The overall goal of this project is to address the postulate that the optimal molecular signature for the common disorder obstructive sleep apnea (OSA) is change in relevant biomarkers during the sleep period. In sleep apnea, events lead to sleep fragmentation and cyclical deoxygenation/reoxygenation. It is proposed that these changes will lead to molecular consequences can be detected by assessing biomarkers in blood. To determine which changes are due to OSA and which to circadian/sleep mechanisms, studies will be done in patients with OSA before and after effective treatment with CPAP and also in controls of similar visceral adiposity without OSA.Multiple assessments of biomarkers will be made before, during and after sleep. Since it is proposed that the magnitude of these dynamic changes across the sleep period will be affected by degree of visceral obesity and be greater in OSA subjects with cardiovascular comorbidities, studies will be done in 4 groups of subjects: lean and obese with and without such morbidities. In assessing biomarkers the primary outcome variables will be: urinary isoprostanes (oxidative stress);plasma TNFa (inflammation); plasma norepinephrine (sympathetic activation);and free fatty acids. Secondary biomarkers will be: IL-6, urinary norepinephrine;urinary normetanephrine;glucose, ICAM, leptin. To complement assessment of circulating biomarkers, an approach utilizing a cellular window will be used. Monocytes will be separated from each blood sample (before, during and after sleep) and RNA extracted. Expression of key genes will be assessed by RT-PCR and microarray studies will be performed in a subset of subjects to assess changes in expression of all genes as a resuft of OSA.A particular focus will be investigating differences between individuals with OSA with and without cardiovascular comorbidities. Three aspects will be evaluated: a) whether individuals with comorbidities have more oxidative stress and inflammatory change for equivalent degrees of OSA than individuals without such comorbidities;b) whether individuals with comorbidities have lower levels of protective mechanisms?melatonin (an anti-oxidant secreted during sleep), IL-10 (anti- inflammatory);c) different gene variants based on a genetic association study using a recently developed CV SNP array. Finally, data will be used to determine whether there is a diagnostic urine and/or blood test for OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Bjornsdottir, Erla; Keenan, Brendan T; Eysteinsdottir, Bjorg et al. (2015) Quality of life among untreated sleep apnea patients compared with the general population and changes after treatment with positive airway pressure. J Sleep Res 24:328-38
Arnardottir, Erna S; Lim, Diane C; Keenan, Brendan T et al. (2015) Effects of obesity on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea Cohort. J Sleep Res 24:148-59
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
Iftikhar, Imran H; Valentine, Christopher W; Bittencourt, Lia R A et al. (2014) Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis. J Hypertens 32:2341-50; discussion 2350
Kim, Andrew M; Keenan, Brendan T; Jackson, Nicholas et al. (2014) Tongue fat and its relationship to obstructive sleep apnea. Sleep 37:1639-48
Kim, Jinyoung; Pack, Allan; Maislin, Greg et al. (2014) Prospective observation on the association of snoring with subclinical changes in carotid atherosclerosis over four years. Sleep Med 15:769-75
Brown, Marishka K; Chan, May T; Zimmerman, John E et al. (2014) Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis. Neurobiol Aging 35:1431-41
Sutherland, Kate; Schwab, Richard J; Maislin, Greg et al. (2014) Facial phenotyping by quantitative photography reflects craniofacial morphology measured on magnetic resonance imaging in Icelandic sleep apnea patients. Sleep 37:959-68
Chirinos, Julio A; Gurubhagavatula, Indira; Teff, Karen et al. (2014) CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 370:2265-75
Schwab, Richard J; Kim, C; Siegel, Lawrence et al. (2014) Examining the mechanism of action of a new device using oral pressure therapy for the treatment of obstructive sleep apnea. Sleep 37:1237-47

Showing the most recent 10 out of 23 publications