Skip to main content

Chronic intermittent hypoxia in obstructive sleep apnea: a narrative review from pathophysiological pathways to a precision clinical approach

Abstract

Obstructive sleep apnea syndrome (OSAS) is a prevalent condition caused by dynamic upper airway collapse during sleep. The pathological impact and consequences are due to chronic intermittent hypoxia (CIH). Hypoxia increases the expression of several inflammatory stress markers and endothelial dysfunction. Recent studies suggest that patients with a similar AHI but with severe nocturnal hypoxia using oximetric parameters, such as the lowest saturation of oxygen during the night (min SaO2), percentage of total sleep time with oxygen saturation < 90% (T90) or the oxygen desaturation index (ODI-3%), commonly reported during the sleep study, are indicative of the increased expression of inflammatory markers due to severe nocturnal hypoxia and CIH during the night compared to subjects with moderate-severe OSAS without severe nocturnal hypoxia. The aim of this review is to describe physiological pathways involved in OSAS and their clinical consequences, focused in CIH and oximetric parameters showed in sleep study and their potential utility as inflammatory markers.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Malhotra A, White DP (2002) Obstructive sleep apnoea. Lancet. 360(9328):237–245

    Article  PubMed  Google Scholar 

  2. Lee W, Nagubadi S, Kryger MH, Mokhlesi B (2008) Epidemiology of obstructive sleep apnea: a population-based perspective. Expert Rev Respir Med 2(3):349–364

    Article  PubMed  PubMed Central  Google Scholar 

  3. Park JG, Ramar K, Olson EJ (2011) Updates on definition, consequences, and management of obstructive sleep apnea. Mayo Clin Proc 86(6):549–554 quiz 54-5

    Article  PubMed  PubMed Central  Google Scholar 

  4. Redline S, Sotres-Alvarez D, Loredo J, Hall M, Patel SR, Ramos A, Shah N, Ries A, Arens R, Barnhart J, Youngblood M, Zee P, Daviglus ML (2014) Sleep-disordered breathing in Hispanic/Latino individuals of diverse backgrounds. The Hispanic Community Health Study/Study of Latinos. Am J Respir Crit Care Med 189(3):335–344

    Article  PubMed  PubMed Central  Google Scholar 

  5. Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, Tobback N, Mooser V, Preisig M, Malhotra A, Waeber G, Vollenweider P, Tafti M, Haba-Rubio J (2015) Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med 3(4):310–318

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Sanchez-de-la-Torre M, Campos-Rodriguez F, Barbe F (2013) Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 1(1):61–72

    Article  PubMed  Google Scholar 

  7. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P, Clinical Guidelines Committee of the American College of Physicians (2014) Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med 161(3):210–220

    Article  PubMed  Google Scholar 

  8. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG (2017) Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 13(3):479–504

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chai-Coetzer CL, Antic NA, Hamilton GS, McArdle N, Wong K, Yee BJ, Yeo A, Ratnavadivel R, Naughton MT, Roebuck T, Woodman R, McEvoy R (2017) Physician decision making and clinical outcomes with laboratory polysomnography or limited-channel sleep studies for obstructive sleep apnea: a randomized trial. Ann Intern Med 166(5):332–340

    Article  PubMed  Google Scholar 

  10. Lam JC, Mak JC, Ip MS (2012) Obesity, obstructive sleep apnoea and metabolic syndrome. Respirology. 17(2):223–236

    Article  PubMed  Google Scholar 

  11. Vicente E, Marin JM, Carrizo SJ, Osuna CS, González R, Marin-Oto M, Forner M, Vicente P, Cubero P, Gil AV, Soler X (2016) Upper airway and systemic inflammation in obstructive sleep apnoea. Eur Respir J 48(4):1108–1117

    CAS  Article  PubMed  Google Scholar 

  12. Lui MM, Sau-Man M (2012) OSA and atherosclerosis. J Thorac Dis 4(2):164–172

    PubMed  PubMed Central  Google Scholar 

  13. Feng J, Zhang D, Chen B (2012) Endothelial mechanisms of endothelial dysfunction in patients with obstructive sleep apnea. Sleep Breath 16(2):283–294

    Article  PubMed  Google Scholar 

  14. Floras JS (2018) Sleep apnea and cardiovascular disease: an enigmatic risk factor. Circ Res 122(12):1741–1764

    CAS  Article  PubMed  Google Scholar 

  15. Labarca G, Cruz NR, Descalzi F (2014) Multisystemic involvement in obstructive sleep apnea. Rev Med Chil 142(6):748–757

    Article  PubMed  Google Scholar 

  16. Zamarron C, Valdes Cuadrado L, Alvarez-Sala R (2013) Pathophysiologic mechanisms of cardiovascular disease in obstructive sleep apnea syndrome. Pulm Med 2013:521087

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ning Y, Zhang TS, Wen WW et al (2019) Effects of continuous positive airway pressure on cardiovascular biomarkers in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. Sleep Breath 23(1):77–86

    Article  PubMed  Google Scholar 

  18. McArdle N, Hillman D, Beilin L, Watts G (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

    CAS  Article  PubMed  Google Scholar 

  19. Akahoshi T, Uematsu A, Akashiba T et al (2010) Obstructive sleep apnoea is associated with risk factors comprising the metabolic syndrome. Respirology. 15(7):1122–1126

    Article  PubMed  Google Scholar 

  20. Takama N, Kurabayashi M (2008) Relationship between metabolic syndrome and sleep-disordered breathing in patients with cardiovascular disease--metabolic syndrome as a strong factor of nocturnal desaturation. Intern Med 47(8):709–715

    Article  PubMed  Google Scholar 

  21. Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY (2011) Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 19(11):2167–2174

    CAS  Article  Google Scholar 

  22. Polotsky VY, Patil SP, Savransky V, Laffan A, Fonti S, Frame LA, Steele KE, Schweizter MA, Clark JM, Torbenson MS, Schwartz AR (2009) Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med 179(3):228–234

    Article  PubMed  Google Scholar 

  23. Newman AB, Foster G, Givelber R, Nieto FJ, Redline S, Young T (2005) Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 165(20):2408–2413

    Article  PubMed  Google Scholar 

  24. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J (2000) Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 284(23):3015–3021

    CAS  Article  PubMed  Google Scholar 

  25. Petermann F, Villagran M, Troncoso C et al (2018) Association between FTO (ns9939609) genotype and adiposity markers in Chilean adults. Rev Med Chil 146(6):717–726

    Article  PubMed  Google Scholar 

  26. Gkouskou K, Vlastos IM, Chaniotis D, Markaki A, Choulakis K, Prokopakis E. Nutrigenetic genotyping study in relation to sleep apnea clinical score. Sleep Breath. 2018.

  27. do Carmo JM, da Silva AA, Moak SP, da Silva FS, Spradley FT, Hall JE (2019) Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia. Acta Physiol (Oxford) 225(4):e13222

    Article  CAS  Google Scholar 

  28. Yang D, Liu Z, Yang H, Luo Q (2013) Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath 17(1):33–38

    Article  PubMed  Google Scholar 

  29. Iftikhar IH, Blankfield RP (2012) Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis. Lung. 190(6):605–611

    CAS  Article  PubMed  Google Scholar 

  30. Labarca G, Reyes T, Jorquera J, Dreyse J, Drake L (2018) CPAP in patients with obstructive sleep apnea and type 2 diabetes mellitus: systematic review and meta-analysis. Clin Respir J 12(8):2361–2368

    Article  PubMed  Google Scholar 

  31. Aronsohn RS, Whitmore H, Van Cauter E, Tasali E (2010) Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 181(5):507–513

    Article  PubMed  Google Scholar 

  32. Jouet P, Sabate JM, Maillard D et al (2007) Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study. Obes Surg 17(4):478–485

    Article  PubMed  Google Scholar 

  33. Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40(6):439–452

    CAS  Article  PubMed  Google Scholar 

  34. Nath B, Szabo G (2012) Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. Hepatology. 55(2):622–633

    CAS  Article  PubMed  Google Scholar 

  35. Byrne TJ, Parish JM, Somers V, Aqel BA, Rakela J (2012) Evidence for liver injury in the setting of obstructive sleep apnea. Ann Hepatol 11(2):228–231

    CAS  Article  PubMed  Google Scholar 

  36. Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R (2013) Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obesity reviews : an official journal of the International Association for the Study of Obesity 14(5):417–431

    CAS  Article  Google Scholar 

  37. Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342(19):1378–1384

    CAS  Article  PubMed  Google Scholar 

  38. Labarca G, Valdivia G, Onate A et al (2019) Prevalence of STOP BANG questionnaire and association with major cardiovascular events in hospitalized population: is it enough with currently used cardiovascular risk measurements? Sleep Med 61:82–87

    Article  PubMed  Google Scholar 

  39. Kuniyoshi FH, Garcia-Touchard A, Gami AS, Romero-Corral A, van der Walt C, Pusalavidyasagar S, Kara T, Caples SM, Pressman GS, Vasquez EC, Lopez-Jimenez F, Somers VK (2008) Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 52(5):343–346

    Article  PubMed  Google Scholar 

  40. Arias MA, Garcia-Rio F, Alonso-Fernandez A, Mediano O, Martinez I, Villamor J (2005) Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 112(3):375–383

    Article  PubMed  Google Scholar 

  41. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O'Connor GT, Boland LL, Schwartz JE, Samet JM (2001) Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163(1):19–25

    CAS  Article  PubMed  Google Scholar 

  42. Mehra R, Benjamin EJ, Shahar E et al (2006) Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 173(8):910–916

    Article  PubMed  PubMed Central  Google Scholar 

  43. Schulz R, Flototto C, Jahn A et al (2006) Circulating adrenomedullin in obstructive sleep apnoea. J Sleep Res 15(1):89–95

    Article  PubMed  Google Scholar 

  44. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK (1999) Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17(1):61–66

    CAS  Article  PubMed  Google Scholar 

  45. Lu D, Abulimiti A, Wu T, Abudureyim A, Li N (2018) Pulmonary surfactant-associated proteins and inflammatory factors in obstructive sleep apnea. Sleep Breath 22(1):99–107

    Article  PubMed  Google Scholar 

  46. Qaseem A, Holty JE, Owens DK, Dallas P, Starkey M, Shekelle P (2013) Management of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med

  47. Labarca G, Cruz R, Jorquera J (2018) Continuous positive airway pressure in patients with obstructive sleep apnea and non-alcoholic steatohepatitis: a systematic review and meta-analysis. J Clin Sleep Med 14(1):133–139

    Article  PubMed  PubMed Central  Google Scholar 

  48. Montesi SB, Edwards BA, Malhotra A, Bakker JP (2012) 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 8(5):587–596

    Article  PubMed  PubMed Central  Google Scholar 

  49. Sun H, Shi J, Li M, Chen X (2013) Impact of continuous positive airway pressure treatment on left ventricular ejection fraction in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. PLoS One 8(5):e62298

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Abud R, Salgueiro M, Drake L, Reyes T, Jorquera J, Labarca G (2019) Efficacy of continuous positive airway pressure (CPAP) preventing type 2 diabetes mellitus in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and insulin resistance: a systematic review and meta-analysis. Sleep Med 62:14–21

    Article  PubMed  Google Scholar 

  51. Yu J, Zhou Z, McEvoy RD et al (2017) Association of positive airway pressure with cardiovascular events and death in adults with sleep apnea: a systematic review and meta-analysis. JAMA. 318(2):156–166

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kaczmarek E, Bakker JP, Clarke DN, Csizmadia E, Kocher O, Veves A, Tecilazich F, O'Donnell CP, Ferran C, Malhotra A (2013) Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. PLoS One 8(7):e70559

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Yilmaz Avci A, Avci S, Lakadamyali H, Can U (2017) Hypoxia and inflammation indicate significant differences in the severity of obstructive sleep apnea within similar apnea-hypopnea index groups. Sleep Breath 21(3):703–711

    Article  PubMed  Google Scholar 

  54. Gagnadoux F, Le Vaillant M, Paris A et al (2016) Relationship between OSA clinical phenotypes and CPAP treatment outcomes. Chest. 149(1):288–290

    Article  PubMed  Google Scholar 

  55. Svensson M, Venge P, Janson C, Lindberg E (2012) Relationship between sleep-disordered breathing and markers of systemic inflammation in women from the general population. J Sleep Res 21(2):147–154

    Article  PubMed  Google Scholar 

  56. Gouveris H, Bahr K, Jahn C, Matthias C, Simon P (2018) The apnea-hypopnea index underestimates systemic inflammation in women with sleep-disordered breathing. J Women's Health (Larchmt) 27(7):920–926

    Article  Google Scholar 

  57. Zhang XB, Zen HQ, Lin QC, Chen GP, Chen LD, Chen H (2014) TST, as a polysomnographic variable, is superior to the apnea hypopnea index for evaluating intermittent hypoxia in severe obstructive sleep apnea. Eur Arch Otorhinolaryngol 271(10):2745–2750

    Article  PubMed  Google Scholar 

  58. Ding H, Huang JF, Xie HS, Wang BY, Lin T, Zhao JM, Lin QC (2019) The association between glycometabolism and nonalcoholic fatty liver disease in patients with obstructive sleep apnea. Sleep Breath 23(1):373–378

    Article  PubMed  Google Scholar 

  59. Martinez-Garcia MA, Campos-Rodriguez F, Barbe F, Gozal D, Agusti A (2019) Precision medicine in obstructive sleep apnoea. Lancet Respir Med 7(5):456–464

    Article  PubMed  Google Scholar 

  60. Labarca G, Campos J, Thibaut K, Dreyse J, Jorquera J (2019) Do T90 and SaO2 nadir identify a different phenotype in obstructive sleep apnea? Sleep Breath

  61. Punjabi NM (2016) COUNTERPOINT: is the apnea-hypopnea index the best way to quantify the severity of sleep-disordered breathing? No Chest 149(1):16–19

    Article  PubMed  Google Scholar 

  62. Stamatakis K, Sanders MH, Caffo B, Resnick HE, Gottlieb DJ, Mehra R, Punjabi NM (2008) Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. Sleep. 31(7):1018–1024

    PubMed  PubMed Central  Google Scholar 

  63. Butler MP, Emch JT, Rueschman M, Sands SA, Shea SA, Wellman A, Redline S (2019) Apnea-hypopnea event duration predicts mortality in men and women in the Sleep Heart Health Study. Am J Respir Crit Care Med 199(7):903–912

    Article  PubMed  PubMed Central  Google Scholar 

  64. Azarbarzin A, Sands SA, Stone KL et al (2019) The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the osteoporotic fractures in men study and the Sleep Heart Health Study. Eur Heart J 40(14):1149–1157

    Article  PubMed  Google Scholar 

  65. Sakairi Y, Nakajima T, Yasufuku K, Ikebe D, Kageyama H, Soda M, Takeuchi K, Itami M, Iizasa T, Yoshino I, Mano H, Kimura H (2010) EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Clin Cancer Res 16(20):4938–4945

    CAS  Article  PubMed  Google Scholar 

  66. Stradling JR, Schwarz EI, Schlatzer C, Manuel AR, Lee R, Antoniades C, Kohler M (2015) Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials. Eur Respir J 46(4):1065–1071

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Campos-Rodriguez F, Asensio-Cruz MI, Cordero-Guevara J et al (2019) Effect of continuous positive airway pressure on inflammatory, antioxidant, and depression biomarkers in women with obstructive sleep apnea: a randomized controlled trial. Sleep.

  68. Thunstrom E, Glantz H, Yucel-Lindberg T, Lindberg K, Saygin M, Peker Y. CPAP does not reduce inflammatory biomarkers in patients with coronary artery disease and nonsleepy obstructive sleep apnea: a randomized controlled trial. Sleep. 2017;40(11).

  69. MacIver DH, Adeniran I, MacIver IR, Revell A, Zhang H (2016) Physiological mechanisms of pulmonary hypertension. Am Heart J 180:1–11

    CAS  Article  PubMed  Google Scholar 

  70. MacIver DH, Dayer MJ, Harrison AJ (2013) A general theory of acute and chronic heart failure. Int J Cardiol 165(1):25–34

    Article  PubMed  Google Scholar 

  71. Domej W, Oettl K, Renner W (2014) Oxidative stress and free radicals in COPD--implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis 9:1207–1224

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Illan Gomez F, Gonzalvez Ortega M, Aragon Alonso A et al (2016) Obesity, endothelial function and inflammation: the effects of weight loss after bariatric surgery. Nutr Hosp 33(6):1340–1346

    Article  PubMed  Google Scholar 

  73. Ocakli B, Tuncay E, Gungor S et al (2018) Inflammatory markers in patients using domiciliary non-invasive mechanical ventilation: C reactive protein, procalcitonin, neutrophil lymphocyte ratio. Front Public Health 6:245

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Dr. Labarca: principal investigator, data extraction, data analysis, manuscript editing, and final approval

Dr. Gower, Lamperti: data extraction, data synthesis, manuscript editing, and final approval

Dr. Dreyse, Jorquera: data conception, critical analysis, manuscript editing, and final approval

Corresponding author

Correspondence to Gonzalo Labarca.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

This article does not require informed consent. This article does not contain any studies with animals performed by any of the authors

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Comments

Obstructive sleep apnea (OSA) is associated with multiple comorbidities, specifically metabolic syndrome and thus remains a serious health issue. Significant clinical as well as basic research, and some review articles have described the pathways that lead to various pathophysiological manifestations

This article by Dr Labarca et al provides an interesting narrative review of these pathophysiological pathways, summarizes its clinical consequences in multiple organ systems, and its effects and association with inflammatory markers. It is unique as it narrows its focus on oximeteric parameters noted on the sleep study, and highlights the current literature that identifies this hypoxia or the hypoxic burden as an element of greater risk and worse prognosis, even in patients with same or similar AHI. It recognizes limitations of the current literature in being able to discern the perfect oximetric parameter that would identify the different "phenotypes" of OSA, that may be associated with worse clinical outcomes and thus calls for further research in this area.

Toshita Kumar Bristol, CT, USA

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Labarca, G., Gower, J., Lamperti, L. et al. Chronic intermittent hypoxia in obstructive sleep apnea: a narrative review from pathophysiological pathways to a precision clinical approach. Sleep Breath 24, 751–760 (2020). https://doi.org/10.1007/s11325-019-01967-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11325-019-01967-4

Keywords

  • Obstructive
  • Sleep Apnea
  • Hypoxia
  • Sleep apnea