International Journal of Neuroscience, 2014; Early Online: 1–8 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.960521
ORIGINAL ARTICLE
Increased plasma soluble tumor necrosis factor receptor-1 and myeloperoxidase activity in patients with obstructive sleep apnea syndrome
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Ferhat Hanikoglu,1 Nergiz Huseyinoglu,2 Serkan Ozben,2 Aysegul Cort,1 Sebahat Ozdem,1 and Tomris Ozben1 1
Medical Faculty, Department of Medical Biochemistry, Akdeniz University, 07070, Antalya, Turkey; 2 Medical Faculty, Department of Neurology, Kafkas University, Kars, Turkey Purpose/Aim: Obstructive sleep apnea (OSA) is characterized by recurrent respiratory disorders associated with increased cardiovascular morbidity and mortality. The increment of systemic inflammation in OSA has been considered as the major pathogenic mechanism leading to cardiovascular diseases. There is limited and conflicting information in the literature investigating myeloperoxidase (MPO) activity and soluble tumor necrosis factor receptor-1 (sTNF-R1) levels in OSA patients. The aim of our study is to assess the clinical utility of plasma MPO activity and sTNF-R1 levels as risk markers for systemic inflammation and development of cardiovascular diseases in OSA patients. Materials and Methods: 59 OSA patients diagnosed with polysomnograhpy for Apnea–Hypopnea index (AHI), and 26 healthy volunteers enrolled into the study. Plasma MPO activity was measured using a spectrophotometric method. An enzyme-linked immunosorbent assay (ELISA) method was used to detect plasma sTNF-R1 levels. Results: Plasma MPO activity and sTNF-R1 levels were significantly higher (43.2 ± 21.65 vs. 30.44 ± 8.05 p = .0046; 2.379 ± 1.2 vs. 1.086 ± 0.86 p < .0001, respectively) in the total OSA patients compared to the control group. There was a significant weak correlation between MPO activity and disease severity indicator AHI (p = .03 r = .27). Conclusions: Elevated plasma MPO activity and sTNF-R1 levels in the OSA patients indicate increased systemic inflammation and oxidative stress which might contribute to the higher incidence of cardiovascular diseases. Therefore, we recommend measurement of plasma MPO activity and sTNF-R1 levels in the OSA patients as potential risk predictors for cardiovascular diseases. KEYWORDS: Obstructive sleep apnea, myeloperoxidase, soluble tumor necrosis factor receptor-1, cardiovascular diseases
Introduction Obstructive sleep apnea (OSA) is a condition characterized by cessation of respiration due to obstruction of the upper airway during sleep [1–3]. Its prevalence is approximately 4% in males and 2% in females in the adult population. It is seen frequently in patients with morbid obesity, cardiac, neurological, renal, and respiratory diseases [2, 4]. In OSA, each episode of airway obstruction is followed by a decreased arterial O2 saturation. An association exists between OSA and development of cardiovascular diseases suggesting intermittent hypoxia Received 3 July 2014; revised 26 August 2014; accepted 28 August 2014. Correspondence: Prof. Tomris Ozben, Department of Medical Biochemistry, Medical Faculty, Akdeniz University, 07070, Antalya, Turkey, Tel: +90 2422496895. Fax: +90 2422274495. E-mail: [email protected]
as the major reason of increased cardiovascular risk. OSA is mediated by several intermediary mechanisms such as systemic inflammation, oxidative stress, and sympathetic activation [4–6]. Previous studies demonstrated a positive relationship between severity of OSA and inflammatory markers. Persistent systemic inflammation plays a crucial role in the pathogenesis of cardiovascular diseases such as systemic arterial hypertension, coronary artery diseases, heart failure, and stroke [7, 8]. Two types of tumor necrosis factor-α (TNF-α) membrane receptors (TNF-R) were identified, namely TNFR1 with 55–60 kDa molecular mass and TNF-R2 with 75–80 kDa molecular mass [9]. Soluble forms of these receptors are present in human serum and plasma. sTNF-R1 is released by proteolysis of cell-bound receptor under the effect of inflammatory cytokines, T-cell activation, and TNF-α itself. sTNF-R1 mediates major bioactivities of TNF-α. Plasma levels of TNF-α are 1
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2
F. Hanikoglu et al.
variable, but sTNF-R1 levels are highly stable. Therefore, plasma sTNF-R1 level might be a better inflammation marker than plasma TNF-α level [10, 11]. Myeloperoxidase (MPO) is an enzyme that is stocked in azurophilic granules of neutrophils and macrophages. During inflammatory events, it is released into extracellular fluid and catalyzes synthesis of some reactive species, including hypochlorous acid, chloramines, tyrosyl radicals, and nitrogen dioxide. MPO causes activation of metalloproteinases leading to atherosclerotic plaque destabilization and susceptibility to plaque rupture. Recently, MPO has been suggested as a risk marker for coronary artery diseases and has been implicated in the oxidation of low-density lipoprotein and acceleration of inflammation at atherosclerotic area [12, 13]. There is limited and conflicting information in a few studies assessing sTNF-R1 levels and plasma MPO activity in OSA patients [10, 14]. Therefore, we aimed to measure blood levels of sTNF-R1 and MPO activity and their correlation with the severity of OSAS as indicated by AHI.
Materials and Methods The study was approved by the local ethical committee in accordance with the Helsinki Declaration and written informed consent was received from the patients and control subjects before being enrolled into the study. The patient and control cohorts were recruited at the Neurology and Cardiology Departments, Medical Faculty, Kafkas University. Blood samples were analyzed at the Biochemistry Laboratory of Akdeniz University Medical Faculty.
Patient Selection A total of 59 patients (m/f: 33/26; mean age ± standard deviation (SD): 51.02 ± 9.37 years) were diagnosed OSA after a night polysomnography (PSG) recording between December 2011 and March 2012 consecutively. They were enrolled into the study following receipt of their written informed consent. They had no history of ischemic cardiovascular diseases, chronic obstructive pulmonary diseases, ischemic cerebral diseases, chronic inflammatory diseases, chronic and acute systemic infections at the time of study. These were exclusion criteria for the OSA patients. Sleep disordered breathing events were scored manually by the same examiner according to the 2007 American Academy of Sleep Medicine criteria. Obstructive apnea was defined as a drop in the peak oronasal thermal sensor excursion by ≥90% of baseline for at least 10 s. Hypopnea
was defined as at least a 50% drop in airflow for at least 10 s despite respiratory efforts and at least a 3% drop in oxyhemoglobin saturation. Patients were diagnosed to have OSA if the apnea-hypopnea index (AHI) was ≥5. The grading was made according to mild OSA having an AHI of 5 and less than 15; moderate OSA having an AHI of 15 to less than 30; and severe OSA having an AHI ≥30 [15]. The patients in the OSA group were divided into two subgroups according to the severity of the disease consisting of 13 moderate OSA and 46 severe OSA patients. A total of 26 blood samples were withdrawn from age- and gender-matched control subjects (m/f: 19/7, 48.42 ± 5.11 years) who were either healthy relatives of the patients or hospital staff without a history of cardiac and cerebral ischemic diseases, chronic obstructive pulmonary diseases, chronic inflammatory diseases, chronic systemic infections, and without a probability of OSA indicated by the absence of snoring, daytime sleepiness, and witnessed apnea. In our study groups, hypertension (HT) is defined a systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater or receiving antihypertensive medication [16]. Obesity is defined as a BMI of 30.0 or greater [17]. Diabetes mellitus is defined a fasting plasma glucose 126 mg/dL or greater, 2-h postload plasma glucose 200 mg/dL or greater, an hemoglobinA1c 6.5% or greater [18]. Smoking is defined as currently smoking cigarettes.
Blood withdrawal and laboratory analysis Fasting morning venous blood samples were collected into EDTA tubes in the following week of PSG recording before starting continuous positive airway pressure therapy. After centrifugation, plasma samples separated were kept at −70◦ C until analysis. Plasma MPO and sTNFR-1 were measured by researchers blinded to the patient and control sample details. Circulating plasma levels of sTNF-R1 were measured in duplicate using an ELISA kit (eBioscience) with a lowest detection limit of 0.053 ng/mL. MPO activity was determined spectrophotometrically using a modification of the O-dianisidine method [19]. 290 μL (50 mM, pH: 6) phosphate buffer, 3 μL (20 mg/mL) O-dianisidine hydrochloride substrate solution, and 3μL hydrogen peroxide (H2 O2 , 20 mM) were added in sequence into each well of a 96-well plate. Then, samples (10 μL) were added into each well to start the reaction and the change in absorbance at 450 nm was followed for 10 min. One unit (U) of MPO activity was defined as that degrading 1 μmol of H2 O2 per minute at 25◦ C and expressed as U/L. International Journal of Neuroscience
sTNFR and MPO activity in OSAS 3
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Statistical Analyses Statistical analysis was performed using SPSS Statistics Base 17.0 (SPSS Inc. Chicago, IL, USA). Quantitative data was given as mean ± SD and categorical data was given as percentages. Normal distribution and differences between variances were determined using Kolmogorov-Smirnov and Levene tests, respectively. For comparisons between the two groups, Student’s t test and Mann–Whitney U test for scalar variables and χ 2 test or Fisher’s exact test for categorical variables were used as appropriate. For subgroup analyses, Kruskal–Wallis test was used to determine significant differences. Mann–Whitney U test was used to determine differences between the groups if a significant difference was found in Kruskal–Wallis test. Pearson correlation test was used to determine correlations between measured parameters and AHI or minimum O2 saturation. In all tests, a two-sided p value < .05 was considered statistically significant. We performed a multivariate regression analysis to evaluate the independent predictors of plasma MPO activities and sTNF-R1 levels in the OSA patients. A logistic regression analysis was performed between OSA patients versus control group as dependent variable and age, cardiovascular risk factors like diabetes mellitus, hypertension, smoking, BMI, and male gender and inflammatory markers sTNF-R1, and MPO as independent variables.
Results The demographical and laboratory findings of the total OSA patients, OSA subgroups (moderate and severe) and control group are given in Table 1. Plasma MPO activity in the total OSA patients (43.2 ± 21.65 U/L) was significantly higher compared to the control group (30.44 ± 8.05 U/L, p = .0046) (Table 1; Fig. 1). Similarly, sTNF-R1 (2.379 ± 1.209 ng/mL) was significantly higher in the OSA patients in comparison to the control group (1.086 ± 0.867 ng/mL, p < .0001) (Table 1; Fig. 2). The body mass index (BMI) and incidence of hypertension (HT), were significantly higher (p < .001, p < .001, respectively) in the OSA patients compared to the control group. The presence of smoking habit was significantly lower in the OSA patients compared to the control group (p = .025). Minimum O2 saturation was significantly lower in the severe OSA group compared to the moderate group (p < .001). We found the presence of HT significantly higher in the moderate and severe OSA subgroups compared to the control group (p = .025 and p < .001; respectively). There was no significant difference in terms of age and gender among the OSA subgroups and control subjects. C
2014 Informa Healthcare USA, Inc.
Figure 1. Box-and-whisker plot of MPO activity in the control
group and OSA patients (Whiskers: 10 and 90 percentile). The middle lines, upper and lower margin of boxes represent medians.
We found BMI significantly higher in both moderate and severe OSA groups compared to the control group (both p < .001), but there was no significant difference in BMI between the OSA subgroups (p = .466). There was a significant weak correlation between MPO levels and AHI (p = .03; r = .27) in the total OSA patients. There was
Figure 2. Box-and-whisker plot of sTNF-R1 levels in the control
group and OSA patients (Whiskers: 10 and 90 percentile). The middle lines, upper and lower margin of boxes represent medians.
4 1.086 ± 0.867 0.12–4.7 30.44 ± 8.05 16.05–57.3
51.00 ± 8.03 6/7 32.33 ± 4.59 22.8–41.0 9 (69.2%)/4 (30.8%) 12 (92.3%)/1 (7.7%) 8 (61.5%)/5 (38.5%) 19.22 ± 4.29 15.5–27.0 80.38 ± 3.91 71.0–84.0 3.397 ± 1.46 1.17–5.49 36.36 ± 14.43 18.69–66.08
Moderate OSA Patients N = 13 51.02 ± 9.79 27/19 33.93 ± 5.69 23.3–46.6 37 (80.4%)/9 (19.6%) 38 (82.6%)/8 (17.4%) 23 (50%)/23 (50%) 61.88 ± 21.51 30–124.0 68.87 ± 11.43 50.0–84.0 2.103 ± 0.977 0.5–4.46 45.14 ± 23.05 11.71–120.4
Severe OSA Patients N = 46
51.02 ± 9.37 33/26 33.58 ± 5.47 22.8–46.6 46 (78%)/13 (22%) 50 (84.7%)/9 (15.3%) 31(52.5%)/28(47.5%) 52.48 ± 26.09 15.5–124 71.41 ± 11.3 50–84 2.379 ± 1.209 0.5–5.49 43.2 ± 21.65 11.71–120.4
Total OSA Patients N = 59
.0025 b .0046 d
ORIGINAL ARTICLE
Increased plasma soluble tumor necrosis factor receptor-1 and myeloperoxidase activity in patients with obstructive sleep apnea syndrome
Int J Neurosci Downloaded from informahealthcare.com by Universiteit Twente on 11/30/14 For personal use only.
Ferhat Hanikoglu,1 Nergiz Huseyinoglu,2 Serkan Ozben,2 Aysegul Cort,1 Sebahat Ozdem,1 and Tomris Ozben1 1
Medical Faculty, Department of Medical Biochemistry, Akdeniz University, 07070, Antalya, Turkey; 2 Medical Faculty, Department of Neurology, Kafkas University, Kars, Turkey Purpose/Aim: Obstructive sleep apnea (OSA) is characterized by recurrent respiratory disorders associated with increased cardiovascular morbidity and mortality. The increment of systemic inflammation in OSA has been considered as the major pathogenic mechanism leading to cardiovascular diseases. There is limited and conflicting information in the literature investigating myeloperoxidase (MPO) activity and soluble tumor necrosis factor receptor-1 (sTNF-R1) levels in OSA patients. The aim of our study is to assess the clinical utility of plasma MPO activity and sTNF-R1 levels as risk markers for systemic inflammation and development of cardiovascular diseases in OSA patients. Materials and Methods: 59 OSA patients diagnosed with polysomnograhpy for Apnea–Hypopnea index (AHI), and 26 healthy volunteers enrolled into the study. Plasma MPO activity was measured using a spectrophotometric method. An enzyme-linked immunosorbent assay (ELISA) method was used to detect plasma sTNF-R1 levels. Results: Plasma MPO activity and sTNF-R1 levels were significantly higher (43.2 ± 21.65 vs. 30.44 ± 8.05 p = .0046; 2.379 ± 1.2 vs. 1.086 ± 0.86 p < .0001, respectively) in the total OSA patients compared to the control group. There was a significant weak correlation between MPO activity and disease severity indicator AHI (p = .03 r = .27). Conclusions: Elevated plasma MPO activity and sTNF-R1 levels in the OSA patients indicate increased systemic inflammation and oxidative stress which might contribute to the higher incidence of cardiovascular diseases. Therefore, we recommend measurement of plasma MPO activity and sTNF-R1 levels in the OSA patients as potential risk predictors for cardiovascular diseases. KEYWORDS: Obstructive sleep apnea, myeloperoxidase, soluble tumor necrosis factor receptor-1, cardiovascular diseases
Introduction Obstructive sleep apnea (OSA) is a condition characterized by cessation of respiration due to obstruction of the upper airway during sleep [1–3]. Its prevalence is approximately 4% in males and 2% in females in the adult population. It is seen frequently in patients with morbid obesity, cardiac, neurological, renal, and respiratory diseases [2, 4]. In OSA, each episode of airway obstruction is followed by a decreased arterial O2 saturation. An association exists between OSA and development of cardiovascular diseases suggesting intermittent hypoxia Received 3 July 2014; revised 26 August 2014; accepted 28 August 2014. Correspondence: Prof. Tomris Ozben, Department of Medical Biochemistry, Medical Faculty, Akdeniz University, 07070, Antalya, Turkey, Tel: +90 2422496895. Fax: +90 2422274495. E-mail: [email protected]
as the major reason of increased cardiovascular risk. OSA is mediated by several intermediary mechanisms such as systemic inflammation, oxidative stress, and sympathetic activation [4–6]. Previous studies demonstrated a positive relationship between severity of OSA and inflammatory markers. Persistent systemic inflammation plays a crucial role in the pathogenesis of cardiovascular diseases such as systemic arterial hypertension, coronary artery diseases, heart failure, and stroke [7, 8]. Two types of tumor necrosis factor-α (TNF-α) membrane receptors (TNF-R) were identified, namely TNFR1 with 55–60 kDa molecular mass and TNF-R2 with 75–80 kDa molecular mass [9]. Soluble forms of these receptors are present in human serum and plasma. sTNF-R1 is released by proteolysis of cell-bound receptor under the effect of inflammatory cytokines, T-cell activation, and TNF-α itself. sTNF-R1 mediates major bioactivities of TNF-α. Plasma levels of TNF-α are 1
Int J Neurosci Downloaded from informahealthcare.com by Universiteit Twente on 11/30/14 For personal use only.
2
F. Hanikoglu et al.
variable, but sTNF-R1 levels are highly stable. Therefore, plasma sTNF-R1 level might be a better inflammation marker than plasma TNF-α level [10, 11]. Myeloperoxidase (MPO) is an enzyme that is stocked in azurophilic granules of neutrophils and macrophages. During inflammatory events, it is released into extracellular fluid and catalyzes synthesis of some reactive species, including hypochlorous acid, chloramines, tyrosyl radicals, and nitrogen dioxide. MPO causes activation of metalloproteinases leading to atherosclerotic plaque destabilization and susceptibility to plaque rupture. Recently, MPO has been suggested as a risk marker for coronary artery diseases and has been implicated in the oxidation of low-density lipoprotein and acceleration of inflammation at atherosclerotic area [12, 13]. There is limited and conflicting information in a few studies assessing sTNF-R1 levels and plasma MPO activity in OSA patients [10, 14]. Therefore, we aimed to measure blood levels of sTNF-R1 and MPO activity and their correlation with the severity of OSAS as indicated by AHI.
Materials and Methods The study was approved by the local ethical committee in accordance with the Helsinki Declaration and written informed consent was received from the patients and control subjects before being enrolled into the study. The patient and control cohorts were recruited at the Neurology and Cardiology Departments, Medical Faculty, Kafkas University. Blood samples were analyzed at the Biochemistry Laboratory of Akdeniz University Medical Faculty.
Patient Selection A total of 59 patients (m/f: 33/26; mean age ± standard deviation (SD): 51.02 ± 9.37 years) were diagnosed OSA after a night polysomnography (PSG) recording between December 2011 and March 2012 consecutively. They were enrolled into the study following receipt of their written informed consent. They had no history of ischemic cardiovascular diseases, chronic obstructive pulmonary diseases, ischemic cerebral diseases, chronic inflammatory diseases, chronic and acute systemic infections at the time of study. These were exclusion criteria for the OSA patients. Sleep disordered breathing events were scored manually by the same examiner according to the 2007 American Academy of Sleep Medicine criteria. Obstructive apnea was defined as a drop in the peak oronasal thermal sensor excursion by ≥90% of baseline for at least 10 s. Hypopnea
was defined as at least a 50% drop in airflow for at least 10 s despite respiratory efforts and at least a 3% drop in oxyhemoglobin saturation. Patients were diagnosed to have OSA if the apnea-hypopnea index (AHI) was ≥5. The grading was made according to mild OSA having an AHI of 5 and less than 15; moderate OSA having an AHI of 15 to less than 30; and severe OSA having an AHI ≥30 [15]. The patients in the OSA group were divided into two subgroups according to the severity of the disease consisting of 13 moderate OSA and 46 severe OSA patients. A total of 26 blood samples were withdrawn from age- and gender-matched control subjects (m/f: 19/7, 48.42 ± 5.11 years) who were either healthy relatives of the patients or hospital staff without a history of cardiac and cerebral ischemic diseases, chronic obstructive pulmonary diseases, chronic inflammatory diseases, chronic systemic infections, and without a probability of OSA indicated by the absence of snoring, daytime sleepiness, and witnessed apnea. In our study groups, hypertension (HT) is defined a systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater or receiving antihypertensive medication [16]. Obesity is defined as a BMI of 30.0 or greater [17]. Diabetes mellitus is defined a fasting plasma glucose 126 mg/dL or greater, 2-h postload plasma glucose 200 mg/dL or greater, an hemoglobinA1c 6.5% or greater [18]. Smoking is defined as currently smoking cigarettes.
Blood withdrawal and laboratory analysis Fasting morning venous blood samples were collected into EDTA tubes in the following week of PSG recording before starting continuous positive airway pressure therapy. After centrifugation, plasma samples separated were kept at −70◦ C until analysis. Plasma MPO and sTNFR-1 were measured by researchers blinded to the patient and control sample details. Circulating plasma levels of sTNF-R1 were measured in duplicate using an ELISA kit (eBioscience) with a lowest detection limit of 0.053 ng/mL. MPO activity was determined spectrophotometrically using a modification of the O-dianisidine method [19]. 290 μL (50 mM, pH: 6) phosphate buffer, 3 μL (20 mg/mL) O-dianisidine hydrochloride substrate solution, and 3μL hydrogen peroxide (H2 O2 , 20 mM) were added in sequence into each well of a 96-well plate. Then, samples (10 μL) were added into each well to start the reaction and the change in absorbance at 450 nm was followed for 10 min. One unit (U) of MPO activity was defined as that degrading 1 μmol of H2 O2 per minute at 25◦ C and expressed as U/L. International Journal of Neuroscience
sTNFR and MPO activity in OSAS 3
Int J Neurosci Downloaded from informahealthcare.com by Universiteit Twente on 11/30/14 For personal use only.
Statistical Analyses Statistical analysis was performed using SPSS Statistics Base 17.0 (SPSS Inc. Chicago, IL, USA). Quantitative data was given as mean ± SD and categorical data was given as percentages. Normal distribution and differences between variances were determined using Kolmogorov-Smirnov and Levene tests, respectively. For comparisons between the two groups, Student’s t test and Mann–Whitney U test for scalar variables and χ 2 test or Fisher’s exact test for categorical variables were used as appropriate. For subgroup analyses, Kruskal–Wallis test was used to determine significant differences. Mann–Whitney U test was used to determine differences between the groups if a significant difference was found in Kruskal–Wallis test. Pearson correlation test was used to determine correlations between measured parameters and AHI or minimum O2 saturation. In all tests, a two-sided p value < .05 was considered statistically significant. We performed a multivariate regression analysis to evaluate the independent predictors of plasma MPO activities and sTNF-R1 levels in the OSA patients. A logistic regression analysis was performed between OSA patients versus control group as dependent variable and age, cardiovascular risk factors like diabetes mellitus, hypertension, smoking, BMI, and male gender and inflammatory markers sTNF-R1, and MPO as independent variables.
Results The demographical and laboratory findings of the total OSA patients, OSA subgroups (moderate and severe) and control group are given in Table 1. Plasma MPO activity in the total OSA patients (43.2 ± 21.65 U/L) was significantly higher compared to the control group (30.44 ± 8.05 U/L, p = .0046) (Table 1; Fig. 1). Similarly, sTNF-R1 (2.379 ± 1.209 ng/mL) was significantly higher in the OSA patients in comparison to the control group (1.086 ± 0.867 ng/mL, p < .0001) (Table 1; Fig. 2). The body mass index (BMI) and incidence of hypertension (HT), were significantly higher (p < .001, p < .001, respectively) in the OSA patients compared to the control group. The presence of smoking habit was significantly lower in the OSA patients compared to the control group (p = .025). Minimum O2 saturation was significantly lower in the severe OSA group compared to the moderate group (p < .001). We found the presence of HT significantly higher in the moderate and severe OSA subgroups compared to the control group (p = .025 and p < .001; respectively). There was no significant difference in terms of age and gender among the OSA subgroups and control subjects. C
2014 Informa Healthcare USA, Inc.
Figure 1. Box-and-whisker plot of MPO activity in the control
group and OSA patients (Whiskers: 10 and 90 percentile). The middle lines, upper and lower margin of boxes represent medians.
We found BMI significantly higher in both moderate and severe OSA groups compared to the control group (both p < .001), but there was no significant difference in BMI between the OSA subgroups (p = .466). There was a significant weak correlation between MPO levels and AHI (p = .03; r = .27) in the total OSA patients. There was
Figure 2. Box-and-whisker plot of sTNF-R1 levels in the control
group and OSA patients (Whiskers: 10 and 90 percentile). The middle lines, upper and lower margin of boxes represent medians.
4 1.086 ± 0.867 0.12–4.7 30.44 ± 8.05 16.05–57.3
51.00 ± 8.03 6/7 32.33 ± 4.59 22.8–41.0 9 (69.2%)/4 (30.8%) 12 (92.3%)/1 (7.7%) 8 (61.5%)/5 (38.5%) 19.22 ± 4.29 15.5–27.0 80.38 ± 3.91 71.0–84.0 3.397 ± 1.46 1.17–5.49 36.36 ± 14.43 18.69–66.08
Moderate OSA Patients N = 13 51.02 ± 9.79 27/19 33.93 ± 5.69 23.3–46.6 37 (80.4%)/9 (19.6%) 38 (82.6%)/8 (17.4%) 23 (50%)/23 (50%) 61.88 ± 21.51 30–124.0 68.87 ± 11.43 50.0–84.0 2.103 ± 0.977 0.5–4.46 45.14 ± 23.05 11.71–120.4
Severe OSA Patients N = 46
51.02 ± 9.37 33/26 33.58 ± 5.47 22.8–46.6 46 (78%)/13 (22%) 50 (84.7%)/9 (15.3%) 31(52.5%)/28(47.5%) 52.48 ± 26.09 15.5–124 71.41 ± 11.3 50–84 2.379 ± 1.209 0.5–5.49 43.2 ± 21.65 11.71–120.4
Total OSA Patients N = 59
.0025 b .0046 d
