Comprehensive biomarker profiling in patients with obstructive sleep apnea

https://doi.org/10.1016/j.clinbiochem.2014.09.005Get rights and content

Highlights

  • We measured a panel of biomarkers in patients with and without significant OSAS.

  • We found a relevant diurnal variation of a number of biomarkers in OSAS patients.

  • The association between biomarkers and OSAS depended on the time of measurement.

  • Insulin measured before sleep was an independent predictor of severe OSAS.

  • Interleukin-6 measured after sleep was an independent predictor of severe OSAS.

Abstract

Objectives

The pathophysiological links between obstructive sleep apnea syndrome (OSAS) and cardiovascular mortality are incompletely understood. We aimed to contribute to a better characterization by using comprehensive biomarker profiling quantifying hemodynamic cardiac stress, cardiomyocyte injury, inflammation, endothelial function, matrix turnover and metabolism.

Design and methods

In 65 patients with moderate or severe OSAS [apnea–hypopnea index (AHI) 39 ± 20/h] and 33 patients with no or mild OSAS (AHI 8 + 4/h), B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-proBNP), high-sensitivity cardiac troponin I (hs-cTnI), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and insulin were measured before and after sleep. In a subgroup measurements were repeated in a second night with continuous positive airway pressure (CPAP).

Results

Patients with moderate/severe OSAS had higher insulin before sleep [median (interquartile range), 36.4 (21.9–52.1) vs. 20.8 (10.6–32.8) mU/mL; p = 0.006], higher IL-6 after sleep [1.00 (0.73–1.58) vs. 0.72 (0.48–0.94) pg/mL; p = 0.005], and larger relative overnight reduction in BNP [− 9 (− 35–0) vs. − 3 (− 21–13)%; p = 0.04] than those with mild/no OSAS. Insulin before sleep was the only independent predictor of moderate/severe OSAS. Insulin before and IL-6 after sleep were independent predictors of severe OSAS, and when combined provided high diagnostic accuracy for severe OSAS (area under the receiver operator characteristic curve 0.80; 95%-confidence interval 0.69–0.91). In contrast, there were no significant differences in NT-proBNP, hs-cTnI, VEGF, and MMP-9 between moderate/severe and mild/no OSAS. Short-term CPAP had no impact on biomarker concentrations before and after sleep.

Conclusions

Significant OSAS is characterized by a distinct biomarker profile including high insulin before and high IL-6 after sleep.

Introduction

There is a large body of epidemiologic evidence linking the obstructive sleep apnea syndrome (OSAS) with important cardiovascular conditions including hypertension, metabolic syndrome, coronary artery disease, arrhythmia, and heart failure [1]. Given the potentially serious consequences of untreated severe OSAS [2], timely recognition, risk stratification, and appropriate treatment are crucial. In contrast to other cardiovascular conditions such as coronary artery disease [3] and heart failure [4], the pathophysiological links between OSAS and cardiovascular mortality as well as the potential role of biomarkers in the characterization and diagnosis of disease are incompletely understood [5]. Previous studies on the association between biomarkers and presence and severity of OSAS have revealed conflicting results. For example, some studies have reported higher B-type natriuretic peptide (BNP) or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) in patients with OSAS than in those without [6], and a reduction in BNP/NT-proBNP following treatment with continuous positive airway pressure (CPAP) ventilation [7] or oral appliances [8], whereas others have found no such association [9], [10], [11], [12]. One possible reason for such discrepant findings may be the existence of a relevant diurnal variation of biomarker plasma concentrations in OSAS, a phenomenon which has only rarely been studied [13], [14]. In addition, a comprehensive multimarker profile including markers reflecting different aspects of pathophysiology may be more useful than the measurement of single markers. Therefore, we aimed to contribute to a better characterization and understanding of OSAS pathophysiology by using comprehensive biomarker profiling quantifying hemodynamic cardiac stress, cardiomyocyte injury, inflammation, endothelial function, matrix turnover and metabolism both before and after sleep and before and after CPAP therapy.

Section snippets

Patients and protocol

This was a prospectively conducted cross-sectional study performed at the University Hospital Basel, Switzerland, during an 18 month period. We measured biomarker concentrations in venous plasma before and after sleep in 98 consecutive patients referred to the sleep laboratory for evaluation of possible OSAS. Patients with a diagnosis of heart failure and/or symptoms or signs suggestive of heart failure were excluded. Such symptoms and signs included exertional dyspnea NYHA class II or more,

Clinical and sleep characteristics of the study population

Among the 98 patients included in the study, 65 had moderate/severe OSAS (AHI 39 ± 20/h), and 33 had mild/no OSAS (AHI 8 ± 4/h; p < 0.001). Clinical characteristics and sleep study findings in patients with moderate/severe OSAS versus those with mild/no OSAS are presented in Table 1. Patients with moderate/severe OSAS were more likely to be male and to take beta-blockers, and had higher body mass index than those with mild/no OSAS. As expected desaturation index and time spent with an arterial oxygen

Discussion

In the present study, we have shown that significant OSAS is associated with a distinctive biomarker profile characterized by higher insulin before sleep, higher IL-6 after sleep, and a more pronounced overnight reduction in BNP than in those without. In contrast, we could find no significant differences in NT-proBNP, cTnT, MMP-9, and VEGF between patients with moderate/severe OSAS and those with mild/no OSAS, and short-term CPAP had no impact on biomarker concentrations. The combination of two

Conclusions

Significant OSAS is characterized by a distinct biomarker profile including high insulin before and high IL-6 after sleep. This profile could be helpful as a diagnostic tool, and possibly also contribute to novel therapeutic concepts. These findings also indicate that a pattern of biomarkers taking into account the diurnal variation of markers rather than the measurement of one single parameter might be appropriate to characterize the patient with significant OSAS.

Competing interests

JT and JE are employees of Singulex, the manufacturer of some of the biomarkers used in this study. CM has received financial support for his research from Singulex, the manufacturer of some of the biomarkers used in this study. The other authors have no competing interests.

References (22)

  • S. Tasci et al.

    NT-pro-BNP in obstructive sleep apnea syndrome is decreased by nasal continuous positive airway pressure

    Clin Res Cardiol

    (2006)
  • Cited by (45)

    • Matrix metalloproteinase 9 (MMP9) level and MMP9 -1562C&gt;T in patients with obstructive sleep apnea: a systematic review and meta-analysis of case-control studies

      2020, Sleep Medicine
      Citation Excerpt :

      Kaditis et al. [32], presented that serum level of MMP9 and C-reactive protein (CRP) were not elevated in moderate-to-severe OSA than mild or without OSA children. Maeder et al. [33], and Bonanno et al. [34], thought that MMP9 serum level in male subjects was not related to OSA severity. In our opinion, these differences may due to the discrepancies in inclusion criteria.

    • The effects of continuous positive airway pressure therapy on Troponin-T and N-terminal pro B-type natriuretic peptide in patients with obstructive sleep apnoea: a randomised controlled trial

      2017, Sleep Medicine
      Citation Excerpt :

      However several studies have failed to show that overnight troponin levels change in untreated OSA patients [28,30,31] and studies assessing the overnight variability in BNP have shown variable results. One study showed a clear rise in BNP in the latter half of sleep that correlated with a rise in systolic blood pressure [30], whilst another showed a paradoxical fall in levels of BNP and NT-pro-BNP after sleep relative to before sleep [31]. A further study showed no significant change in NT-pro-BNP before and after sleep in patient groups with either OSA alone or with OSA and co-morbid CAD.

    View all citing articles on Scopus
    View full text