Abstract
Excessive daytime sleepiness (EDS) is one of the most frequent symptoms in patients with obstructive sleep apnea syndrome (OSAS). However, not all patients with OSAS manifest EDS. The aim of this study was to assess whether differential circulatory levels of inflammatory mediators would account for differences in somnolence among patients with OSAS. Patients were prospectively recruited from referral patient cohort to the university hospital sleep center. A total of 50 consecutive patients with OSAS undergoing overnight polysomnography with or without EDS and 20 controls were evaluated. EDS was assessed using the Epworth sleepiness scale (ESS) and the multiple sleep latency test after overnight polysomnography. EDS was defined when the ESS was >10 and the mean sleep latency <10 min. Fasting blood was drawn in the morning after polysomnography. Circulating levels of tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), 8-isoprostaglandin F2α (8-iso-PGF2α), and P-selectin were measured with commercially available high sensitivity kits. Although patients with OSAS have elevated levels of ICAM-1, IL-6, and TNFα, there were no statistically significant differences in any of the inflammatory mediators between patients with EDS and without EDS. Emergence of EDS in the context of OSA does not appear to result from the selective increase of any particular somnogenic substance, i.e., TNFα, IL-6, ICAM-1, 8-iso-PGF2α, and P-selectin in the context of sleep-disordered breathing.
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References
Douglas NJ, Polo O (1994) Pathogenesis of obstructive sleep apnoea/hypopnoea syndrome (Review) (34 refs). Lancet 344(8923):653–655
Young T, Palta M, Dempsey J et al (1993) The occurrence of sleep-disordered breathing among middle-aged adults (see comment). N Engl J Med 328(17):1230–1235
Carrera M, Barbe F, Sauleda J et al (1999) Patients with obstructive sleep apnea exhibit genioglossus dysfunction that is normalized after treatment with continuous positive airway pressure. Am J Respir Crit Care Med 159(6):1960–1966
Young TB (2004) Epidemiology of daytime sleepiness: definitions, symptomatology, and prevalence. J Clin Psychiatry 65(Suppl 16):12–16
Findley LJ, Barth JT, Powers DC et al (1986) Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest 90(5):686–690
Aldrich MS (1989) Automobile accidents in patients with sleep disorders. Sleep 12(6):487–494
Findley LJ (1990) Automobile driving in sleep apnea. Prog Clin Biol Res 345:337–343
Beutler LE, Ware JC, Karacan I et al (1981) Differentiating psychological characteristics of patients with sleep apnea and narcolepsy. Sleep 4(1):39–47
Vgontzas AN, Bixler EO, Chrousos GP (2003) Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med 254(1):32–44
ICSD—Diagnostic Classification Committee, Thorpy MJ C, American sleep disorders Association (1990) International classification of sleep disorders: diagnostic and coding manual. Rochester, Minnesota
Newman AB, Spiekerman CF, Enright P et al (2000) Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group. J Am Geriatr Soc 48(2):115–123
Barbe F, Mayoralas LR, Duran J et al (2001) Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 134(11):1015–1023
Mastorakos G, Chrousos GP, Weber JS (1993) Recombinant interleukin-6 activates the hypothalamic–pituitary–adrenal axis in humans. J Clin Endocrinol Metab 77(6):1690–1694
Papanicolaou DA, Tsigos C, Oldfield EH et al (1996) Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? J Clin Endocrinol Metab 81(6):2303–2306
Entzian P, Linnemann K, Schlaak M et al (1996) Obstructive sleep apnea syndrome and circadian rhythms of hormones and cytokines. Am J Respir Crit Care Med 153(3):1080–1086
Vgontzas AN, Papanicolaou DA, Bixler EO et al (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 82(5):1313–1316
Vgontzas AN, Papanicolaou DA, Bixler EO et al (2000) Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 85(3):1151–1158
Vgontzas AN, Zoumakis E, Lin HM et al (2004) Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab 89(9):4409–4413
Yudkin JS, Kumari M, Humphries SE et al (2000) Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148(2):209–214
Marin JM, Carrizo SJ, Vicente E et al (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365(9464):1046–1053
Nieto FJ, Young TB, Lind BK et al (2000) Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283(14):1829–1836
Peker Y, Hedner J, Norum J et al (2002) Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 166(2):159–165
Peppard PE, Young T, Palta M et al (2000) Prospective study of the association between sleep-disordered breathing and hypertension (see comment). N Engl J Med 342(19):1378–1384
Shahar E, Whitney CW, Redline S et al (2001) Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study (see comment). Am J Respir Crit Care Med 163(1):19–25
Dean RT, Wilcox I (1993) Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep 16(8 Suppl):S15–S21
Hedner JA, WISCE (1994) Speculations on the interaction between vascular disease and obstructive sleep apnea. In: Dekker M (ed) Sleep and breathing. INC, New York
Lavie L (2003) Obstructive sleep apnoea syndrome—an oxidative stress disorder (comment) (Review) (130 refs). Sleep Med Rev 7(1):35–51
Schulz R, Mahmoudi S, Hattar K et al (2000) Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 162(2 Pt 1):566–570
Barcelo A, Miralles C, Barbe F et al (2000) Abnormal lipid peroxidation in patients with sleep apnoea. Eur Respir J 16(4):644–647
Awad JA, Morrow JD, Takahashi K et al (1993) Identification of non-cyclooxygenase-derived prostanoid (F2-isoprostane) metabolites in human urine and plasma. J Biol Chem 268(6):4161–4169
Roberts LJ, Morrow JD (2000) Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med 28(4):505–513
Schwedhelm E, Maas R, Troost R et al (2003) Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Clin Pharmacokinet 42(5):437–459
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695
Simonini A, Moscucci M, Muller DW et al (2000) IL-8 is an angiogenic factor in human coronary atherectomy tissue. Circulation 101(13):1519–1526
Haught WH, Mansour M, Rothlein R et al (1996) Alterations in circulating intercellular adhesion molecule-1 and L-selectin: further evidence for chronic inflammation in ischemic heart disease. Am Heart J 132(1 Pt 1):1–8
Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809
Pober JS, Bevilacqua MP, Mendrick DL et al (1986) Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 136(5):1680–1687
Chin K, Nakamura T, Shimizu K et al (2000) Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 109(7):562–567
El Solh AA, Mador MJ, Sikka P et al (2002) Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 121(5):1541–1547
Blankenberg S, Barbaux S, Tiret L (2003) Adhesion molecules and atherosclerosis. Atherosclerosis 170(2):191–203
Blann AD, McCollum CN (1998) Increased soluble P-selectin in peripheral artery disease: a new marker for the progression of atherosclerosis. Thromb Haemost 80(6):1031–1032
Ridker PM, Buring JE, Rifai N (2001) Soluble P-selectin and the risk of future cardiovascular events. Circulation 103(4):491–495
Carskadon MA, Dement WC, Mitler MM et al (1986) Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 9(4):519–524
Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14(6):540–545
Benbadis SR, Mascha E, Perry MC et al (1999) Association between the Epworth sleepiness scale and the multiple sleep latency test in a clinical population. Ann Intern Med 130(4 Pt 1):289–292
Ohga E, Nagase T, Tomita T et al (1999) Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol 87(1):10–14
Haddy N, Sass C, Droesch S et al (2003) IL-6, TNF-alpha and atherosclerosis risk indicators in a healthy family population: the STANISLAS cohort. Atherosclerosis 170(2):277–283
Rothlein R, Mainolfi EA, Czajkowski M et al (1991) A form of circulating ICAM-1 in human serum. J Immunol 147(11):3788–3793
Morisaki N, Saito I, Tamura K et al (1997) New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease. Atherosclerosis 131(1):43–48
Ridker PM, Hennekens CH, Roitman-Johnson B et al (1998) Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 351(9096):88–92
Zund G, Uezono S, Stahl GL et al (1997) Hypoxia enhances induction of endothelial ICAM-1: role for metabolic acidosis and proteasomes. Am J Physiol 273(5 Pt 1):C1571–C1580
Blann AD, Steele C, McCollum CN (1997) The influence of smoking on soluble adhesion molecules and endothelial cell markers. Thromb Res 85(5):433–438
Ponthieux A, Herbeth B, Droesch S et al (2004) Biological determinants of serum ICAM-1, E-selectin, P-selectin and L-selectin levels in healthy subjects: the Stanislas study. Atherosclerosis 172(2):299–308
Bokinsky G, Miller M, Ault K et al (1995) Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 108(3):625–630
Eisensehr I, Ehrenberg BL, Noachtar S et al (1998) Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome. Neurology 51(1):188–195
Geiser T, Buck F, Meyer BJ et al (2002) In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 69(3):229–234
Hui DS, Ko FW, Fok JP et al (2004) The effects of nasal continuous positive airway pressure on platelet activation in obstructive sleep apnea syndrome. Chest 125(5):1768–1775
Sanner BM, Konermann M, Tepel M et al (2000) Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 16(4):648–652
von Kanel R, Dimsdale JE (2003) Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease. Chest 124(5):1956–1967
Robinson GV, Pepperell JC, Segal HC et al (2004) Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 59(9):777–782
Olson LJ, Olson EJ, Somers VK (2004) Obstructive sleep apnea and platelet activation: another potential link between sleep-disordered breathing and cardiovascular disease. Chest 126(2):339–341
Papanicolaou DA, Wilder RL, Manolagas SC et al (1998) The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 128(2):127–137
Biasucci LM, Vitelli A, Liuzzo G et al (1996) Elevated levels of interleukin-6 in unstable angina. Circulation 94(5):874–877
Carpagnano GE, Kharitonov SA, Resta O et al (2002) Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients. Chest 122(4):1162–1167
Yokoe T, Minoguchi K, Matsuo H et al (2003) Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 107(8):1129–1134
Inoue Ki, Takano H, Yoshikawa T et al (2003) Interleukin-6, Obstructive Sleep Apnea, and Obesity. Chest 124(4):1621–162a
Teramoto S, Yamamoto H, Ouchi Y (2003) Increased C-reactive protein and increased plasma interleukin-6 may synergistically affect the progression of coronary atherosclerosis in obstructive sleep apnea syndrome. Circulation 107(5):E40
Tauman R, Ivanenko A, O’Brien LM et al (2004) Plasma C-reactive protein levels among children with sleep-disordered breathing. Pediatrics 113(6):e564–e569
Bauer J, Hohagen F, Ebert T et al (1994) Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle. Clin Investig 72(4):315
De Simoni MG, De Luigi A, Gemma L et al (1993) Modulation of systemic interleukin-6 induction by central interleukin-1. Am J Physiol Regul Integr Comp Physiol 265(4):R739–R742
Opp MR (2002) Cytokines and sleep promotion: a potential mechanism for disorders of excessive daytime sleepiness. In: Pack AI (ed) Sleep apnea: pathogenesis, diagnosis, and treatment. Dekker, New York, pp 327–352
Vgontzas AN, Papanicolaou DA, Bixler EO et al (1999) Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 84(8):2603–2607
Vgontzas AN, Zoumakis E, Bixler EO et al (2004) Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 89(5):2119–2126
Vgontzas AN, Papanicolaou DA, Bixler EO et al (1999) Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 84(8):2603–2607
Fang J, Wang Y, Krueger JM (1997) Mice lacking the TNF 55 kDa receptor fail to sleep more after TNFalpha treatment. J Neurosci 17(15):5949–5955
Takahashi S, Kapas L, Krueger JM (1996) A tumor necrosis factor (TNF) receptor fragment attenuates TNF-alpha- and muramyl dipeptide-induced sleep and fever in rabbits. J Sleep Res 5(2):106–114
Minoguchi K, Tazaki T, Yokoe T et al (2004) Elevated production of tumor necrosis factor-α by monocytes in patients with obstructive sleep apnea syndrome. Chest 126(5):1473–1479
Row BW, Liu R, Xu W et al (2003) Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 167(11):1548–1553
Zhan G, Serrano F, Fenik P et al (2005) NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 172(7):921–929
Yamauchi M, Nakano H, Maekawa J et al (2005) Oxidative stress in obstructive sleep apnea. Chest 127(5):1674–1679
Morrow JD, Hill KE, Burk RF et al (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A 87(23):9383–9387
Janssen LJ (2000) Isoprostanes: generation, pharmacology, and roles in free-radical-mediated effects in the lung. Pulm Pharmacol Ther 13(4):149–155
Dworski D, Jackson L, Roberts L et al (2001) Assessment of oxidant stress in allergic asthma by measurement of the major urinary metabolite of F2-isoprostane, 15-F2t-IsoP (8-iso-PGF2). Clin Exp Allergy 31(3):387
Pratico D, Basili S, Vieri M et al (1998) Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 158(6):1709–1714
Montuschi P, Ciabattoni G, Paredi P et al (1998) 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am J Respir Crit Care Med 158(5 Pt 1):1524–1527
Acknowledgment
This study was supported by grants from the National Institutes of Health HL65270, The Children’s Foundation Endowment for Sleep Research, the Commonwealth of Kentucky Challenge for Excellence Trust Fund to DG, the Fondo de Investigaciones Sanitarias from Spain (02/0334, 04/1593 and CM-0300049), and by Red Respira (RTIC 03/11) to FB.
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The work was performed in Hospital Universitario Son Dureta and Kosair Children’s Hospital Research Institute.
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Bravo, M., Serpero, L.D., Barceló, A. et al. Inflammatory proteins in patients with obstructive sleep apnea with and without daytime sleepiness. Sleep Breath 11, 177–185 (2007). https://doi.org/10.1007/s11325-007-0100-7
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DOI: https://doi.org/10.1007/s11325-007-0100-7