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.

Public Health Relevance

The proposed project will uncover the mechanism of sleepiness symptoms in sleep apnea and how they relate to the risks of cardiovascular disease. The findings of this study will identify whether sleepiness is related to elevated genetic and biological markers for oxidative stress and inflammation, which subsequently increase the risk for cardiovascular disease. The results of this study will inform clinical practice by allowing for the identification of those who are in need of prevention of excessive daytime sleepiness to treat OSA at an early stage prior to sequelae such as sleepiness related motor vehicle accidents or cardiovascular events.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Career Transition Award (K99)
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Nursing Science Review Committee (NRRC)
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Tully, Lois
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University of Pennsylvania
Schools of Medicine
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Pak, Victoria M; Dai, Feng; Keenan, Brendan T et al. (2018) Lower plasma choline levels are associated with sleepiness symptoms. Sleep Med 44:89-96
Onen, Fannie; Lalanne, Christophe; Pak, Victoria M et al. (2016) A Three-Item Instrument for Measuring Daytime Sleepiness: The Observation and Interview Based Diurnal Sleepiness Inventory (ODSI). J Clin Sleep Med 12:505-12
Masterson Creber, Ruth; Pak, Victoria M; Varrasse, Miranda et al. (2016) Determinants of Behavioral Alertness in Adults with Heart Failure. J Clin Sleep Med 12:589-96
Pak, V M; Keenan, B T; Jackson, N et al. (2015) Adhesion molecule increases in sleep apnea: beneficial effect of positive airway pressure and moderation by obesity. Int J Obes (Lond) 39:472-9
Liu, Jianghong; Liu, Xianchen; Pak, Victoria et al. (2015) Early Blood Lead Levels and Sleep Disturbance in Preadolescence. Sleep 38:1869-74