Obstructive Sleep Apnea, Gender Biology, and Autonomic Regulation

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）发生在成年人群中近20%的男性和10%的女性中，是心血管疾病和死亡的独立风险因素。尽管女性患病率较低，但女性OSA患者比男性患者表现出更严重的心血管和神经心理后果。与OSA相关的健康问题的原因尚不清楚，并且很少有临床指南用于治疗与气道正压通气（PAP）呼吸支持有关的症状;该支持有助于通气，但对恢复交感神经功能障碍几乎没有作用，这可能是导致高血压和其他心血管后遗症的一个因素。由于交感神经流出受大脑调节，因此对心血管后遗症的可能贡献是由于间歇性缺氧和OSA的其他特征引起的神经损伤而导致的调节受损。我们发现，阻塞性睡眠呼吸暂停综合征患者的这种损伤，以及许多脑区心血管控制的缺陷，包括岛叶皮质，这是一个整合 更高的大脑处理和感觉输入，以调节脑干和下丘脑自主神经流出。我们的R21数据显示，女性OSA患者比男性OSA患者具有更大程度的岛叶皮质损伤和功能障碍。因此，我们假设在OSA患者中，岛叶皮质由于损伤而功能受损，导致心血管调节效果较差，这些影响在女性OSA患者中尤其严重。我们将通过弥散张量成像评估大脑结构，通过功能性磁共振成像（fMRI）评估大脑功能，并通过三种自主挑战（吸气性呼吸暂停、Valsalva动作和静态握力）中的心率测量评估心血管功能。我们将从高分辨率MRI扫描中定位参与交感神经调制的岛叶皮层分区。我们将研究四个年龄匹配组的144人：新诊断的OSA女性和男性，疾病严重程度匹配，健康对照女性和男性。将评估女性的绝经和激素状态，目的是平衡绝经前和绝经后女性的数量，并在统计模型中纳入激素因素。在男性和女性中，研究结果将显示OSA中是否发生交感神经活动的神经调节中断，脑损伤是否会导致功能障碍，以及心血管反应性是否也受损。我们还将对15名男性和15名女性患者进行3个月PAP治疗对自主神经功能的影响进行探索性评估，并收集关于自主神经中枢功能是否可以恢复的证据，至少在短期内。缺乏恢复将表明应研究PAP的其他治疗。在女性中发现OSA的更差影响将强调需要扩大OSA治疗，目前仅关注解决中度和重度OSA的呼吸中断，并且通常忽略女性中的轻度OSA，尽管有证据表明女性中的轻度OSA伴有严重的心血管特征。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) occurs in close to 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe cardiovascular and neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and there are few clinical guidelines for treating symptoms other breathing support with positive airway pressure (PAP); that support assists ventilation, but does little to restore sympathetic dysfunction, one factor that likely contributes to hypertension and other cardiovascular sequelae in the syndrome. Since sympathetic outflow is regulated by the brain, a possible contribution to the cardiovascular sequelae is impaired regulation due to neural injury from the intermittent hypoxia and other characteristics of OSA. We showed such injury in OSA together with deficient cardiovascular control in many brain regions, including the insular cortex, an area that integrates higher brain processing and sensory input to modulate brainstem and hypothalamic autonomic outflow. Our R21 data show that female OSA patients have an even greater extent of insular cortex injury and dysfunction than male OSA patients. We therefore hypothesize that in OSA patients, the insular cortex has impaired function due to injury, resulting in less effective cardiovascular regulation, and these effects are especially severe in female OSA patients. We will evaluate brain structure with diffusion tensor imaging, brain function with functional magneti resonance imaging (fMRI), and cardiovascular function with heart rate measurements during three autonomic challenges, an inspiratory apnea, Valsalva maneuver, and static hand grip. We will localize the insular cortex subdivisions involved in sympathetic modulation from high-resolution MRI scans. We will study 144 people across four age-matched groups: newly-diagnosed OSA females and males matched for disease severity, and healthy control females and males. Females will be assessed for menopausal and hormonal status, with the aim of balancing the numbers of pre- and post-menopausal women, and including hormonal factors in statistical models. In males and females, the findings will show whether disrupted neural regulation of sympathetic activity occurs in OSA, whether that dysfunction is paralleled by brain injury, and whether cardiovascular responsiveness is also impaired. We will also perform an exploratory assessment of the effects of 3 months of PAP treatment on autonomic function in 15 male and 15 female patients, and gather evidence as to whether autonomic central function can recover, at least in the short term. A lack of recovery would suggest additional treatments to PAP should be investigated. Findings of worse effects of OSA in women would highlight the need to broaden OSA treatment, which currently solely focuses on resolving breathing disruptions for moderate and severe OSA, and is typically ignored in mild OSA in women, despite evidence that mild OSA in females is accompanied by severe cardiovascular characteristics.