Skip to main content
SpringerLink
Log in

Homocysteine as a predictor of apnea–hypopnea index in obstructive sleep apnea: a longitudinal epidemiological study (EPISONO)

  • Miscellaneous
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Background

Obstructive sleep apnea (OSA) affects nearly 1 billion people globally, and has established links with cardiovascular and neurocognitive complications. Although it has some limitations, the apnea–hypopnea index (AHI) is commonly used to gauge OSA severity and therapeutic response. Homocysteine (Hcy) metabolism, when impaired, can elicit cellular senescence mechanisms that may be shared with OSA. Hence, our objective was to explore the role of Hcy concentrations both as a predictor of AHI values and as a potential risk factor for OSA.

Methods

Involving 1042 volunteers aged 20 to 80 years, the initial study (2007) included polysomnographic evaluations, questionnaires on sleep and general health, as well as biochemical analyses. After an 8-year interval, 715 participants from the initial study were invited for a follow-up assessment in 2015.

Results

Our findings showed that Hcy was a predictor for an increased AHI, and AHI increased over time. Individuals with plasma Hcy concentrations ≥ 15 µmol/L experienced an average AHI increase of 7.43 events/hour ([beta coefficient] β = 7.43; 95%CI 2.73 to 12.13) over time, compared to those with plasma concentrations < 10 µmol/L. A similar trend was apparent in those with plasma Hcy concentrations between 10 ≥  and  < 15 µmol/L, who had an AHI increase with an average beta coefficient of 3.20 events/hour (95%CI 1.01 to 5.39) compared to those with plasma Hcy concentrations < 10 µmol/L.

Conclusions

In summary, our study suggests that increased plasma Hcy concentrations could be considered a risk factor for the development of OSA. These findings highlight that elevated plasma Hcy concentrations can predict the severity of OSA, underscoring their correlation with the AHI.

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

Similar content being viewed by others

References

  1. Thorpy MJ (2012) Classification of sleep disorders. Neurotherapeutics 9:687–701

    Article  PubMed  PubMed Central  Google Scholar 

  2. Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ et al (2019) Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med 7:687–698

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR (2010) Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study. Sleep Med 11:441–446

    Article  PubMed  Google Scholar 

  4. Watson NF (2016) Health care savings: the economic value of diagnostic and therapeutic care for obstructive sleep apnea. J Clin Sleep Med 12:1075–1077

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sullivan F (2016) Hidden health crisis costing America billions. Underdiagnosing and undertreating obstructive sleep apnea draining healthcare system. American Academy of Sleep Medicine.

  6. Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S, Initiative I (2017) Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Circulation 136:1840–1850

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jean-Louis G, Zizi F, Clark LT, Brown CD, McFarlane SI (2008) Obstructive sleep apnea and cardiovascular disease: role of the metabolic syndrome and its components. J Clin Sleep Med 4:261–272

    Article  PubMed  PubMed Central  Google Scholar 

  8. Durgan DJ, Bryan RM Jr (2012) Cerebrovascular consequences of obstructive sleep apnea. J Am Heart Assoc 1:e000091

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sales LV, Bruin VM, D’Almeida V, Pompeia S, Bueno OF, Tufik S et al (2013) Cognition and biomarkers of oxidative stress in obstructive sleep apnea. Clinics 68:449–455

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fiedorczuk P, Polecka A, Walasek M, Olszewska E (2022) Potential diagnostic and monitoring biomarkers of obstructive sleep apnea—umbrella review of meta-analyses. J Clin Med 12:60

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim J, Lee SK, Yoon DW, Shin C (2018) Concurrent presence of obstructive sleep apnea and elevated homocysteine levels exacerbate the development of hypertension: a KoGES six-year follow-up study. Sci Rep 8:2665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Selhub J (1999) Homocysteine metabolism. Annu Rev Nutr 19:217–246

    Article  CAS  PubMed  Google Scholar 

  13. Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC (2005) Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol 289:H2649–H2656

    Article  CAS  PubMed  Google Scholar 

  14. Yuan D, Chu J, Lin H, Zhu G, Qian J, Yu Y et al (2022) Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis. Front Cardiovasc Med 9:1109445

    Article  CAS  PubMed  Google Scholar 

  15. Sun T, Ghosh AK, Eren M, Miyata T, Vaughan DE (2019) PAI-1 contributes to homocysteine-induced cellular senescence. Cell Signal 64:109394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tempaku PF, Mazzotti DR, Hirotsu C, Andersen ML, Xavier G, Maurya PK et al (2016) The effect of the severity of obstructive sleep apnea syndrome on telomere length. Oncotarget 7:69216–69224

    Article  PubMed  PubMed Central  Google Scholar 

  17. Herrmann W, Herrmann M (2022) The controversial role of HCY and vitamin B deficiency in cardiovascular diseases. Nutrients 14:1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Santos-Silva R, Tufik S, Conway SG, Taddei JA, Bittencourt LR (2009) Sao Paulo epidemiologic sleep study: rationale, design, sampling, and procedures. Sleep Med 10:679–685

    Article  PubMed  Google Scholar 

  19. Rosenberg RS, Van Hout S (2013) The American academy of sleep medicine inter-scorer reliability program: sleep stage scoring. J Clin Sleep Med 9:81–87

    Article  PubMed  PubMed Central  Google Scholar 

  20. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK et al (2012) Rules for scoring respiratory events in sleep: update of the 2007 AASM manual for the scoring of sleep and associated events. Deliberations of the sleep apnea definitions task force of the American academy of sleep medicine. J Clin Sleep Med 8:597–619

    Article  PubMed  PubMed Central  Google Scholar 

  21. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP et al (2009) Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 5:263–276

    Article  PubMed  Google Scholar 

  22. de Melo MB, Daldegan-Bueno D, Menezes Oliveira MG, de Souza AL (2022) Beyond ANOVA and MANOVA for repeated measures: Advantages of generalized estimated equations and generalized linear mixed models and its use in neuroscience research. Eur J Neurosci 56:6089–6098

    Article  PubMed  Google Scholar 

  23. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S (1999) Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131:363–375

    Article  CAS  PubMed  Google Scholar 

  24. Kim JH (2019) Multicollinearity and misleading statistical results. Korean J Anesthesiol 72:558–569

    Article  PubMed  PubMed Central  Google Scholar 

  25. Johnston R, Jones K, Manley D (2018) Confounding and collinearity in regression analysis: a cautionary tale and an alternative procedure, illustrated by studies of British voting behaviour. Qual Quant 52:1957–1976

    Article  PubMed  Google Scholar 

  26. Li K, Zhang J, Qin Y, Wei YX (2017) Association between serum homocysteine level and obstructive sleep apnea: a meta-analysis. Biomed Res Int 2017:7234528

    PubMed  PubMed Central  Google Scholar 

  27. Lavie L, Perelman A, Lavie P (2001) Plasma homocysteine levels in obstructive sleep apnea: association with cardiovascular morbidity. Chest 120:900–908

    Article  CAS  PubMed  Google Scholar 

  28. Mitra AK, Bhuiyan AR, Jones EA (2021) Association and risk factors for obstructive sleep apnea and cardiovascular diseases: a systematic review. Diseases 9:88

    Article  PubMed  PubMed Central  Google Scholar 

  29. Familtseva A, Chaturvedi P, Kalani A, Jeremic N, Metreveli N, Kunkel GH et al (2016) Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension. Am J Physiol Cell Physiol 311:C596–C606

    Article  PubMed  PubMed Central  Google Scholar 

  30. Fu Y, Wang X, Kong W (2018) Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol 175:1173–1189

    Article  CAS  PubMed  Google Scholar 

  31. Esse R, Barroso M, Tavares de Almeida I, Castro R (2019) The contribution of homocysteine metabolism disruption to endothelial dysfunction: state-of-the-art. Int J Mol Sci 20:867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mohsenin V (2014) Obstructive sleep apnea and hypertension: a critical review. Curr Hypertens Rep 16:482

    Article  PubMed  Google Scholar 

  33. Ann L, Lee CH, Immen R, Dyken ME, Im K (2023) Older age is associated with positional obstructive sleep apnea. Am J Geriatr Psychiatry 31:943–952

    Article  PubMed  Google Scholar 

  34. Franklin KA, Lindberg E (2015) Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis 7:1311–1322

    PubMed  PubMed Central  Google Scholar 

  35. da Silva VC, Fernandes L, Haseyama EJ, Agamme AL, Guerra Shinohara EM, Muniz MT et al (2014) Effect of vitamin B deprivation during pregnancy and lactation on homocysteine metabolism and related metabolites in brain and plasma of mice offspring. PLoS ONE 9:e92683

    Article  PubMed  PubMed Central  Google Scholar 

  36. de Rezende MM, D’Almeida V (2014) Central and systemic responses to methionine-induced hyperhomocysteinemia in mice. PLoS ONE 9:e105704

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chiu LW, Lin CW, Lin PW, Chai HT, Chang CT, Friedman M et al (2023) Homocysteine levels in severe OSA patients before and after TORS-OSA surgery. Otolaryngol Head Neck Surg 168:1238–1244

    Article  PubMed  Google Scholar 

  38. Jordan W, Berger C, Cohrs S, Rodenbeck A, Mayer G, Niedmann PD et al (2004) CPAP-therapy effectively lowers serum homocysteine in obstructive sleep apnea syndrome. J Neural Transm 111:683–689

    Article  CAS  PubMed  Google Scholar 

  39. Chen X, Niu X, Xiao Y, Dong J, Zhang R, Lu M et al (2014) Effect of continuous positive airway pressure on homocysteine levels in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath 18:687–694

    Article  PubMed  Google Scholar 

  40. Koklesova L, Mazurakova A, Samec M, Biringer K, Samuel SM, Busselberg D et al (2021) Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J 12:477–505

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Associação Fundo de Incentivo à Pesquisa (AFIP), São Paulo, Brazil. MLA, ST and VDA are recipients of CNPq fellowships. MLA is supported by the São Paulo Research Foundation (FAPESP #2020/13467–8).

Author information

Authors and Affiliations

  1. Departamento de Psicobiologia, Universidade Federal de São Paulo, Rua Napoleão de Barros, 925 – CEP, São Paulo, 04024-002, Brazil

    Vanessa Cavalcante-Silva, Priscila Kalil Morelhão, Guilherme Luiz Fernandes, Vânia D’Almeida, Sergio Tufik & Monica L. Andersen

  2. Sleep Institute, São Paulo, Brazil

    Priscila Kalil Morelhão, Sergio Tufik & Monica L. Andersen

Authors
  1. Vanessa Cavalcante-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priscila Kalil Morelhão
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guilherme Luiz Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vânia D’Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergio Tufik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monica L. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monica L. Andersen.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to disclose.

Research involving human participants and/or animals

The current study was approved by the Research Ethics Committee of the Universidade Federal de São Paulo/Hospital, Sao Paulo (National Health Council—Resolution nº 466/2012: 0593/06 and 610.516/2014), and was also registered with ClinicalTrials.gov (NCT00596713). No animals were involved.

Informed consent

Written informed consent was obtained.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cavalcante-Silva, V., Morelhão, P.K., Fernandes, G.L. et al. Homocysteine as a predictor of apnea–hypopnea index in obstructive sleep apnea: a longitudinal epidemiological study (EPISONO). Eur Arch Otorhinolaryngol 281, 3237–3243 (2024). https://doi.org/10.1007/s00405-024-08614-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-024-08614-z

Keywords

Search

Navigation