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

摘要 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， 由于除了持续气道正压通气（CPAP）之外的治疗选择很少，因此仍然治疗不足。 替代治疗是可用的，如下颌前移装置（MAD）和舌下神经 刺激（HGNS）。然而，这些治疗并不总是有效的，成功的预测因素是 不太了解或者很难获得。此外，这些治疗失败的患者往往得不到治疗 因此易受OSA临床后果的影响。 在上一个资助期，我们开发了估计肿瘤病理生理学内型的方法， OSA（咽部可吸收性、环路增益、咽肌补偿和唤醒阈值），以及 根据临床多导睡眠图，气道塌陷的主要部位（腭、舌、侧壁、会厌） （PSG）。该基金的目的是将这些方法应用于1）寻找MAD和HGNS反应的预测因子 和2）在MAD和HGNS无应答者中测试内型特异性药物疗法。我们的假设是 这些内型/塌陷部位（由PSG确定）是MAD和HGNS的重要预测因子 反应我们还假设，添加靶向异常内型的药物，高环路 增益，可用于更有效地治疗MAD和HGNS无应答者。 在前两个目标中，将从生理学内型和塌陷部位来确定。 临床PSG使用的方法在以前的资助周期开发。然后患者将接受MAD（目标1） 或HGNS（Aim 2）疗法。将进行随访PSG以评估治疗的成功率。使用 多变量逻辑回归，将确定成功的重要生理预测因子。 在目标3中，在先前目标中MAD或HGNS失败的患者中，约有三分之一 个体，将用靶向最异常的内型的药物（用于高环增益的乙酰唑胺， 阿托莫西汀加奥昔布宁治疗咽肌代偿不良，或曲唑酮治疗低觉醒 阈值）。最近的证据表明，这些药物可以操纵内型。药物将 与MAD或HGNS治疗同时施用（组合疗法）。 目的1和目的2期望找到MAD和HGNS反应的重要生理预测因子， 分别使用从临床PSG导出的新度量。目标3预计将提供原理证明 对于治疗MAD和HGNS失败的药物方法， 治疗方案。最终，这些研究有可能改善非CPAP患者的选择 替代品和扩大OSA的治疗选择。

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.