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Sleep and Breathing

, Volume 23, Issue 1, pp 95–101 | Cite as

Biochemical markers of cardiac dysfunction in children with obstructive sleep apnoea (OSA)

  • Daniel Hirsch
  • Carla A. Evans
  • Melanie Wong
  • Rita Machaalani
  • Karen A. WatersEmail author
Sleep Breathing Physiology and Disorders • Original Article

Abstract

Objectives

We explored relationships between biochemical markers and cardiac responses of children with and without obstructive sleep apnoea (OSA) during exercise. We hypothesised that serum markers of sympathetic nervous system activity and low-grade inflammation would correlate with cardiac responses to exercise in children with or without OSA.

Methodology

The study included 40 of 71 children with previously characterised responses to cardiopulmonary exercise testing. Measures included serum cytokine levels using a multiplex bead-based assay (interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α and IFN-γ). Serum amyloid A (SAA) was quantified by nephelometry, and metanephrine/normetanephrine levels were measured by liquid chromatography, mass-spectroscopy. Comparisons were made between children with and without OSA, and with and without obesity. Relationships between biomarkers and various cardiac parameters were explored by linear regression.

Results

Amongst the 40 children in this study, OSA was present in 23. Compared to the 17 children without OSA, those with OSA had higher resting serum IL-6 levels compared to those without (median 3.22 pg/ml vs. 2.31, p < 0.05). Regarding correlations with cardiac function after adjusting for OSA, IL-8 negatively correlated to heart rate (HR) response following exercise (p = 0.03) and IFN-γ negatively correlated with Stroke Volume Index (SVI) (p = 0.03). Both metanephrine and normetanephrine levels positively correlated with SVI (p = 0.04, p = 0.047; respectively) and QI (p = 0.04, p = 0.04; respectively) during exercise when adjusting for OSA.

Conclusions

Children with OSA have raised morning levels of serum IL-6. Separately, higher levels of IFN-γ and IL-8 and lower levels of metanephrine and normetanephrine related to poorer cardiac function during exercise.

Keywords

Biochemical markers Cardiac responses Obstructive sleep apnoea Cardiopulmonary exercise testing (CPET) 

Abbreviations

BMI

Body mass index

BP

Blood pressure

CRP

C-reactive protein

CPET

Cardiopulmonary exercise testing

GM-CSF

Granulocyte-macrophage colony-stimulating factor

HR

Heart rate

IFN-γ

Interferon-gamma

IL-1β

Interleukin-1-beta

IL-2

Interleukin-2

IL-4

Interleukin-4

IL-6

Interleukin-6

IL-8

Interleukin-8

IL-10

Interleukin-10

OSA

Obstructive sleep apnoea

Q

Cardiac output

QI

Cardiac Output Index

SAA

Serum amyloid A

SV

Stroke volume

SVI

Stroke Volume Index

TNF-α

Tumour necrosis factor-alpha

Notes

Acknowledgements

The authors thank the staff from the David Read Sleep Unit, Respiratory Function Unit, The Children’s Hospital Institute of Sport’s Medicine and Weight Management Service and the Immunology laboratory at The Children’s Hospital at Westmead for contributing and supporting this study. Also, we thank the children and families who agree to participate in this study.

Funding

The National Health and Medical Research Council (NHMRC) provided financial support in the form of a postgraduate scholarship for Dr. Evans. The sponsor had no role in the design or conduct of this research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (name the institution/committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

11325_2018_1666_MOESM1_ESM.docx (39 kb)
ESM 1 (DOCX 38 kb)

References

  1. 1.
    Parish JM, Somers VK (2004) Obstructive sleep apnea and cardiovascular disease. In: Mayo clinic proceedings. ElsevierGoogle Scholar
  2. 2.
    Arias MA, García-Río F, Alonso-Fernández A, Martínez I, Villamor J (2006) Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J 27(9):1106–1113CrossRefGoogle Scholar
  3. 3.
    Guilleminault C, Connolly SJ, Winkle RA (1983) Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 52(5):490–494CrossRefGoogle Scholar
  4. 4.
    Alonso-Fernández A, García-Río F, Arias MA, Mediano O, Pino JM, Martínez I, Villamor J (2006) Obstructive sleep apnoea–hypoapnoea syndrome reversibly depresses cardiac response to exercise. Eur Heart J 27(2):207–215CrossRefGoogle Scholar
  5. 5.
    Kohyama J, Ohinata J, Hasegawa T (2003) Blood pressure in sleep disordered breathing. Arch Dis Child 88(2):139–142CrossRefGoogle Scholar
  6. 6.
    Amin R, Somers VK, McConnell K, Willging P, Myer C, Sherman M, McPhail G, Morgenthal A, Fenchel M, Bean J, Kimball T, Daniels S (2008) Activity-adjusted 24-hour ambulatory blood pressure and cardiac remodeling in children with sleep disordered breathing. Hypertension 51(1):84–91CrossRefGoogle Scholar
  7. 7.
    Xu Z, Li B, Shen K (2013) Ambulatory blood pressure monitoring in Chinese children with obstructive sleep apnea/hypopnea syndrome. Pediatr Pulmonol 48(3):274–279CrossRefGoogle Scholar
  8. 8.
    Walter LM, Nixon GM, Davey MJ, Anderson V, Walker AM, Horne RS (2013) Autonomic dysfunction in children with sleep disordered breathing. Sleep Breath 17(2):605–613CrossRefGoogle Scholar
  9. 9.
    Evans CA, Selvadurai H, Baur LA, Waters KA (2014) Effects of obstructive sleep apnea and obesity on exercise function in children. Sleep 37(6):1103–1110CrossRefGoogle Scholar
  10. 10.
    Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk H-D, Coats AJ (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102(25):3060–3067CrossRefGoogle Scholar
  11. 11.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure an analysis of the cytokine database from the Vesnarinone Trial (VEST). Circulation 103(16):2055–2059CrossRefGoogle Scholar
  12. 12.
    Martins TB, Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Roberts WL, Hill HR (2006) Risk factor analysis of plasma cytokines in patients with coronary artery disease by a multiplexed fluorescent immunoassay. Am J Clin Pathol 125(6):906–913CrossRefGoogle Scholar
  13. 13.
    Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R (2005) C-reactive protein in heart failure. Circulation 112(10):1428–1434CrossRefGoogle Scholar
  14. 14.
    Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M (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):1129–1134CrossRefGoogle Scholar
  15. 15.
    Gozal D, Serpero LD, Capdevila OS, Kheirandish-Gozal L (2008) Systemic inflammation in non-obese children with obstructive sleep apnea. Sleep Med 9(3):254–259CrossRefGoogle Scholar
  16. 16.
    Ryan S, Taylor CT, McNicholas WT (2005) Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112(17):2660–2667CrossRefGoogle Scholar
  17. 17.
    Lago F, Dieguez C, Gómez-Reino J, Gualillo O (2007) The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev 18(3):313–325CrossRefGoogle Scholar
  18. 18.
    Johnson BD, Kip KE, Marroquin OC, Ridker PM, Kelsey SF, Shaw LJ, Pepine CJ, Sharaf B, Merz CNB, Sopko G (2004) Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute–Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109(6):726–732CrossRefGoogle Scholar
  19. 19.
    Kosuge M, Ebina T, Ishikawa T, Hibi K, Tsukahara K, Okuda J, Iwahashi N, Ozaki H, Yano H, Kusama I (2007) Serum amyloid A is a better predictor of clinical outcomes than C-reactive protein in non-ST-segment elevation acute coronary syndromes. Circ J 71(2):186–190CrossRefGoogle Scholar
  20. 20.
    Wang Z, Nakayama T (2010) Inflammation, a link between obesity and cardiovascular disease. Mediat Inflamm 2010:1–17CrossRefGoogle Scholar
  21. 21.
    Liao D, Li X, Vgontzas AN, Liu J, Rodriguez-Colon S, Calhoun S, Bixler EO (2010) Sleep-disordered breathing in children is associated with impairment of sleep stage-specific shift of cardiac autonomic modulation. J Sleep Res 19(2):358–365CrossRefGoogle Scholar
  22. 22.
    O Brien LM, Gozal D (2005) Autonomic dysfunction in children with sleep-disordered breathing. Sleep 28(6):747–752CrossRefGoogle Scholar
  23. 23.
    Chaicharn J, Lin Z, Chen ML, Ward S, Keens T, Khoo M (2009) Model-based assessment of cardiovascular autonomic control in children with obstructive sleep apnea. Sleep 32(7):927–938CrossRefGoogle Scholar
  24. 24.
    Guilleminault C, Khramsov A, Stoohs RA, Kushida C, Pelayo R, Kreutzer ML, Chowdhuri S (2004) Abnormal blood pressure in prepubertal children with sleep-disordered breathing. Pediatr Res 55(1):76–84CrossRefGoogle Scholar
  25. 25.
    Nakra N, Bhargava S, Dzuira J, Caprio S, Bazzy-Asaad A (2008) Sleep-disordered breathing in children with metabolic syndrome: the role of leptin and sympathetic nervous system activity and the effect of continuous positive airway pressure. Pediatrics 122(3):e634–e642CrossRefGoogle Scholar
  26. 26.
    O’Driscoll DM, Horne RS, Davey MJ, Hope SA, Anderson V, Trinder J, Walker AM, Nixon GM (2011) Increased sympathetic activity in children with obstructive sleep apnea: cardiovascular implications. Sleep Med 12(5):483–488CrossRefGoogle Scholar
  27. 27.
    Snow AB, Khalyfa A, Serpero LD, Capdevila OS, Kim J, Buazza MO, Gozal D (2009) Catecholamine alterations in pediatric obstructive sleep apnea: effect of obesity. Pediatr Pulmonol 44(6):559–567CrossRefGoogle Scholar
  28. 28.
    Lam JC, Yan CS, Lai AY, Tam S, Fong DY, Lam B, Ip MS (2009) Determinants of daytime blood pressure in relation to obstructive sleep apnea in men. Lung 187(5):291–298CrossRefGoogle Scholar
  29. 29.
    Eisenhofer G, Kopin IJ, Goldstein DS (2004) Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 56(3):331–349CrossRefGoogle Scholar
  30. 30.
    Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL (2000) CDC growth charts: United States. Adv Data (314): 1–27Google Scholar
  31. 31.
    Society AT (1996) Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 153:866–878CrossRefGoogle Scholar
  32. 32.
    Medicine, A.A.O.S (2007) AASM manual for the scoring of sleep and associated events. American Academy of Sleep Medicine, DarienGoogle Scholar
  33. 33.
    Katz ES, Marcus CL (2005) Diagnosis of obstructive sleep apnea syndrome in infants and children. In: Sheldon SH, Ferber R, Kryger MH (eds) Principles and practice of pediatric sleep medicine. Elsevier Saunders, Philadelphia, pp 197–210CrossRefGoogle Scholar
  34. 34.
    Society, A.T (2003) ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167(2):211CrossRefGoogle Scholar
  35. 35.
    Li AM, Lam HS, Chan M, So HK, Ng SK, Chan I, Lam C, Wing YK (2008) Inflammatory cytokines and childhood obstructive sleep apnoea. Ann Acad Med Singap 37(8):649–654Google Scholar
  36. 36.
    Cheng X, Ding Y, Xia C, Tang T, Yu X, Xie J, Liao M, Yao R, Chen Y, Wang M (2009) Atorvastatin modulates Th1/Th2 response in patients with chronic heart failure. J Card Fail 15(2):158–162CrossRefGoogle Scholar
  37. 37.
    Garcia AG, Wilson RM, Heo J, Murthy NR, Baid S, Ouchi N, Sam F (2012) Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am J Phys Heart Circ Phys 303(5):H587–H596Google Scholar
  38. 38.
    Reifenberg K, Lehr H-A, Torzewski M, Steige G, Wiese E, Küpper I, Becker C, Ott S, Nusser P, Yamamura K-I (2007) Interferon-γ induces chronic active myocarditis and cardiomyopathy in transgenic mice. Am J Pathol 171(2):463–472CrossRefGoogle Scholar
  39. 39.
    Borda E, Leirós CP, Sterin-Borda L, de Bracco MM (1991) Cholinergic response of isolated rat atria to recombinant rat interferon-γ. J Neuroimmunol 32(1):53–59CrossRefGoogle Scholar
  40. 40.
    Tam CS, Wong M, Tarn K, Aouad L, Waters KA (2007) The effect of acute intermittent hypercapnic hypoxia treatment on IL-6, TNF-alpha, and CRP levels in piglets. Sleep 30(6):723–727CrossRefGoogle Scholar
  41. 41.
    Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295CrossRefGoogle Scholar
  42. 42.
    Gileles-Hillel A, Alonso-Álvarez ML, Kheirandish-Gozal L, Peris E, Cordero-Guevara JA, Terán-Santos J, Martinez MG, Jurado-Luque MJ, Corral-Peñafiel J, Duran-Cantolla J (2014) Inflammatory markers and obstructive sleep apnea in obese children: the NANOS study. Mediat Inflamm 2014:1–9CrossRefGoogle Scholar
  43. 43.
    Tam CS, Wong M, McBain R, Bailey S, Waters KA (2006) Inflammatory measures in children with obstructive sleep apnoea. J Paediatr Child Health 42(5):277–282CrossRefGoogle Scholar
  44. 44.
    Gaines J, Vgontzas AN, Fernandez-Mendoza J, Calhoun SL, He F, Liao D, Sawyer MD, Bixler EO (2016) Inflammation mediates the association between visceral adiposity and obstructive sleep apnea in adolescents. Am J Physiol-Endocrinol Metab 311(5):E851–E858CrossRefGoogle Scholar
  45. 45.
    Janssen SP, Gayan-Ramirez G, Van Den Bergh A, Herijgers P, Maes K, Verbeken E, Decramer M (2005) Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 111(8):996–1005CrossRefGoogle Scholar
  46. 46.
    Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257(5068):387–389CrossRefGoogle Scholar
  47. 47.
    Patten M, Krämer E, Bünemann J, Wenck C, Thoenes M, Wieland T, Long C (2001) Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo. Pflugers Arch 442(6):920–927CrossRefGoogle Scholar
  48. 48.
    Zhao Y, He X, Shi X, Huang C, Liu J, Zhou S, Heng C-K (2010) Association between serum amyloid A and obesity: a meta-analysis and systematic review. Inflamm Res 59(5):323–334CrossRefGoogle Scholar
  49. 49.
    Kaditis AG, Alexopoulos EI, Damani E, Hatzi F, Chaidas K, Kostopoulou T, Tzigeroglou A, Gourgoulianis K (2009) Urine levels of catecholamines in Greek children with obstructive sleep-disordered breathing. Pediatr Pulmonol 44(1):38–45CrossRefGoogle Scholar
  50. 50.
    Franscini LC, Vazquez-Montes M, Buclin T, Perera R, Dunand M, Grouzmann E, Beck-Popovic M (2015) Pediatric reference intervals for plasma free and total metanephrines established with a parametric approach: relevance to the diagnosis of neuroblastoma. Pediatr Blood Cancer 62(4):587–593CrossRefGoogle Scholar
  51. 51.
    Weise M, Merke DP, Pacak K, Walther MM, Eisenhofer G (2002) Utility of plasma free metanephrines for detecting childhood pheochromocytoma. J Clin Endocrinol Metab 87(5):1955–1960CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Daniel Hirsch
    • 1
  • Carla A. Evans
    • 2
  • Melanie Wong
    • 3
  • Rita Machaalani
    • 2
    • 3
  • Karen A. Waters
    • 2
    • 3
    Email author
  1. 1.School of MedicineUniversity of SydneySydneyAustralia
  2. 2.Department of MedicineUniversity of SydneySydneyAustralia
  3. 3.The Children’s HospitalSydneyAustralia

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