Mechanisms of Sleepiness Symptoms in Sleep Apnea and Cardiovascular Disease

睡眠呼吸暂停和心血管疾病中嗜睡症状的机制

• 批准号: 8743828
• 负责人: Victoria M Pak
• 金额: $ 8.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743828
• 关键词: Adult; Age; Antioxidants; Apnea; Area; Award; Biological; Biological Factors; Biological Markers; Blood; Blood Pressure; Breathing; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Clinic; Clinical Investigator; Cognitive; Comorbidity; Complement; Disease; Environmental Risk Factor; Event; Excessive Daytime Sleepiness; Exercise; F2-Isoprostanes; Frequencies; Gender; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomics; Genotype; Goals; Hour; Impairment; Individual; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Laboratories; Lead; Measures; Mentors; Molecular; Newly Diagnosed; Obstructive Sleep Apnea; Outcome; Oxidative Stress; Pathway interactions; Patients; Phase; Phenotype; Physiologic pulse; Physiology; Polysomnography; Population; Predisposition; Prevention; Quality of life; Recruitment Activity; Research; Risk; Risk Reduction; Sampling; Severities; Severity of illness; Single Nucleotide Polymorphism; Sleep; Sleep Apnea Syndromes; Smoking; Social Work; Staging; Symptoms; TNF gene; Testing; Time; Training; Translational Research; Tumor Necrosis Factor-alpha; Urine; Woman; adverse outcome; base; cardiovascular disorder risk; cardiovascular risk factor; case control; clinical practice; cohort; experience; genetic risk factor; human CYBA protein; indexing; interest; medical attention; men; public health relevance; urinary; vehicular accident; vigilance

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.

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上都会出现日间过度嗜睡(EDS)或心血管疾病。OSA的不良后果可能由基因组、生物和/或环境因素驱动，但机制尚不清楚。有必要确定遗传和生物标志物，以及它们如何影响阻塞性睡眠呼吸暂停综合征患者的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共享共同的分子途径。因此，与嗜睡风险相关的遗传和生物因素可能会预测出现不良心血管后果的个体。在该奖项的K99指导阶段，遗传标记及其与EDS症状的关系将通过对正在进行的冰岛睡眠呼吸暂停队列(ISAC)的回顾分析来确定。翻译研究方面的高级教学和实验室培训将补充这一分析，并建立在我以前的遗传学和生物标记研究经验的基础上。我们假设，NOX-2、NOX p22Phox、肿瘤坏死因子-α(TNF-α)和PDE4D等基因的不同频率的多态性将改变睡眠呼吸紊乱程度相似的个体的嗜睡症状的程度。在R00阶段，将进行病例对照研究，以进一步调查在K99阶段发现的相关遗传标记。我们将从宾夕法尼亚睡眠中心的临床人群中招募嗜睡和不嗜睡的阻塞性睡眠呼吸暂停患者，以确定遗传和生物标记物升高是否与嗜睡症状有关。我们的主要假设是，有EDS症状的患者(主观测量)将有更多的生物和遗传标记。第二种假设是，与没有任何症状的人相比，那些有EDS症状的人(主观和客观)将有更多的生物和遗传标记。这项研究将招募为阻塞性睡眠呼吸暂停综合症寻求医疗护理的个人。多导睡眠监测后将采集血样和尿样。还将使用爱普沃斯嗜睡量表(ESS)和精神运动警觉性测试(PVT)来衡量EDS症状。心血管风险测量[动态血压(ABP)和脉搏波速度(PWV)]也将在此时获得。我们假设EDS的症状与心血管风险措施的增加有关。

项目成果

Candidate gene analysis in the São Paulo Epidemiologic Sleep Study (EPISONO) shows an association of variant in PDE4D and sleepiness.

圣保罗流行病学睡眠研究 (EPISONO) 的候选基因分析显示 PDE4D 变异与嗜睡之间存在关联。

• DOI: 10.1016/j.sleep.2017.12.010
• 发表时间: 2018
• 期刊: Sleep medicine
• 影响因子: 4.8
• 作者: Pak,VictoriaM;Mazzotti,DiegoR;Keenan,BrendanT;Hirotsu,Camila;Gehrman,Philip;Bittencourt,Lia;Pack,AllanI;Tufik,Sergio
• 通讯作者: Tufik,Sergio

A Three-Item Instrument for Measuring Daytime Sleepiness: The Observation and Interview Based Diurnal Sleepiness Inventory (ODSI).

• DOI: 10.5664/jcsm.5676
• 发表时间: 2016-04
• 期刊: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
• 作者: F. Onen;Christophe Lalanne;Victoria M Pak;N. Gooneratne;B. Falissard;S. Onen