Predicting response to non-PAP therapies in OSA using PSG-derived endotypes

使用 PSG 衍生的内型预测 OSA 对非 PAP 疗法的反应

• 批准号: 10440108
• 负责人: DAVID ANDREW WELLMAN
• 金额: $ 81.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440108
• 关键词: Acetazolamide; Address; Algorithms; Anterior; Apnea; Arousal; Clinical; Combined Modality Therapy; Continuous Positive Airway Pressure; Data; Development; Devices; Disease; Drug Targeting; Effectiveness; Electric Stimulation; Epiglottis structure; Failure; Financial compensation; Goals; Grant; Health; Hypoglossal nerve structure; Individual; Intelligence; Lateral; Left; Logistic Regressions; Mandibular Advancement; Measurement; Measures; Methods; Mission; Movement; National Heart, Lung, and Blood Institute; Obstruction; Obstructive Sleep Apnea; Outcome; Palate; Patient Selection; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Physiology; Public Health; Research; Residual state; Severities; Signal Transduction; Site; Sleep; Sleep Disorders; System; Techniques; Testing; Therapeutic; Tongue; Trazodone; United States National Institutes of Health; Work; alternative treatment; atomoxetine; base; common treatment; effective therapy; follow-up; hyoepiglottic ligament; improved; novel; outcome prediction; oxybutynin; pharynx muscle; pilot test; predicting response; prevent; respiratory; response; success; trait; treatment choice; treatment response; treatment strategy

ABSTRACT Obstructive Sleep Apnea (OSA) is a common disorder with serious health consequences that often remains undertreated due to few therapeutic options beyond continuous positive airway pressure (CPAP). Alternative treatments are available, such as mandibular advancement devices (MADs) and hypoglossal nerve stimulation (HGNS). However, these treatments are not always effective, and the predictors of success are poorly understood or difficult to obtain. Furthermore, patients who fail these therapies are often left untreated and therefore susceptible to the clinical consequences of OSA. In the previous grant period, we developed methods for estimating the pathophysiological endotypes of OSA (pharyngeal collapsibility, loop gain, pharyngeal muscle compensation, and arousal threshold), as well as the primary site of airway collapse (palate, tongue, lateral walls, epiglottis), from the clinical polysomnogram (PSG). The objective of this grant is to apply these methods to 1) find predictors of MAD and HGNS response and 2) test endotype-specific pharmacotherapies in MAD and HGNS non-responders. Our hypothesis is that these endotypes/sites of collapse, as determined from the PSG, are important predictors of MAD and HGNS response. We also hypothesize that the addition of a drug targeting an abnormal endotype, e.g., high loop gain, can be used to more effectively treat MAD and HGNS non-responders. In the first two aims, the physiological endotypes and sites of collapse will be determined from the clinical PSG using the methods developed in the previous grant cycle. Patients will then undergo MAD (Aim 1) or HGNS (Aim 2) therapy. A follow-up PSG will be performed to evaluate the success of treatment. Using multivariable logistic regression, the significant physiological predictors of success will be determined. In Aim 3, the patients who fail MAD or HGNS in the previous aims, approximately one-third of individuals, will be treated with a drug targeting the most abnormal endotype (acetazolamide for high loop gain, atomoxetine-plus-oxybutynin for poor pharyngeal muscle compensation, or trazodone for low arousal threshold). Recent evidence suggests that these drugs can manipulate the endotypes. The drug will be administered concurrently with MAD or HGNS treatment (combination therapy). Aims 1 and 2 are expected to find the important physiological predictors of MAD and HGNS response, respectively, using novel metrics derived from the clinical PSG. Aim 3 is expected to provide proof-of-principle for a pharmacologic approach to treating MAD and HGNS failures, patients who otherwise have limited treatment options. Ultimately, these studies have the potential to improve patient selection for non-CPAP alternatives and broaden the treatment options for OSA.

抽象的 阻塞性睡眠呼吸暂停（OSA）是一种常见的疾病，具有严重的健康后果 由于持续正气道压力（CPAP）以外的治疗选择很少，因此仍未治疗。 提供替代性治疗，例如下颌前进设备（MAD）和腹神经 刺激（HGN）。但是，这些治疗并不总是有效的，成功的预测因素是 不理解或难以获得。此外，这些疗法失败的患者通常不受治疗 因此容易受到OSA的临床后果的影响。 在上一个赠款期间，我们开发了估算病理生理内型的方法 OSA（咽可折叠，循环增益，咽部肌肉补偿和唤醒阈值）以及 来自临床多聚词图 （PSG）。这笔赠款的目的是将这些方法应用于1）查找MAD和HGN响应的预测指标 2）MAD和HGN非反应者中测试内型特异性药物治疗。我们的假设是 根据PSG确定的这些内型/倒塌部位是MAD和HGN的重要预测指标 回复。我们还假设添加靶向异常内型的药物，例如高环 增益可用于更有效地治疗MAD和HGN非反应者。 在前两个目标中，生理内部型和崩溃部位将从 使用上一个赠款周期中开发的方法的临床PSG。然后，患者会发疯（AIM 1） 或HGNS（AIM 2）疗法。将进行后续PSG以评估治疗的成功。使用 多变量逻辑回归，将确定成功的重要生理预测指标。 在AIM 3中，在以前的目标中发疯或HGN的患者大约是三分之一 个体将使用靶向最异常内型的药物（乙酰唑胺可获得高环的增益， 阿诺西汀 - 加氧布丁氏素可用于不良咽部肌肉补偿，或曲唑酮用于低唤醒 临界点）。最近的证据表明，这些药物可以操纵内型。该药物将是 与MAD或HGNS治疗（联合疗法）同时管理。 目的1和2有望找到MAD和HGNS反应的重要生理预测因子， 分别使用源自临床PSG的新型指标。 AIM 3有望提供原理证明 对于治疗疯狂和HGN失败的药理方法，否则限制的患者 治疗选择。最终，这些研究有可能改善非CPAP的患者选择 替代方案并扩大OSA的治疗选择。