Skip to main content

Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea

Abstract

Background

Obstructive sleep apnea (OSA) syndrome is associated with cardiovascular complications attributed to endothelial dysfunction. There are contradictory reports on whether lactoferrin is protective or injurious to the blood vessels.

Objectives

To determine circulating plasma lactoferrin level in OSA patients in relation to endothelial dysfunction and to assess its relation to other criteria of OSA.

Patients and methods

In a cross-sectional study, 40 OSA patients were recruited after an established diagnosis in the sleep laboratory of the pulmonary medicine department. Doppler flow-mediated dilatation percentage (FMD%) was tested as an indicator of endothelial function. Anthropometric measurements, systolic and diastolic blood pressure, lipid profile, plasma lactoferrin level, fasting, and 2 h postprandial plasma glucose (PPG) were estimated in the patients and the control groups. Moreover, the apnea–hypopnea index, and the mean and nadir nocturnal oxygen saturation of OSA patients were determined.

Results

OSA patients were found to have significantly higher BMI, waist circumference (WC), neck circumference, fasting plasma glucose (FPG), 2h PPG, low-density lipoprotein-cholesterol, and lower plasma lactoferrin, FMD%, and high-density lipoprotein (HDL)-cholesterol compared with the control group. There was a significant direct correlation between FMD%, as an indicator of endothelial function, and plasma lactoferrin level as well as HDL-cholesterol, and an inverse correlation between FMD% and BMI, WC, FPG, 2h PPG, and basal brachial artery diameter. Multiple regression analysis showed that lactoferrin was the only independent predictor for FMD% among OSA patients.

However, plasma lactoferrin level was inversely correlated with BMI, WC, FPG, and 2h PPG, and was directly correlated with HDL-cholesterol and FMD%. Multiple regression analysis selected BMI and FMD% as the independent predictors for lactoferrin level.

Conclusion

The present study showed that low circulating plasma lactoferrin levels in OSA patients independently predict endothelial dysfunction as assessed by FMD%. High BMI in OSA patients negatively influences plasma lactoferrin levels unrelated to other OSA severity predictors.

References

  1. Vengen IT, Dale AC, Wiseth R, Midthjell K, Videm V. Lactoferrin is a novel predictor of fatal ischemic heart disease in diabetes mellitus type 2: long-term follow-up of the HUNT 1 study. Atherosclerosis 2010; 212: 614–620.

    Article  CAS  PubMed  Google Scholar 

  2. Yeom M, Park J, Lee B, Choi SY, Kim KS, Lee H, et al. Lactoferrin inhibits the inflammatory and angiogenic activation of bovine aortic endothelial cells. Inflamm Res 2011; 60:475–482.

    Article  CAS  PubMed  Google Scholar 

  3. El Solh AA, Akinnusi ME, Baddoura FH, Mankowski CR. Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. Am J Respir Crit Care Med 2007; 175:1186–1191.

    Article  PubMed  Google Scholar 

  4. Ip MSM, Tse HF, Lam B, Tsang KWT, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004; 169:348–353.

    Article  PubMed  Google Scholar 

  5. Patt BT, Jarjoura D, Haddad DN, Sen CK, Roy S, Flavahan NA, et al. Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am J Respir Crit Care Med 2010; 182:1540–1545.

    Article  PubMed  Google Scholar 

  6. Jurado Gámez B, Fernandez Marin MC, Gómez Chaparro JL, Muñoz Cabrera L, Lopez Barea J, Perez Jimenez F, et al. Relationship of oxidative stress and endothelial dysfunction in sleep apnoea. Eur Respir J 2011; 37:873–879.

    Article  PubMed  Google Scholar 

  7. Budhiraja R, Parthasarathy S, Quan SF. Endothelial dysfunction in obstructive sleep apnea. J Clin Sleep Med 2007; 3:409–415.

    Article  PubMed  Google Scholar 

  8. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5:136–143.

    Article  PubMed  Google Scholar 

  9. Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 2002; 166:159–165.

    Article  Google Scholar 

  10. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to Ankle–Brachial Pressure Index. Circulation 2003; 108:2093–2098.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  12. Schulz R, Mahmoudi S, Hattar K, Sibelius ULF, Olschewski H, Mayer K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000; 162 (2 I):566–570.

    Article  CAS  PubMed  Google Scholar 

  13. Moreno Navarrete JM, Ortega FJ, Bassols J, Castro A, Ricart W, Fernández Real JM. Association of circulating lactoferrin concentration and 2 non-synonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin Chem 2008; 54:301–309.

    Article  CAS  PubMed  Google Scholar 

  14. Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005; 62:2540–2548.

    Article  CAS  PubMed  Google Scholar 

  15. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230–1235.

    Article  CAS  Google Scholar 

  16. Wall H, Smith C, Hubbard R. Body mass index and obstructive sleep apnoea in the UK: a cross-sectional study of the over-50 s. Prim Care Respir J 2012; 21:371–376.

    Article  PubMed  Google Scholar 

  17. Rollheim J, Osnes T, Miljeteig H. The relationship between obstructive sleep apnoea and body mass index. Clin Otolaryngol Allied Sci 1997; 22:419–422.

    Article  CAS  PubMed  Google Scholar 

  18. Morris LGT, Kleinberger A, Lee KC, Liberatore LA, Burschtin O. Rapid risk stratification for obstructive sleep apnea, based on snoring severity and body mass index. Otolaryngol Head Neck Surg 2008; 139:615–618.

    Article  PubMed  Google Scholar 

  19. Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: The Sleep Heart Health Study. Arch Intern Med 2002; 162:893–900.

    Article  PubMed  Google Scholar 

  20. Davies RJO, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax 1992; 47:101–105.

    Article  CAS  PubMed  Google Scholar 

  21. Namtvedt SK, Hisdal J, Randby A, Agewall S, Stranden E, Somers VK, et al. Impaired endothelial function in persons with obstructive sleep apnoea: impact of obesity. Heart 2013; 99:30–34.

    Article  CAS  Google Scholar 

  22. Yang HB, Wang Y, Dong MM. Effect of Han-uvulopalatopharyngoplasty on flow-mediated dilatation in patients with moderate or severe obstructive sleep apnea syndrome. Acta Otolaryngol 2012; 132:769–772.

    Article  Google Scholar 

  23. Meyers MR, Gokce N. Endothelial dysfunction in obesity: etiological role in atherosclerosis. Curr Opin Endocrinol Diabetes Obes 2007; 14:365–369.

    Article  CAS  Google Scholar 

  24. De Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction and metabolic consequences. Clin Chem 2008; 54:945–955.

    Article  Google Scholar 

  25. Barbosa JA, Rodrigues AB, Mota CC, Barbosa MM, Simões e Silva AC. Cardiovascular dysfunction in obesity and new diagnostic imaging techniques: the role of noninvasive image methods. Vasc Health Risk Manag 2011; 7:287–295.

    Article  PubMed  Google Scholar 

  26. Gill H, Mugo M, Whaley Connell A, Stump C, Sowers JR. The key role of insulin resistance in the cardiometabolic syndrome. Am J Med Sci 2005; 330:290–294.

    Article  Google Scholar 

  27. Jenssen H, Hancock REW. Antimicrobial properties of lactoferrin. Biochimie 2009; 91:19–29.

    Article  CAS  Google Scholar 

  28. Britigan BE, Lewis TS, Waldschmidt M, McCormick ML, Krieg AM. Lacto-ferrin binds CpG-containing oligonucleotides and inhibits their immuno-stimulatory effects on human B cells. J Immunol 2001; 167:2921–2928.

    Article  CAS  Google Scholar 

  29. Elass Rochard E, Roseanu A, Legrand D, Trif M, Salmon V, Motas C, et al. Lactoferrin-lipopolysaccharide interaction: involvement of the 28–34 loop region of human lactoferrin in the high-affinity binding to Escherichia coli 055B5 lipopolysaccharide. Biochem J 1995; 312:839–845.

    Article  CAS  PubMed  Google Scholar 

  30. Elass E, Masson M, Mazurier J, Legrand D. Lactoferrin inhibits the lipopolysaccharide-induced expression and proteoglycan-binding ability of interleukin-8 in human endothelial cells. Infect Immun 2002; 70: 1860–1866.

    Article  CAS  PubMed  Google Scholar 

  31. Hayashida KI, Takeuchi T, Ozaki T, Shimizu H, Ando K, Miyamoto A, et al. Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats. Am J Physiol Regul Integr Comp Physiol 2004; 286:R359–R365.

    Article  CAS  PubMed  Google Scholar 

  32. Hayashida KI, Takeuchi T, Harada E. Lactoferrin enhances peripheral opioid-mediated antinociception via nitric oxide in rats. Eur J Pharmacol 2004; 484 (2–3): 175–181.

    Article  CAS  PubMed  Google Scholar 

  33. Hayashida KI, Kaneko T, Takeuchi T, Shimizu H, Ando K, Harada E. Oral administration of lactoferrin inhibits inflammation and nociception in rat adjuvant-induced arthritis. J Vet Med Sci 2004; 66:149–154.

    Article  CAS  PubMed  Google Scholar 

  34. Takeuchi T, Shimizu H, Ando K, Harada E. Bovine lactoferrin reduces plasma triacylglycerol and NEFA accompanied by decreased hepatic cholesterol and triacylglycerol contents in rodents. Br J Nutr 2004; 91:533–538.

    Article  CAS  PubMed  Google Scholar 

  35. Vassiliou G, Benoist F, Lau P, Kavaslar GN, McPherson R. The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. J Biol Chem 2001; 276:48823–48830.

    Article  CAS  PubMed  Google Scholar 

  36. Crouch SPM, Slater KJ, Fletcher J. Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin. Blood 1992; 80:235–240.

    Article  CAS  PubMed  Google Scholar 

  37. Ip MSM, Lam B, Ng MMT, Lam WK, Tsang KWT, Lam KSL. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165:670–676.

    Article  PubMed  Google Scholar 

  38. Li YM. Glycation ligand binding motif in lactoferrin: implications in diabetic infection. Adv Exp Med Biol 1998; 443:57–63.

    Article  CAS  PubMed  Google Scholar 

  39. Tsuda H, Sekine K, Ushida Y, Kuhara T, Takasuka N, Iigo M, et al. Milk and dairy products in cancer prevention: focus on bovine lactoferrin. Mutat Res Rev Mutat Res 2000; 462 (2–3):227–233.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Abir Zakaria.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zakaria, A., El Shazly, M. & Rashed, L. Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea. Egypt J Intern Med 25, 86–91 (2013). https://doi.org/10.7123/01.EJIM.0000428097.62173.17

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.7123/01.EJIM.0000428097.62173.17

Keywords