Mechanisms of Sleepiness Symptoms in Sleep Apnea and Cardiovascular Disease

描述（由申请人提供）：并非所有阻塞性睡眠呼吸暂停（OSA）患者在任何给定的疾病严重程度下都会出现白天嗜睡（EDS）或心血管疾病。OSA的不良后果可能由基因组、生物学和/或环境因素驱动，但机制尚不清楚。有必要确定遗传和生物学标记，以及它们如何影响OSA患者的EDS症状和心血管风险。我们的总体假设是嗜睡和心血管疾病的机制有共同的分子途径。因此，与嗜睡风险相关的遗传和生物因素可能预测个体发展不良心血管结果。在K99指导阶段，遗传标记及其与EDS症状的关系将通过正在进行的冰岛睡眠呼吸暂停队列（ISAC）的回顾性分析来确定。在转化研究方面的高级教学和实验室培训将补充这一分析，并建立在我之前在遗传学和生物标志物研究方面的经验之上。我们假设，不同频率的基因多态性，如NOX-2、NOX p22phox、肿瘤坏死因子- α (TNF-?)和PDE4D，将改变睡眠呼吸障碍程度相似的个体的嗜睡症状的程度。在R00期，将进行病例对照研究，进一步研究在K99期鉴定的相关遗传标记。我们将从宾夕法尼亚大学睡眠中心的临床人群中招募64名困倦和64名非困倦OSA患者，以确定升高的遗传和生物标记是否与困倦症状有关。我们的主要假设是，有EDS症状（主观测量）的患者将有增加的生物和遗传标记。第二个假设是，与没有症状的人相比，那些有EDS症状（主观和客观）的人会有更多的生物和遗传标记。本研究将招募因阻塞性睡眠呼吸暂停而寻求医疗照顾的个人。多导睡眠检查后将采集血样和尿样。EDS的症状也将通过Epworth嗜睡量表（ESS）和精神运动警觉性测试（PVT）来测量。心血管风险测量[动态血压（ABP）和脉搏波速度（PWV）]也将在此期间获得。我们假设EDS的症状与心血管风险增加有关。

DESCRIPTION (provided by applicant): Not all patients with obstructive sleep apnea (OSA) develop excessive daytime sleepiness (EDS) or cardiovascular disease at any given level of disease severity. Adverse outcomes of OSA may be driven by genomic, biological, and/or environmental factors, but mechanisms remain unclear. There is a need to determine genetic and biological markers and how they may influence EDS symptoms and cardiovascular risk among patients with OSA. Our overall hypothesis is that mechanisms of sleepiness and cardiovascular disease share common molecular pathways. Thus, genetic and biological factors associated with risk for sleepiness likely predict individuals who develop adverse cardiovascular outcomes. In the K99 mentored phase of the award, genetic markers and their relationship to EDS symptoms will be determined via retrospective analysis of the ongoing Icelandic Sleep Apnea Cohort (ISAC). Advanced didactic and laboratory training in translational research will complement this analysis and build upon my prior experience with genetics and biomarker research. We hypothesize that a different frequency of polymorphisms in genes such as NOX-2, NOX p22phox, tumor necrosis factor-alpha (TNF-?), and PDE4D, will modify the degree of sleepiness symptoms in individuals with similar degrees of sleep-disordered breathing. In the R00 phase, a case-control study will be conducted to investigate further the relevant genetic markers identified in the K99 phase. We will recruit 64 sleepy and 64 non-sleepy OSA patients from the clinic population at the Penn Sleep Center to determine whether elevated genetic and biological markers are related to sleepiness symptoms. Our primary hypothesis is that patients with EDS symptoms (measured subjectively) will have increased biological and genetic markers. The secondary hypothesis is that those with EDS symptoms (subjective and objectively) will have increased biological and genetic markers compared to those with neither symptoms. Individuals seeking medical attention for OSA will be recruited for the study. Blood and urine samples will be obtained after polysomnography. EDS symptoms will also be measured by using the Epworth Sleepiness Scale (ESS) and the Psychomotor Vigilance Test (PVT). Cardiovascular risk measures [ambulatory blood pressure (ABP) and Pulse-Wave Velocity (PWV)] will also be obtained at this time. We hypothesize that the symptoms of EDS are associated with increased cardiovascular risk measures.