Skip to main content

Advertisement

SpringerLink
Log in

Obstructive sleep apnea, immuno-inflammation, and atherosclerosis

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder leading to cardiovascular and metabolic complications. OSA is also a multicomponent disorder, with intermittent hypoxia (IH) as the main trigger for the associated cardiovascular and metabolic alterations. Indeed, recurrent pharyngeal collapses during sleep lead to repetitive sequences of hypoxia–reoxygenation. This IH induces several consequences such as hemodynamic, hormonometabolic, oxidative, and immuno-inflammatory alterations that may interact and aggravate each other, resulting in artery changes, from adaptive to degenerative atherosclerotic remodeling. Atherosclerosis has been found in OSA patients free of other cardiovascular risk factors and is related to the severity of nocturnal hypoxia. Early stages of artery alteration, including functional and structural changes, have been evidenced in both OSA patients and rodents experimentally exposed to IH. Impaired vasoreactivity with endothelial dysfunction and/or increased vasoconstrictive responses due to sympathetic, endothelin, and renin–angiotensin systems have been reported and also contribute to vascular remodeling and inflammation. Oxidative stress, inflammation, and vascular remodeling can be directly triggered by IH, further aggravated by the OSA-associated hormonometabolic alterations, such as insulin resistance, dyslipidemia, and adipokine imbalance. As shown in OSA patients and in the animal model, genetic susceptibility, comorbidities (obesity), and life habits (high fat diet) may aggravate atherosclerosis development or progression. The intimate molecular mechanisms are still largely unknown, and their understanding may contribute to delineate new targets for prevention strategies and/or development of new treatment of OSA-related atherosclerosis, especially in patients at risk for cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AHI:

Apnea–hypopnea index

BP:

Blood pressure

CPAP:

Continuous positive airway pressure

CRP:

C-reactive protein

EDS:

Excessive daytime sleepiness

ET-1:

Endothelin-1

HIF-1:

Hypoxia inducible factor-1

ICAM-1:

Intercellular adhesion molecule-1

IH:

Intermittent hypoxia

IL:

Interleukin

IMT:

Intima–media thickness

LTB4:

Leukotriene B4

MCP-1/CCL2:

Monocyte chemoattractant protein-1/C–C chemokine ligand 2

OSA:

Obstructive sleep apnea

NFkB:

Nuclear factor kappa B

PECAM-1:

Platelet endothelial cell adhesion molecule-1

RANTES/CCL5:

Regulated upon activation, normal T cell expressed and secreted/C–C chemokine ligand 5

TNF-α:

Tumor necrosis factor-alpha

VCAM-1:

Vascular cell adhesion molecule-1

References

  1. Malhotra A, White DP (2002) Obstructive sleep apnoea. Lancet 360(9328):237–245. doi:10.1016/S0140-6736(02) 09464-3

    Article  PubMed  Google Scholar 

  2. Somers VK et al (2008) Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 118(10):1080–1111. doi:10.1161/CIRCULATIONAHA.107.189420

    Article  PubMed  Google Scholar 

  3. Mayer P et al (1996) Relationship between body mass index, age and upper airway measurements in snorers and sleep apnoea patients. Eur Respir J 9(9):1801–1809. doi:10.1183/09031936.96.09091801

    Article  CAS  PubMed  Google Scholar 

  4. White DP (2005) Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 172(11):1363–1370. doi:10.1164/rccm.200412-1631SO

    Article  PubMed  Google Scholar 

  5. Horner RL (2007) Contributions of passive mechanical loads and active neuromuscular compensation to upper airway collapsibility during sleep. J Appl Physiol 102(2):510–512. doi:10.1152/japplphysiol.01213.2006

    Article  PubMed  Google Scholar 

  6. Levy P et al (2008) Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives. Eur Respir J 32(4):1082–1095. doi:10.1183/09031936.00013308

    Article  CAS  PubMed  Google Scholar 

  7. Young T et al (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328(17):1230–1235. doi:10.1056/NEJM199304293281704

    Article  CAS  PubMed  Google Scholar 

  8. Young T, Peppard PE, Gottlieb DJ (2002) Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 165(9):1217–1239. doi:10.1164/rccm.2109080

    Article  PubMed  Google Scholar 

  9. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J (1999) The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 340(11):847–851. doi:10.1056/NEJM199903183401104

    Article  CAS  PubMed  Google Scholar 

  10. Mazza S et al (2002) Analysis of error profiles occurring during the OSLER test: a sensitive mean of detecting fluctuations in vigilance in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 166(4):474–478. doi:10.1164/rccm.2107065

    Article  PubMed  Google Scholar 

  11. Marin JM 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

    PubMed  Google Scholar 

  12. Pepperell JC et al (2002) Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 359(9302):204–210. doi:10.1016/S0140-6736(02)07445-7

    Article  PubMed  Google Scholar 

  13. Yaggi HK et al (2005) Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 353(19):2034–2041. doi:10.1056/NEJMoa043104

    Article  CAS  PubMed  Google Scholar 

  14. Somers VK et al (2008) Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 52(8):686–717. doi:10.1016/j.jacc.2008.05.002

    Article  PubMed  Google Scholar 

  15. Young T et al (2008) Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 31(8):1071–1078

    PubMed  Google Scholar 

  16. Baguet JP et al (2005) The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 128(5):3407–3412. doi:10.1378/chest.128.5.3407

    Article  PubMed  Google Scholar 

  17. Minoguchi K et al (2005) Increased carotid intima–media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 172(5):625–630. doi:10.1164/rccm.200412-1652OC

    Article  PubMed  Google Scholar 

  18. Drager LF et al (2005) Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 172(5):613–618. doi:10.1164/rccm.200503-340OC

    Article  PubMed  Google Scholar 

  19. Turmel J et al (2009) Relationship between atherosclerosis and the sleep apnea syndrome: an intravascular ultrasound study. Int J Cardiol 132(2):203–209. doi:10.1016/j.ijcard.2007.11.063

    Article  PubMed  Google Scholar 

  20. Basner RC (2007) Continuous positive airway pressure for obstructive sleep apnea. N Engl J Med 356(17):1751–1758. doi:10.1056/NEJMct066953

    Article  CAS  PubMed  Google Scholar 

  21. Jenkinson C et al (1999) Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 353(9170):2100–2105. doi:10.1016/S0140-6736(98)10532-9

    Article  CAS  PubMed  Google Scholar 

  22. Montserrat JM et al (2001) Effectiveness of CPAP treatment in daytime function in sleep apnea syndrome. A randomized controlled study with an optimized placebo. Am J Respir Crit Care Med 164(4):608–613

    CAS  PubMed  Google Scholar 

  23. Haentjens P et al (2007) 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 167(8):757–764. doi:10.1001/archinte.167.8.757

    Article  PubMed  Google Scholar 

  24. Lévy P et al (2009) Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis 51(5):400–410. doi:10.1016/j.pcad.2008.03.001

    Article  PubMed  CAS  Google Scholar 

  25. Gay P et al (2006) Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 29(3):381–401

    PubMed  Google Scholar 

  26. Pepin JL et al (1999) Effective compliance during the first 3 months of continuous positive airway pressure. A European prospective study of 121 patients. Am J Respir Crit Care Med 160(4):1124–1129

    CAS  PubMed  Google Scholar 

  27. Weaver TE et al (2007) Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 30(6):711–719

    PubMed  Google Scholar 

  28. Harsch IA et al (2004) Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 169(2):156–162. doi:10.1164/rccm.200302-206OC

    Article  PubMed  Google Scholar 

  29. Coughlin SR et al (2007) Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 29(4):720–727. doi:10.1183/09031936.00043306

    Article  CAS  PubMed  Google Scholar 

  30. West SD et al (2007) Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 62(11):969–974. doi:10.1136/thx.2006.074351

    Article  PubMed  Google Scholar 

  31. Dematteis M et al. (2009) Cardiovascular consequences of sleep disordered breathing: contribution of animal models to understanding the human disease. ILAR J 50(3)

  32. Kimoff RJ et al (1994) Canine model of obstructive sleep apnea: model description and preliminary application. J Appl Physiol 76(4):1810–1817

    CAS  PubMed  Google Scholar 

  33. Brooks D et al (1997) Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 99(1):106–109. doi:10.1172/JCI119120

    Article  CAS  PubMed  Google Scholar 

  34. Nacher M et al (2007) Recurrent obstructive apneas trigger early systemic inflammation in a rat model of sleep apnea. Respir Physiol Neurobiol 155(1):93–96. doi:10.1016/j.resp. 2006.06.004

    Article  PubMed  Google Scholar 

  35. Neubauer JA (2001) Invited review: physiological and pathophysiological responses to intermittent hypoxia. J Appl Physiol 90(4):1593–1599

    CAS  PubMed  Google Scholar 

  36. Fletcher EC (2001) Invited review: physiological consequences of intermittent hypoxia: systemic blood pressure. J Appl Physiol 90(4):1600–1605

    CAS  PubMed  Google Scholar 

  37. Morgan BJ (2007) Vascular consequences of intermittent hypoxia. Adv Exp Med Biol 618:69–84. doi:10.1007/978-0-387-75434-5_6

    Article  PubMed  Google Scholar 

  38. Prabhakar NR (2001) Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90(5):1986–1994

    CAS  PubMed  Google Scholar 

  39. Dyugovskaya L, Lavie P, Lavie L (2002) Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165(7):934–939

    PubMed  Google Scholar 

  40. Ryan S, Taylor CT, McNicholas WT (2005) Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112(17):2660–2667. doi:10.1161/CIRCULATIONAHA.105.556746

    Article  CAS  PubMed  Google Scholar 

  41. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695. doi:10.1056/NEJMra043430

    Article  CAS  PubMed  Google Scholar 

  42. Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874. doi:10.1038/nature01323

    Article  CAS  PubMed  Google Scholar 

  43. Lusis AJ (2000) Atherosclerosis. Nature 407(6801):233–241. doi:10.1038/35025203

    Article  CAS  PubMed  Google Scholar 

  44. Peppard PE et al (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342(19):1378–1384. doi:10.1056/NEJM200005113421901

    Article  CAS  PubMed  Google Scholar 

  45. Brooks D et al (1997) Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 155(5):1609–1617

    CAS  PubMed  Google Scholar 

  46. Smith ML, Pacchia CF (2007) Sleep apnoea and hypertension: role of chemoreflexes in humans. Exp Physiol 92(1):45–50. doi:10.1113/expphysiol.2006.033753

    Article  PubMed  Google Scholar 

  47. Somers VK et al (1995) Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96(4):1897–1904. doi:10.1172/JCI118235

    Article  CAS  PubMed  Google Scholar 

  48. Dematteis M et al (2008) Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med 177(2):227–235. doi:10.1164/rccm.200702-238OC

    Article  PubMed  Google Scholar 

  49. Chatzizisis YS et al (2007) Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 49(25):2379–2393. doi:10.1016/j.jacc.2007.02.059

    Article  CAS  PubMed  Google Scholar 

  50. Kato M et al (2000) Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102(21):2607–2610

    CAS  PubMed  Google Scholar 

  51. Kraiczi H et al (2001) Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep. Chest 119(4):1085–1091. doi:10.1378/chest.119.4.1085

    Article  CAS  PubMed  Google Scholar 

  52. Imadojemu VA et al (2002) Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med 165(7):950–953

    PubMed  Google Scholar 

  53. Imadojemu VA et al (2002) Obstructive apnea during sleep is associated with peripheral vasoconstriction. Am J Respir Crit Care Med 165(1):61–66

    PubMed  Google Scholar 

  54. Tahawi Z et al (2001) Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. J Appl Physiol 90(5):2007–2013 discussion 2000

    CAS  PubMed  Google Scholar 

  55. Phillips SA et al (2004) Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol 286(1):H388–H393. doi:10.1152/ajpheart.00683.2003

    Article  CAS  PubMed  Google Scholar 

  56. Lefebvre B et al (2006) Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat. Respir Physiol Neurobiol 150(2–3):278–286. doi:10.1016/j.resp. 2005.05.020

    Article  CAS  PubMed  Google Scholar 

  57. Ip MS et al (2000) Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 162(6):2166–2171

    CAS  PubMed  Google Scholar 

  58. Lavie L et al (2003) Plasma levels of nitric oxide and L-arginine in sleep apnea patients: effects of nCPAP treatment. J Mol Neurosci 21(1):57–63. doi:10.1385/JMN:21:1:57

    Article  CAS  PubMed  Google Scholar 

  59. Teramoto S et al (2003) Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome. Sleep Med 4(5):403–407. doi:10.1016/S1389-9457(03)00102-3

    Article  PubMed  Google Scholar 

  60. Ohike Y et al (2005) Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure—possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine. Circ J 69(2):221–226. doi:10.1253/circj.69.221

    Article  CAS  PubMed  Google Scholar 

  61. Duchna HW et al (2005) Long-term effects of nasal continuous positive airway pressure on vasodilatory endothelial function in obstructive sleep apnea syndrome. Sleep Breath 9(3):97–103. doi:10.1007/s11325-005-0024-z

    Article  PubMed  Google Scholar 

  62. Lattimore JL et al (2006) Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 61(6):491–495. doi:10.1136/thx.2004.039164

    Article  CAS  PubMed  Google Scholar 

  63. Noda A et al (2007) Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome. Hypertens Res 30(8):669–676. doi:10.1291/hypres.30.669

    Article  CAS  PubMed  Google Scholar 

  64. Ozkan Y et al (2008) Circulating nitric oxide (NO), asymmetric dimethylarginine (ADMA), homocysteine, and oxidative status in obstructive sleep apnea–hypopnea syndrome (OSAHS). Sleep Breath 12(2):149–154. doi:10.1007/s11325-007-0148-4

    Article  PubMed  Google Scholar 

  65. Mason RP (2006) Nitric oxide mechanisms in the pathogenesis of global risk. J Clin Hypertens (Greenwich) 8(8 Suppl 2):31–38. doi:10.1111/j.1524-6175.2006.05838.x quiz 40

    Article  CAS  Google Scholar 

  66. Belaidi E et al (2009) Major role for HIF-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J Am Coll Cardiol 53(15):1309–1317

    Article  CAS  PubMed  Google Scholar 

  67. Mulvany MJ et al (1996) Vascular remodeling. Hypertension 28(3):505–506

    CAS  PubMed  Google Scholar 

  68. Drager LF et al (2007) Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 176(7):706–712. doi:10.1164/rccm.200703-500OC

    Article  CAS  PubMed  Google Scholar 

  69. Arnaud C et al. (2008) Intermittent hypoxia induces inflammatory vascular remodeling in C57bl6 mice. In: American Thoracic Society 2008 International Conference. Am J Resp Crit Care Med 177, Meeting abstracts, 2008, Toronto, Canada

  70. Belaidi E et al. (2008) Dual endothelin-1 receptor antagonism prevents chronic intermittent hypoxia-induced cardiovascular alterations in rat. In: European Respiratory Society 2008 International Conference. Eur Resp J 32(suppl 52), Meeting abstract, 2008, Berlin, Germany

  71. Arnaud C et al. (2009) Intermittent hypoxia induces inflammatory vascular and myocardial remodeling: role of the endothelin system. In: American Thoracic Society 2009 International Conference. Am J Respir Crit Care Med 179, Meeting Abstracts, 2009, San Diego, USA

  72. Allahdadi KJ, Walker BR, Kanagy NL (2005) Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension. Hypertension 45(4):705–709. doi:10.1161/01.HYP.0000153794.52852.04

    Article  CAS  PubMed  Google Scholar 

  73. Lefebvre B et al (2008) Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea? Eur Respir J 32(1):113–120. doi:10.1183/09031936.00137107

    Article  CAS  PubMed  Google Scholar 

  74. Chapman MJ, Sposito AC (2008) Hypertension and dyslipidaemia in obesity and insulin resistance: pathophysiology, impact on atherosclerotic disease and pharmacotherapy. Pharmacol Ther 117(3):354–373. doi:10.1016/j.pharmthera.2007.10.004

    Article  CAS  PubMed  Google Scholar 

  75. Newman AB et al (2005) Progression and regression of sleep-disordered breathing with changes in weight: the sleep heart health study. Arch Intern Med 165(20):2408–2413. doi:10.1001/archinte.165.20.2408

    Article  PubMed  Google Scholar 

  76. Peled N et al (2007) The association of OSA with insulin resistance, inflammation and metabolic syndrome. Respir Med 101(8):1696–1701. doi:10.1016/j.rmed.2007.02.025

    Article  PubMed  Google Scholar 

  77. Kono M et al (2007) Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest 131(5):1387–1392. doi:10.1378/chest.06-1807

    Article  CAS  PubMed  Google Scholar 

  78. Meslier N et al (2003) Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome. Eur Respir J 22(1):156–160. doi:10.1183/09031936.03.00089902

    Article  CAS  PubMed  Google Scholar 

  79. Strohl KP et al (1994) Insulin levels, blood pressure and sleep apnea. Sleep 17(7):614–618

    CAS  PubMed  Google Scholar 

  80. Vgontzas AN 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. doi:10.1210/jc.85.3.1151

    Article  CAS  PubMed  Google Scholar 

  81. Ip MS et al (2002) Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 165(5):670–676

    PubMed  Google Scholar 

  82. McArdle N et al (2007) Metabolic risk factors for vascular disease in obstructive sleep apnea: a matched controlled study. Am J Respir Crit Care Med 175(2):190–195. doi:10.1164/rccm.200602-270OC

    Article  CAS  PubMed  Google Scholar 

  83. Punjabi NM et al (2002) Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 165(5):677–682

    PubMed  Google Scholar 

  84. Stoohs RA, Facchini F, Guilleminault C (1996) Insulin resistance and sleep-disordered breathing in healthy humans. Am J Respir Crit Care Med 154(1):170–174

    CAS  PubMed  Google Scholar 

  85. Sharma SK et al (2007) Obesity, and not obstructive sleep apnea, is responsible for metabolic abnormalities in a cohort with sleep-disordered breathing. Sleep Med 8(1):12–17. doi:10.1016/j.sleep. 2006.06.014

    Article  CAS  PubMed  Google Scholar 

  86. Barcelo A et al (2008) Insulin resistance and daytime sleepiness in patients with sleep apnoea. Thorax 63(11):946–950. doi:10.1136/thx.2007.093740

    Article  CAS  PubMed  Google Scholar 

  87. Polotsky VY et al (2009) Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med 179(3):228–234. doi:10.1164/rccm.200804-608OC

    Article  PubMed  Google Scholar 

  88. Muniyappa R et al (2007) Cardiovascular actions of insulin. Endocr Rev 28(5):463–491. doi:10.1210/er.2007-0006

    Article  CAS  PubMed  Google Scholar 

  89. Nigro J et al (2006) Insulin resistance and atherosclerosis. Endocr Rev 27(3):242–259. doi:10.1210/er.2005-0007

    Article  CAS  PubMed  Google Scholar 

  90. Polotsky VY et al (2003) Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552(Pt 1):253–264. doi:10.1113/jphysiol.2003.048173

    Article  CAS  PubMed  Google Scholar 

  91. Martin SS, Qasim A, Reilly MP (2008) Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 52(15):1201–1210. doi:10.1016/j.jacc.2008.05.060

    Article  CAS  PubMed  Google Scholar 

  92. Dubey L, Hesong Z (2006) Role of leptin in atherogenesis. Exp Clin Cardiol 11(4):269–275

    CAS  PubMed  Google Scholar 

  93. Beltowski J (2006) Leptin and atherosclerosis. Atherosclerosis 189(1):47–60. doi:10.1016/j.atherosclerosis.2006.03.003

    Article  CAS  PubMed  Google Scholar 

  94. Sierra-Johnson J et al (2008) Effect of altitude on leptin levels, does it go up or down? J Appl Physiol 105(5):1684–1685. doi:10.1152/japplphysiol.01284.2007

    Article  PubMed  Google Scholar 

  95. Grosfeld A et al (2002) Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J Biol Chem 277(45):42953–42957. doi:10.1074/jbc.M206775200

    Article  CAS  PubMed  Google Scholar 

  96. Barcelo A et al (2005) Neuropeptide Y and leptin in patients with obstructive sleep apnea syndrome: role of obesity. Am J Respir Crit Care Med 171(2):183–187. doi:10.1164/rccm.200405-579OC

    Article  PubMed  Google Scholar 

  97. Borgel J et al (2006) Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels. Eur Respir J 27(1):121–127. doi:10.1183/09031936.06.00131304

    Article  CAS  PubMed  Google Scholar 

  98. Saarelainen S, Lahtela J, Kallonen E (1997) Effect of nasal CPAP treatment on insulin sensitivity and plasma leptin. J Sleep Res 6(2):146–147

    CAS  PubMed  Google Scholar 

  99. Chin K et al (1999) 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 100(7):706–712

    CAS  PubMed  Google Scholar 

  100. Ip MS et al (2000) Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 118(3):580–586. doi:10.1378/chest.118.3.580

    Article  CAS  PubMed  Google Scholar 

  101. Shimizu K et al (2002) Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea–hypopnoea syndrome. Thorax 57(5):429–434. doi:10.1136/thorax.57.5.429

    Article  CAS  PubMed  Google Scholar 

  102. Okamoto Y et al (2006) Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond) 110(3):267–278. doi:10.1042/CS20050182

    Article  CAS  Google Scholar 

  103. Gualillo O, Gonzalez-Juanatey JR, Lago F (2007) The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Trends Cardiovasc Med 17(8):275–283. doi:10.1016/j.tcm.2007.09.005

    Article  CAS  PubMed  Google Scholar 

  104. Lago F et al (2007) Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 3(12):716–724. doi:10.1038/ncprheum0674

    Article  CAS  PubMed  Google Scholar 

  105. Makino S et al (2006) Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance. Clin Endocrinol (Oxf) 64(1):12–19. doi:10.1111/j.1365-2265.2005.02407.x

    Article  CAS  Google Scholar 

  106. Tokuda F et al (2008) Serum levels of adipocytokines, adiponectin and leptin, in patients with obstructive sleep apnea syndrome. Intern Med 47(21):1843–1849. doi:10.2169/internalmedicine.47.1035

    Article  PubMed  Google Scholar 

  107. Wolk R et al (2005) Plasma levels of adiponectin, a novel adipocyte-derived hormone, in sleep apnea. Obes Res 13(1):186–190. doi:10.1038/oby.2005.24

    Article  CAS  PubMed  Google Scholar 

  108. Zhang XL et al (2004) Serum adiponectin level in patients with obstructive sleep apnea hypopnea syndrome. Chin Med J (Engl) 117(11):1603–1606

    CAS  Google Scholar 

  109. Zhang XL et al (2006) Serum adiponectin levels in adult male patients with obstructive sleep apnea hypopnea syndrome. Respiration 73(1):73–77. doi:10.1159/000088690

    Article  PubMed  CAS  Google Scholar 

  110. Masserini B et al (2006) Reduced levels of adiponectin in sleep apnea syndrome. J Endocrinol Invest 29(8):700–705

    CAS  PubMed  Google Scholar 

  111. Zhang XL et al (2007) Effect of continuous positive airway pressure treatment on serum adiponectin level and mean arterial pressure in male patients with obstructive sleep apnea syndrome. Chin Med J (Engl) 120(17):1477–1481

    Google Scholar 

  112. Nakagawa Y et al (2008) Nocturnal reduction in circulating adiponectin concentrations related to hypoxic stress in severe obstructive sleep apnea–hypopnea syndrome. Am J Physiol Endocrinol Metab 294(4):E778–E784. doi:10.1152/ajpendo.00709.2007

    Article  CAS  PubMed  Google Scholar 

  113. Kanbay A et al (2008) Comparison of serum adiponectin and tumor necrosis factor-alpha levels between patients with and without obstructive sleep apnea syndrome. Respiration 76(3):324–330. doi:10.1159/000134010

    Article  CAS  PubMed  Google Scholar 

  114. Lam JC et al (2008) Hypoadiponectinemia is related to sympathetic activation and severity of obstructive sleep apnea. Sleep 31(12):1721–1727

    PubMed  Google Scholar 

  115. Chen B et al (2006) Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 341(2):549–556. doi:10.1016/j.bbrc.2006.01.004

    Article  CAS  PubMed  Google Scholar 

  116. Hosogai N et al (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56(4):901–911. doi:10.2337/db06-0911

    Article  CAS  PubMed  Google Scholar 

  117. Wang B, Wood IS, Trayhurn P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455(3):479–492. doi:10.1007/s00424-007-0301-8

    Article  CAS  PubMed  Google Scholar 

  118. Ye J et al (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293(4):E1118–E1128. doi:10.1152/ajpendo.00435.2007

    Article  CAS  PubMed  Google Scholar 

  119. Magalang UJ et al (2008) Intermittent hypoxia suppresses adiponectin secretion by adipocytes. Exp Clin Endocrinol Diabetes 117:129–134

    Article  PubMed  CAS  Google Scholar 

  120. Yamamoto Y et al (2008) Resistin is closely related to systemic inflammation in obstructive sleep apnea. Respiration 76(4):377–385. doi:10.1159/000141866

    Article  CAS  PubMed  Google Scholar 

  121. Wu H et al (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115(8):1029–1038. doi:10.1161/CIRCULATIONAHA.106.638379

    Article  CAS  PubMed  Google Scholar 

  122. Thalmann S, Meier CA (2007) Local adipose tissue depots as cardiovascular risk factors. Cardiovasc Res 75(4):690–701. doi:10.1016/j.cardiores.2007.03.008

    Article  CAS  PubMed  Google Scholar 

  123. Henrichot E et al (2005) Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler Thromb Vasc Biol 25(12):2594–2599. doi:10.1161/01.ATV.0000188508.40052.35

    Article  CAS  PubMed  Google Scholar 

  124. McGill HC Jr et al (2002) Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 105(23):2712–2718. doi:10.1161/01.CIR.0000018121.67607.CE

    Article  PubMed  Google Scholar 

  125. Fantuzzi G, Mazzone T (2007) Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 27(5):996–1003. doi:10.1161/ATVBAHA.106.131755

    Article  CAS  PubMed  Google Scholar 

  126. Ohman MK et al (2008) Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 117(6):798–805. doi:10.1161/CIRCULATIONAHA.107.717595

    Article  PubMed  CAS  Google Scholar 

  127. Vela D et al (2007) The role of periadventitial fat in atherosclerosis. Arch Pathol Lab Med 131(3):481–487

    PubMed  Google Scholar 

  128. Newman AB et al (2001) Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 154(1):50–59. doi:10.1093/aje/154.1.50

    Article  CAS  PubMed  Google Scholar 

  129. Robinson GV et al (2004) Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 59(9):777–782. doi:10.1136/thx.2003.018739

    Article  CAS  PubMed  Google Scholar 

  130. Lavie L (2003) Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev 7(1):35–51. doi:10.1053/smrv.2002.0261

    Article  PubMed  Google Scholar 

  131. Tan KC et al (2005) HDL dysfunction in obstructive sleep apnea. Atherosclerosis 184:377–382

    Article  PubMed  CAS  Google Scholar 

  132. Lavie L, Vishnevsky A, Lavie P (2004) Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 27(1):123–128

    PubMed  Google Scholar 

  133. Li J et al (2005) Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 97(7):698–706. doi:10.1161/01.RES.0000183879.60089.a9

    Article  CAS  PubMed  Google Scholar 

  134. Li J et al (2007) Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 102(2):557–563. doi:10.1152/japplphysiol.01081.2006

    Article  CAS  PubMed  Google Scholar 

  135. Lattimore JD et al (2005) Repetitive hypoxia increases lipid loading in human macrophages—a potentially atherogenic effect. Atherosclerosis 179(2):255–259. doi:10.1016/j.atherosclerosis.2004.11.010

    Article  CAS  PubMed  Google Scholar 

  136. Savransky V et al (2007) Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 175(12):1290–1297. doi:10.1164/rccm.200612-1771OC

    Article  CAS  PubMed  Google Scholar 

  137. Savransky V et al (2008) Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res 103(10):1173–1180. doi:10.1161/CIRCRESAHA.108.178533

    Article  CAS  PubMed  Google Scholar 

  138. McNicholas WT, Bonsignore MR (2007) Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 29(1):156–178. doi:10.1183/09031936.00027406

    Article  CAS  PubMed  Google Scholar 

  139. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867. doi:10.1038/nature05485

    Article  CAS  PubMed  Google Scholar 

  140. Shamsuzzaman AS et al (2002) Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 105(21):2462–2464. doi:10.1161/01.CIR.0000018948.95175.03

    Article  CAS  PubMed  Google Scholar 

  141. Yokoe T 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. doi:10.1161/01.CIR.0000052627.99976.18

    Article  CAS  PubMed  Google Scholar 

  142. Yao M et al (2006) The relationship between sleep-disordered breathing and high-sensitivity C-reactive protein in Japanese men. Sleep 29(5):661–665

    PubMed  Google Scholar 

  143. Taheri S et al (2007) Correlates of serum C-reactive protein (CRP)—no association with sleep duration or sleep disordered breathing. Sleep 30(8):991–996

    PubMed  Google Scholar 

  144. Guilleminault C, Kirisoglu C, Ohayon MM (2004) C-reactive protein and sleep-disordered breathing. Sleep 27(8):1507–1511

    PubMed  Google Scholar 

  145. Kohler M et al (2009) Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial. Thorax 64(1):67–73. doi:10.1136/thx.2008.097931

    Article  CAS  PubMed  Google Scholar 

  146. Carpagnano GE et al (2002) Increased 8-isoprostane and interleukin-6 in breath condensate of obstructive sleep apnea patients. Chest 122(4):1162–1167. doi:10.1378/chest.122.4.1162

    Article  CAS  PubMed  Google Scholar 

  147. Ohga E 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

    CAS  PubMed  Google Scholar 

  148. Ohga E et al (2003) Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 94(1):179–184

    CAS  PubMed  Google Scholar 

  149. Schulz R 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

    CAS  PubMed  Google Scholar 

  150. Dyugovskaya L et al (2008) Delayed neutrophil apoptosis in patients with sleep apnea. Am J Respir Crit Care Med 177(5):544–554. doi:10.1164/rccm.200705-675OC

    Article  CAS  PubMed  Google Scholar 

  151. Dyugovskaya L et al (2005) Activated CD8+ T-lymphocytes in obstructive sleep apnoea. Eur Respir J 25(5):820–828. doi:10.1183/09031936.05.00103204

    Article  CAS  PubMed  Google Scholar 

  152. Dyugovskaya L, Lavie P, Lavie L (2005) Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci 1051:340–350. doi:10.1196/annals.1361.076

    Article  CAS  PubMed  Google Scholar 

  153. van Buul JD, Hordijk PL (2004) Signaling in leukocyte transendothelial migration. Arterioscler Thromb Vasc Biol 24(5):824–833. doi:10.1161/01.ATV.0000122854.76267.5c

    Article  PubMed  CAS  Google Scholar 

  154. Tzima E et al (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437(7057):426–431. doi:10.1038/nature03952

    Article  CAS  PubMed  Google Scholar 

  155. Greenberg H et al (2006) Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem Biophys Res Commun 343(2):591–596. doi:10.1016/j.bbrc.2006.03.015

    Article  CAS  PubMed  Google Scholar 

  156. Minoguchi K et al (2004) Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 126(5):1473–1479. doi:10.1378/chest.126.5.1473

    Article  CAS  PubMed  Google Scholar 

  157. Paigen B et al (1985) Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57(1):65–73. doi:10.1016/0021-9150(85)90138-8

    Article  CAS  PubMed  Google Scholar 

  158. Stewart-Phillips JL, Lough J (1991) Pathology of atherosclerosis in cholesterol-fed, susceptible mice. Atherosclerosis 90(2–3):211–218. doi:10.1016/0021-9150(91)90117-L

    Article  CAS  PubMed  Google Scholar 

  159. Hofker MH, van Vlijmen BJ, Havekes LM (1998) Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis. Atherosclerosis 137(1):1–11. doi:10.1016/S0021-9150(97)00266-9

    Article  CAS  PubMed  Google Scholar 

  160. Jun JC et al. (2008) Intermittent hypoxia accelerates aortic atherosclerosis in ApoE deficient mice. In: American Thoracic Society 2008 International Conference. Am J Resp Crit Care Med 177, Meeting abstract, 2008, Toronto, Canada

  161. Arnaud C et al. (2008) Chronic intermittent hypoxia accelerates atherosclerotic plaque formation in ApoE knockout mice independently of cholesterol levels. In: European Respiratory Society 2008 International Conference. Eur Resp J 32(suppl 52), Meeting abstract, 2008, Berlin, Germany.

Download references

Acknowledgments

This work was supported by a grant from AGIR@dom to CA and MD. CA is recipient of fellowship from the Fondation pour la Recherche Médicale (France).

Author information

Authors and Affiliations

  1. INSERM ERI17, Grenoble, 38043, France

    Claire Arnaud, Maurice Dematteis, Jean-Louis Pepin & Patrick Lévy

  2. Faculté de Médecine, Université Joseph Fourier, Grenoble, 38403, France

    Claire Arnaud, Maurice Dematteis, Jean-Louis Pepin, Jean-Philippe Baguet & Patrick Lévy

  3. Laboratoires du Sommeil et EFCR, Pole Rééducation et Physiologie, CHU, Grenoble, 38043, France

    Maurice Dematteis, Jean-Louis Pepin & Patrick Lévy

  4. Département de Cardiologie et Hypertension, Hôpital A. Michallon, CHU, Grenoble, 38043, France

    Jean-Philippe Baguet

  5. INSERM U877, Grenoble, 38042, France

    Jean-Philippe Baguet

  6. Laboratoire HP2, EFCR, CHU Grenoble, 38043, Grenoble Cedex, France

    Patrick Lévy

Authors
  1. Claire Arnaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maurice Dematteis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Louis Pepin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Philippe Baguet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick Lévy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Lévy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arnaud, C., Dematteis, M., Pepin, JL. et al. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis. Semin Immunopathol 31, 113–125 (2009). https://doi.org/10.1007/s00281-009-0148-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-009-0148-5

Keywords

Search

Navigation