Obstructive Sleep Apnea: Role of Intermittent Hypoxia and Inflammation

Anna M. May; Reena Mehra

doi:10.1055/s-0034-1390023

Seminars in Respiratory and Critical Care Medicine, Inhaltsverzeichnis

Semin Respir Crit Care Med 2014; 35(05): 531-544
DOI: 10.1055/s-0034-1390023

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Obstructive Sleep Apnea: Role of Intermittent Hypoxia and Inflammation

Anna M. May

¹Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Cleveland, Ohio

,

Reena Mehra

²Neurologic Institute, Respiratory Institute, Heart and Vascular Institute and Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Research University, Cleveland Clinic Foundation, Cleveland, Ohio

› Institutsangaben

Abstract

Obstructive sleep apnea results in intermittent hypoxia via repetitive upper airway obstruction leading to partial or complete upper airway closure, apneas and hypopneas, respectively. Intermittent hypoxia leads to sympathetic nervous system activation and oxidative stress with a resultant systemic inflammatory cascade. The putative mechanism by which obstructive sleep apnea has been linked to numerous pathologic conditions including stoke, cardiovascular disease, hypertension, and metabolic derangements is through these systemic effects. Treatment of obstructive sleep apnea appears to reduce systemic markers of inflammation and ameliorates the adverse sequelae of this disease.

Keywords

obstructive sleep apnea - inflammation - intermittent hypoxia - sympathetic nervous system activation

Volltext

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References
1 Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999; 22 (5) 667-689
2 Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013; 177 (9) 1006-1014
3 Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ 2009; 108 (5) 246-249
4 Jennum P, Riha RL. Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing. Eur Respir J 2009; 33 (4) 907-914
5 Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR. Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study. Sleep Med 2010; 11 (5) 441-446
6 Quintana-Gallego E, Carmona-Bernal C, Capote F , et al. Gender differences in obstructive sleep apnea syndrome: a clinical study of 1166 patients. Respir Med 2004; 98 (10) 984-989
7 Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004; 291 (16) 2013-2016
8 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000; 284 (23) 3015-3021
9 Li KK, Kushida C, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome: a comparison between Far-East Asian and white men. Laryngoscope 2000; 110 (10, Pt 1) 1689-1693
10 Bixler EO, Vgontzas AN, Lin HM , et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001; 163 (3, Pt 1) 608-613
11 Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003; 167 (9) 1181-1185
12 Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev 2000; 4 (6) 583-602
13 Mehra R, Xu F, Babineau DC , et al. Sleep-disordered breathing and prothrombotic biomarkers: cross-sectional results of the Cleveland Family Study. Am J Respir Crit Care Med 2010; 182 (6) 826-833
14 Mody P, Rukhadze I, Kubin L. Rats subjected to chronic-intermittent hypoxia have increased density of noradrenergic terminals in the trigeminal sensory and motor nuclei. Neurosci Lett 2011; 505 (2) 176-179
15 Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L. Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med 2010; 182 (10) 1321-1329
16 Prabhakar NR, Kumar GK. Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem 2004; 385 (3-4) 217-221
17 Kumar GK, Rai V, Sharma SD , et al. Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress. J Physiol 2006; 575 (Pt 1) 229-239
18 Souvannakitti D, Kumar GK, Fox A, Prabhakar NR. Contrasting effects of intermittent and continuous hypoxia on low O(2) evoked catecholamine secretion from neonatal rat chromaffin cells. Adv Exp Med Biol 2009; 648: 345-349
19 Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993; 103 (6) 1763-1768
20 Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176 (7) 706-712
21 Rossi VA, Stradling JR, Kohler M. Effects of obstructive sleep apnoea on heart rhythm. Eur Respir J 2013; 41 (6) 1439-1451
22 Can M, Açikgöz S, Mungan G , et al. Serum cardiovascular risk factors in obstructive sleep apnea. Chest 2006; 129 (2) 233-237
23 Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome. Int Heart J 2005; 46 (5) 801-809
24 Shamsuzzaman AS, Winnicki M, Lanfranchi P , et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002; 105 (21) 2462-2464
25 Yokoe T, Minoguchi K, Matsuo H , et al. 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 2003; 107 (8) 1129-1134
26 Barceló A, Barbé F, Llompart E , et al. Effects of obesity on C-reactive protein level and metabolic disturbances in male patients with obstructive sleep apnea. Am J Med 2004; 117 (2) 118-121
27 Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleep-disordered breathing. Sleep 2004; 27 (8) 1507-1511
28 Ryan S, Nolan GM, Hannigan E, Cunningham S, Taylor C, McNicholas WT. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity. Thorax 2007; 62 (6) 509-514
29 Taheri S, Austin D, Lin L, Nieto FJ, Young T, Mignot E. Correlates of serum C-reactive protein (CRP)—no association with sleep duration or sleep disordered breathing. Sleep 2007; 30 (8) 991-996
30 Steiropoulos P, Tsara V, Nena E , et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007; 132 (3) 843-851
31 Akashiba T, Akahoshi T, Kawahara S, Majima T, Horie T. Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome. Intern Med 2005; 44 (8) 899-900
32 Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004; 28 (2) 87-91
33 Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008; 134 (4) 686-692
34 Minoguchi K, Tazaki T, Yokoe T , et al. Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 2004; 126 (5) 1473-1479
35 Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006; 174 (7) 824-830
36 Alzoghaibi MA, Bahammam AS. Lipid peroxides, superoxide dismutase and circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: a pilot study. Sleep Breath 2005; 9 (3) 119-126
37 Li C, Zhang XL, Liu H, Wang ZG, Yin KS. Association among plasma interleukin-18 levels, carotid intima- media thickness and severity of obstructive sleep apnea. Chin Med J (Engl) 2009; 122 (1) 24-29
38 Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol (1985) 2003; 94 (1) 179-184
39 Mehra R, Storfer-Isser A, Kirchner HL , et al. Soluble interleukin 6 receptor: A novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med 2006; 166 (16) 1725-1731
40 Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997; 82 (5) 1313-1316
41 El-Solh AA, Mador MJ, Sikka P, Dhillon RS, Amsterdam D, Grant BJ. Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 2002; 121 (5) 1541-1547
42 Ohga E, Nagase T, Tomita T , et al. Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol (1985) 1999; 87 (1) 10-14
43 Ursavaş A, Karadağ M, Rodoplu E, Yilmaztepe A, Oral HB, Gözü RO. Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome. Respiration 2007; 74 (5) 525-532
44 Zamarrón-Sanz C, Ricoy-Galbaldon J, Gude-Sampedro F, Riveiro-Riveiro A. Plasma levels of vascular endothelial markers in obstructive sleep apnea. Arch Med Res 2006; 37 (4) 552-555
45 Chin K, Nakamura T, Shimizu K , et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000; 109 (7) 562-567
46 Robinson GV, Pepperell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 2004; 59 (9) 777-782
47 Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995; 108 (3) 625-630
48 Eisensehr I, Ehrenberg BL, Noachtar S , et al. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome. Neurology 1998; 51 (1) 188-195
49 Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff C, Zidek W. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000; 16 (4) 648-652
50 Chin K, Ohi M, Kita H , et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996; 153 (6, Pt 1) 1972-1976
51 Peled N, Kassirer M, Kramer MR , et al. Increased erythrocyte adhesiveness and aggregation in obstructive sleep apnea syndrome. Thromb Res 2008; 121 (5) 631-636
52 Phillips CL, McEwen BJ, Morel-Kopp MC , et al. Effects of continuous positive airway pressure on coagulability in obstructive sleep apnoea: a randomised, placebo-controlled crossover study. Thorax 2012; 67 (7) 639-644
53 von Känel R, Natarajan L, Ancoli-Israel S , et al. Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea. Sleep Med 2013; 14 (1) 58-65
54 Wessendorf TE, Thilmann AF, Wang YM, Schreiber A, Konietzko N, Teschler H. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000; 162 (6) 2039-2042
55 Nannapaneni S, Ramar K, Surani S. Effect of obstructive sleep apnea on type 2 diabetes mellitus: A comprehensive literature review. World J Diabetes 2013; 4 (6) 238-244
56 Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol 1999; 19 (4) 972-978
57 Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta 2013; 417: 80-84
58 Polotsky VY, Li J, Punjabi NM , et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 2003; 552 (Pt 1) 253-264
59 Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 2011; 19 (11) 2167-2174
60 Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000; 118 (3) 580-586
61 Cuhadaroğlu C, Utkusavaş A, Oztürk L, Salman S, Ece T. Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea. Lung 2009; 187 (2) 75-81
62 Chin K, Shimizu K, Nakamura T , et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999; 100 (7) 706-712
63 Iiyori N, Alonso LC, Li J , et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007; 175 (8) 851-857
64 Chan SL, Perrett CW, Morgan NG. Differential expression of alpha 2-adrenoceptor subtypes in purified rat pancreatic islet A- and B-cells. Cell Signal 1997; 9 (1) 71-78
65 Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (1985) 2009; 106 (5) 1538-1544
66 Furukawa S, Fujita T, Shimabukuro M , et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114 (12) 1752-1761
67 Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (1985) 2009; 106 (5) 1538-1544
68 Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 2009; 122 (12) 1122-1127
69 Strohl KP, Novak RD, Singer W , et al. Insulin levels, blood pressure and sleep apnea. Sleep 1994; 17 (7) 614-618
70 Vgontzas AN, Papanicolaou DA, Bixler EO , et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85 (3) 1151-1158
71 Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165 (5) 670-676
72 Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE. Sleep Heart Health Study Investigators. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004; 160 (6) 521-530
73 Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 2005; 172 (12) 1590-1595
74 Togeiro SM, Carneiro G, Ribeiro Filho FF , et al. Consequences of obstructive sleep apnea on metabolic profile: a Population-Based Survey. Obesity (Silver Spring) 2013; 21 (4) 847-851
75 Stamatakis K, Sanders MH, Caffo B , et al. Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. Sleep 2008; 31 (7) 1018-1024
76 Iftikhar IH, Khan MF, Das A, Magalang UJ. Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc 2013; 10 (2) 115-120
77 West SD, Nicoll DJ, Wallace TM, Matthews DR, Stradling JR. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007; 62 (11) 969-974
78 Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007; 29 (4) 720-727
79 Vgontzas AN, Zoumakis E, Bixler EO , et al. Selective effects of CPAP on sleep apnoea-associated manifestations. Eur J Clin Invest 2008; 38 (8) 585-595
80 Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest 1982; 69 (6) 1286-1292
81 Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens 1997; 15 (12, Pt 2) 1593-1603
82 Iturriaga R, Rey S, Del Río R. Cardiovascular and ventilatory acclimatization induced by chronic intermittent hypoxia: a role for the carotid body in the pathophysiology of sleep apnea. Biol Res 2005; 38 (4) 335-340
83 Kanagala R, Murali NS, Friedman PA , et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003; 107 (20) 2589-2594
84 Allahdadi KJ, Cherng TW, Pai H , et al. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 2008; 295 (1) H434-H440
85 Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98 (11) 1071-1077
86 Kanagy NL, Walker BR, Nelin LD. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 2001; 37 (2, Pt 2) 511-515
87 Marcus NJ, Olson Jr EB, Bird CE, Philippi NR, Morgan BJ. Time-dependent adaptation in the hemodynamic response to hypoxia. Respir Physiol Neurobiol 2009; 165 (1) 90-96
88 Troncoso Brindeiro CM, da Silva AQ, Allahdadi KJ, Youngblood V, Kanagy NL. Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. Am J Physiol Heart Circ Physiol 2007; 293 (5) H2971-H2976
89 Patel D, Mohanty P, Di Biase L , et al. Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure. Circ Arrhythm Electrophysiol 2010; 3 (5) 445-451
90 Fein AS, Shvilkin A, Shah D , et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62 (4) 300-305
91 Owens RL, Malhotra A. Sleep-disordered breathing and COPD: the overlap syndrome. Respir Care 2010; 55 (10) 1333-1344 , discussion 1344–1346
92 Friedman JK, Nitta CH, Henderson KM , et al. Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 incrasing endothelin-1 vasoconstrictor reactivity. Vascul Pharmacol 2014; 60 (1) 17-24
93 Leung RS. Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 2009; 51 (4) 324-338
94 Liu LC, Damman K, Lipsic E, Maass AH, Rienstra M, Westenbrink BD. Heart failure highlights in 2012-2013. Eur J Heart Fail 2014; 16 (2) 122-132
95 Chugh SS, Havmoeller R, Narayanan K , et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (8) 837-847
96 Rienstra M, Yin X, Larson MG , et al. Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation. Am Heart J 2014; 167 (1) 109-115 , e2
97 Pedrosa RP, Drager LF, Gonzaga CC , et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011; 58 (5) 811-817
98 Konecny T, Kara T, Somers VK. Obstructive sleep apnea and hypertension: an update. Hypertension 2014; 63 (2) 203-209
99 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342 (19) 1378-1384
100 Nieto FJ, Young TB, Lind BK , et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000; 283 (14) 1829-1836
101 Haentjens P, Van Meerhaeghe A, Moscariello A , et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007; 167 (8) 757-764
102 Giles TL, Lasserson TJ, Smith BH, White J, Wright J, Cates CJ. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006; (3) CD001106
103 Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med 2012; 8 (5) 587-596
104 Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007; 50 (2) 417-423
105 Alajmi M, Mulgrew AT, Fox J , et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007; 185 (2) 67-72
106 Pepperell JC, Ramdassingh-Dow S, Crosthwaite N , et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359 (9302) 204-210
107 Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest 2013; 144 (5) 1487-1494
108 Martínez-García MA, Capote F, Campos-Rodríguez F , et al; Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013; 310 (22) 2407-2415
109 Chobanian AV, Bakris GL, Black HR , et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289 (19) 2560-2572
110 Lévy P, Pépin JL, Arnaud C, Baguet JP, Dematteis M, Mach F. Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis 2009; 51 (5) 400-410
111 Savransky V, Nanayakkara A, Li J , et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007; 175 (12) 1290-1297
112 Allahdadi KJ, Walker BR, Kanagy NL. Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension. Hypertension 2005; 45 (4) 705-709
113 Lefebvre B, Godin-Ribuot D, Joyeux-Faure M , et al. Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat. Respir Physiol Neurobiol 2006; 150 (2-3) 278-286
114 Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004; 169 (3) 348-353
115 Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997; 96 (5) 1432-1437
116 Nadeem R, Harvey M, Singh M , et al. Patients with obstructive sleep apnea display increased carotid intima media: a meta-analysis. Int J Vasc Med 2013; 2013: 839582
117 Chambless LE, Folsom AR, Clegg LX , et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000; 151 (5) 478-487
118 Chambless LE, Heiss G, Folsom AR , et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997; 146 (6) 483-494
119 Hodis HN, Mack WJ, LaBree L , et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998; 128 (4) 262-269
120 O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340 (1) 14-22
121 Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991; 11 (5) 1245-1249
122 Kuniyoshi FH, Garcia-Touchard A, Gami AS , et al. Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 2008; 52 (5) 343-346
123 Gami AS, Howard DE, Olson EJ, Somers VK. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005; 352 (12) 1206-1214
124 Cuspidi C, Meani S, Valerio C, Fusi V, Zanchetti A. Nocturnal non-dipping pattern in untreated hypertensives at different cardiovascular risk according to the 2003 ESH/ESC guidelines. Blood Press 2006; 15 (1) 37-44
125 Eguchi K, Pickering TG, Hoshide S , et al. Ambulatory blood pressure is a better marker than clinic blood pressure in predicting cardiovascular events in patients with/without type 2 diabetes. Am J Hypertens 2008; 21 (4) 443-450
126 Gorostidi M, Sobrino J, Segura J , et al; Spanish Society of Hypertension ABPM Registry investigators. Ambulatory blood pressure monitoring in hypertensive patients with high cardiovascular risk: a cross-sectional analysis of a 20,000-patient database in Spain. J Hypertens 2007; 25 (5) 977-984
127 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365 (9464) 1046-1053
128 Lavie P, Herer P, Peled R , et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 1995; 18 (3) 149-157
129 Cassar A, Morgenthaler TI, Lennon RJ, Rihal CS, Lerman A. Treatment of obstructive sleep apnea is associated with decreased cardiac death after percutaneous coronary intervention. J Am Coll Cardiol 2007; 50 (14) 1310-1314
130 Milleron O, Pillière R, Foucher A , et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004; 25 (9) 728-734
131 Gottlieb DJ, Yenokyan G, Newman AB , et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010; 122 (4) 352-360
132 Chan J, Sanderson J, Chan W , et al. Prevalence of sleep-disordered breathing in diastolic heart failure. Chest 1997; 111 (6) 1488-1493
133 Wang HQ, Chen G, Li J , et al. Subjective sleepiness in heart failure patients with sleep-related breathing disorder. Chin Med J (Engl) 2009; 122 (12) 1375-1379
134 Ferrier K, Campbell A, Yee B , et al. Sleep-disordered breathing occurs frequently in stable outpatients with congestive heart failure. Chest 2005; 128 (4) 2116-2122
135 Javaheri S, Parker TJ, Liming JD , et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998; 97 (21) 2154-2159
136 Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160 (4) 1101-1106
137 Vazir A, Hastings PC, Dayer M , et al. A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction. Eur J Heart Fail 2007; 9 (3) 243-250
138 Serizawa T, Vogel WM, Apstein CS, Grossman W. Comparison of acute alterations in left ventricular relaxation and diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand imbalance. J Clin Invest 1981; 68 (1) 91-102
139 Sano K, Watanabe E, Hayano J , et al. Central sleep apnoea and inflammation are independently associated with arrhythmia in patients with heart failure. Eur J Heart Fail 2013; 15 (9) 1003-1010
140 Liu JN, Zhang JX, Lu G , et al. The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia. Chin Med J (Engl) 2010; 123 (1) 74-78
141 Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW, Scharf SM. Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 2005; 172 (7) 915-920
142 Hayashi T, Yamashita C, Matsumoto C , et al. Role of gp91phox-containing NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress. Am J Physiol Heart Circ Physiol 2008; 294 (5) H2197-H2203
143 Parker JD, Brooks D, Kozar LF , et al. Acute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med 1999; 160 (6) 1888-1896
144 Wang H, Parker JD, Newton GE , et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007; 49 (15) 1625-1631
145 Kasai T, Narui K, Dohi T , et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest 2008; 133 (3) 690-696
146 Arias MA, García-Río F, Alonso-Fernández A, Mediano O, Martínez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation 2005; 112 (3) 375-383
147 Kahwash R, Kikta D, Khayat R. Recognition and management of sleep-disordered breathing in chronic heart failure. Curr Heart Fail Rep 2011; 8 (1) 72-79
148 Bradley TD, Logan AG, Kimoff RJ , et al; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353 (19) 2025-2033
149 Arzt M, Floras JS, Logan AG , et al; CANPAP Investigators. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007; 115 (25) 3173-3180
150 Yuan G, Nanduri J, Khan S, Semenza GL, Prabhakar NR. Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 2008; 217 (3) 674-685
151 Dudley Jr SC, Hoch NE, McCann LA , et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005; 112 (9) 1266-1273
152 Bayés de Luna A, Bayés Genís A, Guindo J , et al. Mechanisms favoring and triggering atrial fibrillation [in French]. Arch Mal Coeur Vaiss 1994; 87 (1 Spec No) 19-25
153 Tse HF, Lau CP. Electrophysiological properties of the fibrillating atrium: implications for therapy. Clin Exp Pharmacol Physiol 1998; 25 (5) 293-302
154 Lin YK, Lai MS, Chen YC , et al. Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium. Clin Sci (Lond) 2012; 122 (3) 121-132
155 Mehra R, Benjamin EJ, Shahar E , et al; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173 (8) 910-916
156 Mehra R, Stone KL, Varosy PD , et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009; 169 (12) 1147-1155
157 Gami AS, Hodge DO, Herges RM , et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007; 49 (5) 565-571
158 Leung RS, Comondore VR, Ryan CM, Stevens D. Mechanisms of sleep-disordered breathing: causes and consequences. Pflugers Arch 2012; 463 (1) 213-230
159 Simantirakis EN, Schiza SI, Marketou ME , et al. Severe bradyarrhythmias in patients with sleep apnoea: the effect of continuous positive airway pressure treatment: a long-term evaluation using an insertable loop recorder. Eur Heart J 2004; 25 (12) 1070-1076
160 Harbison J, O'Reilly P, McNicholas WT. Cardiac rhythm disturbances in the obstructive sleep apnea syndrome: effects of nasal continuous positive airway pressure therapy. Chest 2000; 118 (3) 591-595
161 Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983; 52 (5) 490-494
162 Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010; 90 (1) 47-112
163 Niijima M, Kimura H, Edo H , et al. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1999; 159 (6) 1766-1772
164 Marrone O, Bonsignore MR, Romano S, Bonsignore G. Slow and fast changes in transmural pulmonary artery pressure in obstructive sleep apnoea. Eur Respir J 1994; 7 (12) 2192-2198
165 Schäfer H, Hasper E, Ewig S , et al. Pulmonary haemodynamics in obstructive sleep apnoea: time course and associated factors. Eur Respir J 1998; 12 (3) 679-684
166 Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006; 99 (7) 675-691
167 Campen MJ, Shimoda LA, O'Donnell CP. Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol (1985) 2005; 99 (5) 2028-2035
168 Fagan KA. Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia. J Appl Physiol (1985) 2001; 90 (6) 2502-2507
169 Nisbet RE, Graves AS, Kleinhenz DJ , et al. The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. Am J Respir Cell Mol Biol 2009; 40 (5) 601-609
170 Sajkov D, McEvoy RD. Obstructive sleep apnea and pulmonary hypertension. Prog Cardiovasc Dis 2009; 51 (5) 363-370
171 Bradley TD, Rutherford R, Grossman RF , et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131 (6) 835-839
172 Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest 1996; 109 (2) 380-386
173 Krieger J, Sforza E, Apprill M, Lampert E, Weitzenblum E, Ratomaharo J. Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients. Chest 1989; 96 (4) 729-737
174 Weitzenblum E, Chaouat A. Obstructive sleep apnea syndrome and the pulmonary circulation. Ital Heart J 2005; 6 (10) 795-798
175 Weitzenblum E, Krieger J, Apprill M , et al. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988; 138 (2) 345-349
176 Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration 2001; 68 (6) 566-572
177 Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997; 157 (21) 2483-2487
178 Arias MA, García-Río F, Alonso-Fernández A, Martínez I, Villamor J. Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J 2006; 27 (9) 1106-1113
179 Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax 2000; 55 (11) 934-939
180 Hetzel M, Kochs M, Marx N , et al. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003; 181 (3) 157-166
181 Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994; 149 (2, Pt 1) 416-422
182 Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Douglas Mcevoy R. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med 1999; 159 (5, Pt 1) 1518-1526
183 Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002; 165 (2) 152-158
184 Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995; 151 (1) 82-86
185 Ganga HV, Nair SU, Puppala VK, Miller WL. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort study. J Geriatr Cardiol 2013; 10 (2) 129-134
186 Owens RL, Malhotra A, Eckert DJ, White DP, Jordan AS. The influence of end-expiratory lung volume on measurements of pharyngeal collapsibility. J Appl Physiol (1985) 2010; 108 (2) 445-451
187 Nadel JA, Widdicombe JG. Reflex effects of upper airway irritation on total lung resistance and blood pressure. J Appl Physiol 1962; 17: 861-865
188 Resta O, Foschino Barbaro MP, Brindicci C, Nocerino MC, Caratozzolo G, Carbonara M. Hypercapnia in overlap syndrome: possible determinant factors. Sleep Breath 2002; 6 (1) 11-18
189 Thun MJ, Carter BD, Feskanich D , et al. 50-year trends in smoking-related mortality in the United States. N Engl J Med 2013; 368 (4) 351-364
190 Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010; 182 (3) 325-331
191 Machado MC, Vollmer WM, Togeiro SM , et al. CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD. Eur Respir J 2010; 35 (1) 132-137
192 Nobili L, Schiavi G, Bozano E, De Carli F, Ferrillo F, Nobili F. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000; 22 (1) 21-27
193 Harbison J, Gibson GJ, Birchall D, Zammit-Maempel I, Ford GA. White matter disease and sleep-disordered breathing after acute stroke. Neurology 2003; 61 (7) 959-963
194 Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med 2010; 6 (2) 131-137
195 Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353 (19) 2034-2041
196 Mooe T, Franklin KA, Holmström K, Rabben T, Wiklund U. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001; 164 (10, Pt 1) 1910-1913
197 Redline S, Yenokyan G, Gottlieb DJ , et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010; 182 (2) 269-277
198 Li M, Hou WS, Zhang XW, Tang ZY. Obstructive sleep apnea and risk of stroke: a meta-analysis of prospective studies. Int J Cardiol 2014; 172 (2) 466-469
199 Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest 1990; 97 (1) 27-32
200 Ryan CM, Bayley M, Green R, Murray BJ, Bradley TD. Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke 2011; 42 (4) 1062-1067
201 Bravata DM, Concato J, Fried T , et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep 2011; 34 (9) 1271-1277
202 Martínez-García MA, Soler-Cataluña JJ, Ejarque-Martínez L , et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med 2009; 180 (1) 36-41
203 Xie H, Yung WH. Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor. Acta Pharmacol Sin 2012; 33 (1) 5-10
204 Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology 2013; 18 (1) 61-70
205 Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 2001; 21 (7) 2442-2450
206 Row BW, Kheirandish L, Neville JJ, Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr Res 2002; 52 (3) 449-453
207 Goldbart A, Cheng ZJ, Brittian KR, Gozal D. Intermittent hypoxia induces time-dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat. Neurobiol Dis 2003; 14 (3) 440-446
208 Gozal D, Row BW, Gozal E , et al. Temporal aspects of spatial task performance during intermittent hypoxia in the rat: evidence for neurogenesis. Eur J Neurosci 2003; 18 (8) 2335-2342
209 Kheirandish L, Row BW, Li RC, Brittian KR, Gozal D. Apolipoprotein E-deficient mice exhibit increased vulnerability to intermittent hypoxia-induced spatial learning deficits. Sleep 2005; 28 (11) 1412-1417
210 Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 2003; 167 (11) 1548-1553
211 Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea. Chest 2012; 141 (6) 1601-1610
212 Quan SF, Chan CS, Dement WC , et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2011; 34 (3) 303-314B
213 Kushida CA, Nichols DA, Holmes TH , et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012; 35 (12) 1593-1602
214 Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003; 26 (3) 298-307
215 Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc 2004; 10 (5) 772-785
216 Naismith S, Winter V, Gotsopoulos H, Hickie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004; 26 (1) 43-54
217 Bartlett DJ, Rae C, Thompson CH , et al. Hippocampal area metabolites relate to severity and cognitive function in obstructive sleep apnea. Sleep Med 2004; 5 (6) 593-596
218 Weng HH, Tsai YH, Chen CF , et al. Mapping gray matter reductions in obstructive sleep apnea: an activation likelihood estimation meta-analysis. Sleep 2014; 37 (1) 167-175
219 Hatipoğlu U, Rubinstein I. Inflammation and obstructive sleep apnea syndrome: how many ways do I look at thee?. Chest 2004; 126 (1) 1-2
220 Hopkins RO, Kesner RP, Goldstein M. Memory for novel and familiar spatial and linguistic temporal distance information in hypoxic subjects. J Int Neuropsychol Soc 1995; 1 (5) 454-468
221 Kesner RP, Hopkins RO. Short-term memory for duration and distance in humans: role of the hippocampus. Neuropsychology 2001; 15 (1) 58-68
222 Macey PM, Henderson LA, Macey KE , et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002; 166 (10) 1382-1387
223 Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002; 11 (1) 1-16
224 Canessa N, Castronovo V, Cappa SF , et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 2011; 183 (10) 1419-1426
225 Toffoli S, Michiels C. Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. FEBS J 2008; 275 (12) 2991-3002
226 Liu Y, Song X, Wang X , et al. Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells. J Cell Biochem 2010; 111 (3) 554-563
227 Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res 2007; 67 (3) 854-855
228 Cairns RA, Kalliomaki T, Hill RP. Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 2001; 61 (24) 8903-8908
229 Almendros I, Montserrat JM, Torres M , et al. Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea. Respir Physiol Neurobiol 2013; 186 (3) 303-307
230 Yamauchi M, Nakano H, Maekawa J , et al. Oxidative stress in obstructive sleep apnea. Chest 2005; 127 (5) 1674-1679
231 Almendros I, Wang Y, Becker L , et al. Intermittent hypoxia-induced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea. Am J Respir Crit Care Med 2014; 189 (5) 593-601
232 Gharib SA, Seiger AN, Hayes AL, Mehra R, Patel SR. Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes. Sleep 2014; 37 (4) 709-714 , 714A–714T
233 Christensen AS, Clark A, Salo P , et al. Symptoms of sleep disordered breathing and risk of cancer: a prospective cohort study. Sleep 2013; 36 (10) 1429-1435
234 Campos-Rodriguez F, Martinez-Garcia MA, Martinez M , et al; Spanish Sleep Network. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med 2013; 187 (1) 99-105
235 Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R. Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2012; 186 (2) 190-194