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)发生在成年人口中近20%的男性和10%的女性，是心血管疾病和死亡的独立危险因素。尽管女性的患病率较低，但女性阻塞性睡眠呼吸暂停患者表现出比男性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，而且几乎没有治疗症状的临床指南，除了使用正压呼吸支持(PAP)；这种支持有助于呼吸，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。由于交感神经流出是由大脑调节的，OSA的间歇性低氧和其他特性导致神经损伤，可能是导致心血管后遗症的调节受损。我们在阻塞性睡眠呼吸暂停综合征患者中发现了这种损伤，同时许多脑区的心血管控制不足，包括岛叶皮质，这是一个整合了 更高的大脑处理和感觉输入来调节脑干和下丘脑的自主神经流出。我们的R21数据显示，女性OSA患者的岛叶皮质损伤和功能障碍程度甚至比男性OSA患者更大。因此，我们假设在OSA患者中，由于损伤，岛叶皮质功能受损，导致心血管调节不太有效，这些影响在女性OSA患者中尤其严重。我们将使用弥散张量成像评估大脑结构，使用功能磁共振成像(FMRI)评估脑功能，并在吸入性呼吸暂停、Valsalva动作和静态握手三种自主神经挑战期间通过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质亚区。我们将研究四个年龄匹配的组的144人：新诊断的阻塞性睡眠呼吸暂停综合征女性和疾病严重程度匹配的男性，以及健康对照女性和男性。将评估女性的更年期和荷尔蒙状况，目的是平衡绝经前和绝经后女性的数量，并将荷尔蒙因素纳入统计模型。在男性和女性中，这些发现将显示OSA是否发生了交感活动的神经调节中断，这种功能障碍是否与脑损伤平行，以及心血管反应是否也受到了损害。我们还将对15名男性和15名女性患者进行为期3个月的PAP治疗对自主神经功能影响的探索性评估，并收集证据证明自主中枢功能至少在短期内可以恢复。缺乏恢复将建议对PAP的其他治疗方法进行研究。OSA对女性更严重影响的研究结果将突显扩大OSA治疗的必要性，目前OSA治疗仅专注于解决中度和重度OSA的呼吸中断，而对女性轻度OSA通常被忽视，尽管有证据表明女性轻度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.