used for subcutaneous nerve stimulation (SCNS) to achieve rhythm and rate control of atrial fibrillation (AF) in a canine model. If the canine studies are successful, we will perform pilot clinical trials to facilitate rate control in patients with AF and rapid ventricular responses. The ultimate goal is to motivate Medtronic Inc. to perform additional clinical studies for FDA approval of SCNS as a labeled indication for managing AF. The study is responsive to the RFA-RM-16-027 because it will utilize existing market-approved technology for new market indications. AF is the most common cardiac arrhythmias in developed countries, and is associated with significantly increased mortality and morbidity. Drugs used for rate and rhythm control of AF are not uniformly successful and may be associated with significant side effects. Catheter ablation of the atrioventricular (AV) node is an option for rate control in patients with drug-refractory AF and rapid ventricular responses. However, AV node ablation makes the patient pacemaker dependent. It is highly desirable to develop an alternative method for AF control without the use drugs or ablation procedures. Histological studies showed that skin is well innervated by sympathetic nerves. In dogs, the postganglionic sympathetic nerve fibers of neck and thorax come primarily from the stellate ganglion (SG). Our preliminary studies showed that subcutaneous nerve stimulation (SCNS) from different sites in the thorax can damage SG and reduce SG nerve activity (SGNA). These findings suggest an exciting possibility that electrical stimulation of the skin may reduce SGNA to provide both rate and rhythm control of AF. Medtronic Inc. has a number of neurostimulators approved by FDA for pain and urinary control. The purpose of the present study was to test the hypothesis that the InterStim II Neurostimulator and the 3889 SNS Leads can be used effectively for SCNS and control AF. If the results are promising, it is possible to motivate Medtronic to sponsor pilot clinical studies and translate these findings to human patients. We propose the following specific aims: Specific Aim 1: To perform SCNS at various outputs to test the hypotheses that the magnitudes of output is important in determining the effects of neuromodulation. Specifically, high output stimulation causes SG damage and reduce sympathetic tone while very low output SCNS can cause SG and cardiac nerve sprouting, thus increasing the sympathetic tone. Specific Aim 2: To test the hypothesis that SCNS at high output is effective in rate and rhythm control of AF while at very low output is proarrhythmic. If SG damage underlies the mechanisms of the antiarrhythmic effects of SCNS, then it follows that high output SCNS is both necessary and sufficient to generate antiarrhythmic effects. On the other hand, if very low output SCNS causes nerve sprouting and increases sympathetic tone, then low output stimulation should be proarrhythmic. We will use a canine model of paroxysmal and persistent AF to test these hypotheses.