Download PDF
CC BY-NC-ND 4.0 · Sleep Sci 2025; 18(01): e109-e113
DOI: 10.1055/s-0044-1788287
Review Article

Obstructive Sleep Apnea Endophenotypes

Janna Rae Raphelson
School of Medicine, University of California San Diego, La Jolla, CA, United States
,
Ana Lucia Fuentes
School of Medicine, University of California San Diego, La Jolla, CA, United States
,
Breanna Holloway
School of Medicine, University of California San Diego, La Jolla, CA, United States
,
Atul Malhotra 
School of Medicine, University of California San Diego, La Jolla, CA, United States
› Author Affiliations Funding Source The authors declare that they have received funding from the U.S. Department of Health and Human Services, the National Institutes of Health, and the National Heart, Lung, and Blood Institute.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Obstructive sleep apnea (OSA) is a common disorder with major neurocognitive and cardiometabolic consequences. It is now recognized as a heterogeneous disease with multiple different underlying mechanisms (endotypes) as well as variable clinical expression of disease (phenotypes). The importance of this variability is emphasized since one variable in isolation typically explains only a fraction of the variance in OSA occurrence. This review provides an update of what is known regarding OSA heterogeneity. The importance of OSA endotypes is discussed in the context of how mechanism might affect disease management and/or design of subsequent randomized trials. Further research is recommended to provide further validation of OSA endophenotypes and how this information may influence clinical management in the future.

Keywords

sleep - lung - hypoxemia - arousal


Publication History

Received: 29 November 2023

Accepted: 05 February 2024

Article published online:
09 August 2024

© 2024. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Benjafield AV, Ayas NT, Eastwood PR. et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med 2019; 7 (08) 687-698
    CrossrefPubMedSearch in Google Scholar
  • 2 Heinzer R, Vat S, Marques-Vidal P. et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med 2015; 3 (04) 310-318
    CrossrefPubMedSearch in Google Scholar
  • 3 Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014; 383 (9918) 736-747
    CrossrefPubMedSearch in Google Scholar
  • 4 Malhotra A, Mesarwi O, Pepin JL, Owens RL. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med 2020; 26 (06) 609-614
    CrossrefPubMedSearch in Google Scholar
  • 5 Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med 2003; 168 (06) 645-658
    CrossrefPubMedSearch in Google Scholar
  • 6 Younes M. Pharyngeal anatomy and severity of obstructive apnea. Am J Respir Crit Care Med 2004; 170 (06) 716
    CrossrefPubMedSearch in Google Scholar
  • 7 Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 2004; 169 (05) 623-633
    CrossrefPubMedSearch in Google Scholar
  • 8 Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010; 90 (01) 47-112
    CrossrefPubMedSearch in Google Scholar
  • 9 Badr MS. Pathogenesis of obstructive sleep apnea. Prog Cardiovasc Dis 1999; 41 (05) 323-330
    CrossrefPubMedSearch in Google Scholar
  • 10 Isono S, Feroah TR, Hajduk EA, Brant R, Whitelaw WA, Remmers JE. Interaction of cross-sectional area, driving pressure, and airflow of passive velopharynx. J Appl Physiol 1997; 83 (03) 851-859
    CrossrefPubMedSearch in Google Scholar
  • 11 Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997; 82 (04) 1319-1326
    CrossrefPubMedSearch in Google Scholar
  • 12 Schwab RJ. Upper airway imaging. Clin Chest Med 1998; 19 (01) 33-54
    CrossrefPubMedSearch in Google Scholar
  • 13 Schwab RJ. Imaging for the snoring and sleep apnea patient. Dent Clin North Am 2001; 45 (04) 759-796
    CrossrefPubMedSearch in Google Scholar
  • 14 Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 1992; 89 (05) 1571-1579
    CrossrefPubMedSearch in Google Scholar
  • 15 Khoo MC. Determinants of ventilatory instability and variability. Respir Physiol 2000; 122 (2-3): 167-182
    CrossrefPubMedSearch in Google Scholar
  • 16 Khoo M. Theoretical models of periodic breathing. In: Bradley T, Floras J. eds. Sleep apnea implications in cardiovascular and cerebrovascular disease. 146. New York: Marcel Dekker; 2000: 355-384
    Search in Google Scholar
  • 17 Khoo MC. Using loop gain to assess ventilatory control in obstructive sleep apnea. Am J Respir Crit Care Med 2001; 163 (05) 1044-1045
    CrossrefPubMedSearch in Google Scholar
  • 18 Hlastala MP, Berger AJ. Chemical Control of Breathing. Physiology of Respiration. 2nd ed. New York:: Oxford University Press;; 2001. . p. 151, 5.
    Search in Google Scholar
  • 19 Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2001; 163 (05) 1181-1190
    CrossrefPubMedSearch in Google Scholar
  • 20 Wellman A, Malhotra A, Jordan AS, Schory K, Gautam S, White DP. Chemical control stability in the elderly. J Physiol 2007; 581 (Pt 1): 291-298
    CrossrefPubMedSearch in Google Scholar
  • 21 Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997; 20 (08) 654-675
    CrossrefPubMedSearch in Google Scholar
  • 22 Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 1990; 142 (02) 295-300
    CrossrefPubMedSearch in Google Scholar
  • 23 Stanchina M, Malhotra A, Fogel RB. et al. Genioglossus muscle responsiveness to chemical and mechanical loading during NREM sleep. Am J Respir Crit Care Med 2002; 165: 945-949
    CrossrefPubMedSearch in Google Scholar
  • 24 Malhotra A, Deacon N, Powell F, Katz ES. Adaptive responses using obstructive sleep apnea as the paradigm. Physiology (Bethesda) 2014; 29 (03) 153-155
    PubMedSearch in Google Scholar
  • 25 Jordan AS, Wellman A, Heinzer RC. et al. Mechanisms used to restore ventilation after partial upper airway collapse during sleep in humans. Thorax 2007; 62 (10) 861-867
    CrossrefPubMedSearch in Google Scholar
  • 26 Jordan AS, White DP, Lo YL. et al. Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009; 32 (03) 361-368
    CrossrefPubMedSearch in Google Scholar
  • 27 Edwards BA, Sands SA, Eckert DJ. et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol 2012; 590 (05) 1199-1211
    CrossrefPubMedSearch in Google Scholar
  • 28 Edwards BA, Sands SA, Owens RL. et al. The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility. Sleep 2016; 39 (11) 1973-1983
    CrossrefPubMedSearch in Google Scholar
  • 29 Kezirian EJ, Malhotra A, Goldberg AN, White DP. Changes in obstructive sleep apnea severity, biomarkers, and quality of life after multilevel surgery. Laryngoscope 2010; 120 (07) 1481-1488
    CrossrefPubMedSearch in Google Scholar
  • 30 Kezirian EJ, Simmons M, Schwab RJ. et al. Making Sense of the Noise: Toward Rational Treatment for Obstructive Sleep Apnea. Am J Respir Crit Care Med 2020; 202 (11) 1503-1508
    CrossrefPubMedSearch in Google Scholar
  • 31 Sands SA, Edwards BA, Terrill PI. et al. Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J 2018; 52 (03) 1800674
    CrossrefPubMedSearch in Google Scholar
  • 32 Edwards BA, Connolly JG, Campana LM. et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep 2013; 36 (02) 281-285
    CrossrefPubMedSearch in Google Scholar
  • 33 Edwards BA, O'Driscoll DM, Ali A, Jordan AS, Trinder J, Malhotra A. Aging and sleep: physiology and pathophysiology. Semin Respir Crit Care Med 2010; 31 (05) 618-633
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Edwards BA, Wellman A, Sands SA. et al. Obstructive sleep apnea in older adults is a distinctly different physiological phenotype. Sleep 2014; 37 (07) 1227-1236
    CrossrefPubMedSearch in Google Scholar
  • 35 Kobayashi M, Namba K, Tsuiki S, Matsuo A, Sugiura T, Inoue Y. Clinical characteristics in two subgroups of obstructive sleep apnea syndrome in the elderly: comparison between cases with elderly and middle-age onset. Chest 2010; 137 (06) 1310-1315
    CrossrefPubMedSearch in Google Scholar
  • 36 Ancoli-Israel S. Sleep problems in older adults: putting myths to bed. Geriatrics 1997; 52 (01) 20-30
    PubMedSearch in Google Scholar
  • 37 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 (02) 269-277
    CrossrefPubMedSearch in Google Scholar
  • 38 Lavie P, Herer P, Lavie L. Mortality risk factors in sleep apnoea: a matched case-control study. J Sleep Res 2007; 16 (01) 128-134
    CrossrefPubMedSearch in Google Scholar
  • 39 Stanchina M, Robinson K, Corrao W, Donat W, Sands S, Malhotra A. Clinical Use of Loop Gain Measures to Determine Continuous Positive Airway Pressure Efficacy in Patients with Complex Sleep Apnea. A Pilot Study. Ann Am Thorac Soc 2015; 12 (09) 1351-1357
    CrossrefPubMedSearch in Google Scholar
  • 40 Li Y, Ye J, Han D. et al. Physiology-Based Modeling May Predict Surgical Treatment Outcome for Obstructive Sleep Apnea. J Clin Sleep Med 2017; 13 (09) 1029-1037
    CrossrefPubMedSearch in Google Scholar
  • 41 Li Y, Ye J, Han D. et al. The Effect of Upper Airway Surgery on Loop Gain in Obstructive Sleep Apnea. J Clin Sleep Med 2019; 15 (06) 907-913
    CrossrefPubMedSearch in Google Scholar
  • 42 Ye L, Pien GW, Ratcliffe SJ. et al. The different clinical faces of obstructive sleep apnoea: a cluster analysis. Eur Respir J 2014; 44 (06) 1600-1607
    CrossrefPubMedSearch in Google Scholar
  • 43 Mazzotti DR, Keenan BT, Lim DC, Gottlieb DJ, Kim J, Pack AI. Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes. Am J Respir Crit Care Med 2019; 200 (04) 493-506
    CrossrefPubMedSearch in Google Scholar
  • 44 Mazzotti DR, Lim DC, Sutherland K. et al. Opportunities for utilizing polysomnography signals to characterize obstructive sleep apnea subtypes and severity. Physiol Meas 2018; 39 (09) 09TR01
    CrossrefPubMedSearch in Google Scholar
  • 45 McEvoy RD, Antic NA, Heeley E. et al; SAVE Investigators and Coordinators. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med 2016; 375 (10) 919-931
    CrossrefPubMedSearch in Google Scholar
  • 46 Sánchez-de-la-Torre M, Khalyfa A, Sánchez-de-la-Torre A. et al; Spanish Sleep Network. Precision Medicine in Patients With Resistant Hypertension and Obstructive Sleep Apnea: Blood Pressure Response to Continuous Positive Airway Pressure Treatment. J Am Coll Cardiol 2015; 66 (09) 1023-1032
    CrossrefPubMedSearch in Google Scholar
  • 47 Sánchez-de-la-Torre M, Sánchez-de-la-Torre A, Bertran S. et al; Spanish Sleep Network. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med 2020; 8 (04) 359-367
    CrossrefPubMedSearch in Google Scholar
  • 48 Azarbarzin A, Sands SA, Taranto-Montemurro L, Redline S, Wellman A. Hypoxic burden captures sleep apnoea-specific nocturnal hypoxaemia. Eur Heart J 2019; 40 (35) 2989-2990
    CrossrefPubMedSearch in Google Scholar
  • 49 Azarbarzin A, Sands SA, Taranto-Montemurro L. et al. The Sleep Apnea-Specific Hypoxic Burden Predicts Incident Heart Failure. Chest 2020; 158 (02) 739-750
    CrossrefPubMedSearch in Google Scholar
  • 50 Azarbarzin A, Sands SA, White DP, Redline S, Wellman A. The hypoxic burden: a novel sleep apnoea severity metric and a predictor of cardiovascular mortality-Reply to 'The hypoxic burden: also known as the desaturation severity parameter'. Eur Heart J 2019; 40 (35) 2994-2995
    CrossrefPubMedSearch in Google Scholar
  • 51 Shang F, Wang SC, Gongol B. et al. Obstructive Sleep Apnea-induced Endothelial Dysfunction is Mediated by miR-210. Am J Respir Crit Care Med 2022
    Search in Google Scholar
  • 52 Sánchez-de-la-Torre M, Gracia-Lavedan E, Benitez ID. et al. Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis. JAMA 2023; 330 (13) 1255-1265
    CrossrefPubMedSearch in Google Scholar
  • 53 Platt AB, Kuna ST, Field SH. et al. Adherence to sleep apnea therapy and use of lipid-lowering drugs: a study of the healthy-user effect. Chest 2010; 137 (01) 102-108
    CrossrefPubMedSearch in Google Scholar
  • 54 Karmpaliotis D, Kosmidou I, Ingenito EP. et al. Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2002; 283 (03) L585-L595
    CrossrefPubMedSearch in Google Scholar
  • 55 Gottlieb DJ, Lederer DJ, Kim JS. et al. Effect of positive airway pressure therapy of obstructive sleep apnea on circulating Angiopoietin-2. Sleep Med 2022; 96: 119-121
    CrossrefPubMedSearch in Google Scholar
  • 56 Sands SA, Edwards BA, Terrill PI. et al. Phenotyping Pharyngeal Pathophysiology using Polysomnography in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 2018; 197 (09) 1187-1197
    CrossrefPubMedSearch in Google Scholar
  • 57 Edwards BA, Eckert DJ, McSharry DG. et al. Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2014; 190 (11) 1293-1300
    CrossrefPubMedSearch in Google Scholar
  • 58 Orr JE, Sands SA, Edwards BA. et al. Measuring Loop Gain via Home Sleep Testing in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 2018; 197 (10) 1353-1355
    CrossrefPubMedSearch in Google Scholar
  • 59 Tolbert TM, Schoenholz RL, Parekh A. et al. Night-to-night reliability and agreement of obstructive sleep apnea pathophysiologic mechanisms estimated with phenotyping using polysomnography in cognitively normal elderly participants. Sleep 2023; 46 (08) zsad058
    CrossrefPubMedSearch in Google Scholar
  • 60 Younes M, Schwab R. Con: can physiological risk factors for obstructive sleep apnea be determined by analysis of data obtained from routine polysomnography?. Sleep 2023; 46 (05) zsac158
    CrossrefPubMedSearch in Google Scholar
  • 61 Sands SA, Edwards BA. Pro: can physiological risk factors for obstructive sleep apnea be determined by analysis of data obtained from routine polysomnography?. Sleep 2023; 46 (05) zsac310
    CrossrefPubMedSearch in Google Scholar
  • 62 Montesi SB, Bajwa EK, Malhotra A. Biomarkers of sleep apnea. Chest 2012; 142 (01) 239-245
    CrossrefPubMedSearch in Google Scholar
  • 63 Shih JL, Malhotra A. Could vitamins be helpful to patients with sleep apnea?. Chest 2011; 139 (02) 237-238
    CrossrefPubMedSearch in Google Scholar
  • 64 Malhotra A, Ayappa I, Ayas N. et al. Metrics of sleep apnea severity: beyond the apnea-hypopnea index. Sleep 2021; 44 (07) zsab030
    CrossrefPubMedSearch in Google Scholar
  • 65 Horner RL, Hughes SW, Malhotra A. State-dependent and reflex drives to the upper airway: basic physiology with clinical implications. J Appl Physiol 2014; 116 (03) 325-336
    CrossrefPubMedSearch in Google Scholar
  • 66 Eckert DJ, Owens RL, Kehlmann GB. et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond) 2011; 120 (12) 505-514
    CrossrefPubMedSearch in Google Scholar
  • 67 Patel SR, Althouse AD. Robust Methods Are Needed to Evaluate the Pharmacologic Treatment of Obstructive Sleep Apnea. Am J Respir Crit Care Med 2019; 199 (10) 1294-1295
    CrossrefPubMedSearch in Google Scholar
  • 68 Carson SS, Goss CH, Patel SR. et al; American Thoracic Society Comparative Effectiveness Research Working Group. An official American Thoracic Society research statement: comparative effectiveness research in pulmonary, critical care, and sleep medicine. Am J Respir Crit Care Med 2013; 188 (10) 1253-1261
    CrossrefPubMedSearch in Google Scholar