J Appl Physiol 117: 1141–1148, 2014. First published September 18, 2014; doi:10.1152/japplphysiol.00237.2014.
Morning pentraxin3 levels reflect obstructive sleep apnea–related acute inflammation Yusuke Kobukai, Takashi Koyama, Hiroyuki Watanabe, and Hiroshi Ito Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan Submitted 13 March 2014; accepted in final form 12 September 2014
Kobukai Y, Koyama T, Watanabe H, Ito H. Morning pentraxin3 levels reflect obstructive sleep apnea–related acute inflammation. J Appl Physiol 117: 1141–1148, 2014. First published September 18, 2014; doi:10.1152/japplphysiol.00237.2014.—This study investigated morning levels of pentraxin3 (PTX3) as a sensitive biomarker for acute inflammation in patients with obstructive sleep apnea (OSA). A total of 61 consecutive patients with OSA were divided into two groups: non-to-mild (n ⫽ 20) and moderate-to-severe (n ⫽ 41) OSA based on their apnea-hypopnea index (AHI) score. Those patients with moderate-to-severe OSA were further divided into continuous positive airway pressure (CPAP) treated (n ⫽ 21) and non-CPAP-treated (n ⫽ 20) groups. Morning and evening serum PTX3 and highsensitivity (hs) C-reactive protein (CRP) levels were measured before and after 3 mo of CPAP therapy. The baseline hs-CRP and PTX3 levels were higher in patients with moderate-to-severe OSA than in those with non-to-mild OSA. Moreover, the serum PTX3 levels, but not the hs-CRP levels, were significantly higher after than before sleep in the moderate-to-severe OSA group (morning PTX3, 1.96 ⫾ 0.52; evening PTX3, 1.71 ⫾ 0.44 ng/ml). OSA severity as judged using the AHI was significantly correlated with serum PTX3 levels but not hs-CRP levels. The highest level of correlation was found between the AHI and morning PTX3 levels (r ⫽ 0.563, P ⬍ 0.001). CPAP therapy reduced evening and morning serum hs-CRP and PTX3 levels in patients with moderate-to-severe OSA; however, the reduction in PTX3 levels in the morning was greater than that in the evening (morning ⫺29.8 ⫾ 16.7% vs. evening ⫺12.6 ⫾ 26.8%, P ⫽ 0.029). Improvement in the AHI score following CPAP therapy was strongly correlated with reduced morning PTX3 levels(r ⫽ 0.727, P ⬍ 0.001). Based on these results, morning PTX3 levels reflect OSA-related acute inflammation and are a useful marker for improvement in OSA following CPAP therapy. CPAP therapy; pentraxin3; obstructive sleep apnea; inflammation PATIENTS WITH OBSTRUCTIVE SLEEP APNEA (OSA) are often diagnosed with acute coronary syndrome (21) and have a higher prevalence of midnight or early morning cardiovascular events than do patients without OSA (12). We previously reported that patients with OSA have abnormal blood coagulation and platelet profiles (24). Intermittent hypoxia during sleep, which is frequently observed in patients with OSA, may induce atherogenic stimuli such as oxidative stress (3). Moreover, OSA activates several inflammatory cascades mediated through multifactorial processes including hypoxia, increased sympathetic activation, and transient blood pressure surges, which lead to vascular damage (3). These findings suggest that vascular inflammation progresses rapidly during sleep in patients with OSA and may contribute to the initiation of acute
Address for reprint requests and other correspondence: H. Watanabe, Dept. of Cardiovascular and Respiratory Medicine, Akita Univ. Graduate School of Medicine, Hondoh1-1-1, Akita, 010-8543, Japan (e-mail: [email protected]. akita-u.ac.jp). http://www.jappl.org
coronary syndrome, resulting in midnight or early morning cardiovascular events. An elevated serum C-reactive protein (CRP) level is a useful prognostic marker in patients with acute coronary syndrome (4). Pentraxin3 (PTX3) has recently emerged as a specific biomarker of vascular inflammation. Although PTX3 and CRP belong to the pentraxin superfamily, their respective origins and manner of induction differ. Serum CRP, a classical short pentraxin, is produced primarily in the liver in response to interleukin-6 stimulation (13). However, CRP does not immediately reflect inflammatory responses in patients with OSA. Mills et al. (18) reported that the mean serum CRP levels in patients with OSA were significantly higher during the day than during the night and that elevated daytime CRP levels occurred as a result of nighttime carryover arousal responses. PTX3 is primarily produced in neutrophils, macrophages, smooth muscle cells, and endothelial cells stimulated by interleukin-1 or tumor necrosis factor-␣ (13). PTX3, but not CRP, is considered to be a rapid release, vascular-specific inflammatory biomarker because of its short half-life and rapid clearance rate (5). Furthermore, PTX3 is elevated in patients with OSA (9) and in patients with coronary artery disease (10). However, the difference between evening and morning levels of PTX3 in patients with OSA are unknown. Moreover, it was not fully evaluated whether PTX3 is a more sensitive marker of OSArelated acute inflammation than CRP. Continuous positive airway pressure (CPAP) therapy is an effective therapeutic approach for hypoxia and cessation of breathing in patients with OSA. A previous observational study found that CPAP therapy was associated with a reduced incidence of vascular events in patients with OSA (16). Thus CPAP therapy is suitable for the investigation of biomarker sensitivity to OSArelated acute inflammation. We investigated the hypothesis that the morning PTX3 level is a useful biomarker for OSA-related acute vascular inflammation in patients with OSA. METHODS
Study design. We enrolled 61 consecutive patients who had OSArelated symptoms, including episodes of loud snoring, excessive daytime sleepiness, nocturnal dyspnea, and restless sleep, between April of 2008 and March of 2012. The patients were divided into two groups according to the results of polysomnography (PSG): moderateto-severe OSA [apnea-hypopnea index (AHI) score ⱖ15/h; n ⫽ 41] and non-to-mild OSA (AHI score ⬍15/h; n ⫽ 20). Patients with moderate-to-severe OSA were fitted with a CPAP device during the initial 7 days of treatment to determine whether they would be able to continue CPAP therapy. Some patients refused CPAP therapy because of the discomfort of wearing a mask or because of the positive airway pressure. Thus the patients with moderate-to-severe sleep-disordered breathing (SDB) were further divided into CPAP-treated (n ⫽ 21) and non-CPAP-treated (n ⫽ 20) groups. Figure 1 shows a flow chart of the study protocol. Patients were excluded from the study if they had any
8750-7587/14 Copyright © 2014 the American Physiological Society
1141
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Acute Inflammation in OSA Enrolled patients (n = 61) PSG, Blood Sampling
AHI≥15
AHI
Morning pentraxin3 levels reflect obstructive sleep apnea–related acute inflammation Yusuke Kobukai, Takashi Koyama, Hiroyuki Watanabe, and Hiroshi Ito Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan Submitted 13 March 2014; accepted in final form 12 September 2014
Kobukai Y, Koyama T, Watanabe H, Ito H. Morning pentraxin3 levels reflect obstructive sleep apnea–related acute inflammation. J Appl Physiol 117: 1141–1148, 2014. First published September 18, 2014; doi:10.1152/japplphysiol.00237.2014.—This study investigated morning levels of pentraxin3 (PTX3) as a sensitive biomarker for acute inflammation in patients with obstructive sleep apnea (OSA). A total of 61 consecutive patients with OSA were divided into two groups: non-to-mild (n ⫽ 20) and moderate-to-severe (n ⫽ 41) OSA based on their apnea-hypopnea index (AHI) score. Those patients with moderate-to-severe OSA were further divided into continuous positive airway pressure (CPAP) treated (n ⫽ 21) and non-CPAP-treated (n ⫽ 20) groups. Morning and evening serum PTX3 and highsensitivity (hs) C-reactive protein (CRP) levels were measured before and after 3 mo of CPAP therapy. The baseline hs-CRP and PTX3 levels were higher in patients with moderate-to-severe OSA than in those with non-to-mild OSA. Moreover, the serum PTX3 levels, but not the hs-CRP levels, were significantly higher after than before sleep in the moderate-to-severe OSA group (morning PTX3, 1.96 ⫾ 0.52; evening PTX3, 1.71 ⫾ 0.44 ng/ml). OSA severity as judged using the AHI was significantly correlated with serum PTX3 levels but not hs-CRP levels. The highest level of correlation was found between the AHI and morning PTX3 levels (r ⫽ 0.563, P ⬍ 0.001). CPAP therapy reduced evening and morning serum hs-CRP and PTX3 levels in patients with moderate-to-severe OSA; however, the reduction in PTX3 levels in the morning was greater than that in the evening (morning ⫺29.8 ⫾ 16.7% vs. evening ⫺12.6 ⫾ 26.8%, P ⫽ 0.029). Improvement in the AHI score following CPAP therapy was strongly correlated with reduced morning PTX3 levels(r ⫽ 0.727, P ⬍ 0.001). Based on these results, morning PTX3 levels reflect OSA-related acute inflammation and are a useful marker for improvement in OSA following CPAP therapy. CPAP therapy; pentraxin3; obstructive sleep apnea; inflammation PATIENTS WITH OBSTRUCTIVE SLEEP APNEA (OSA) are often diagnosed with acute coronary syndrome (21) and have a higher prevalence of midnight or early morning cardiovascular events than do patients without OSA (12). We previously reported that patients with OSA have abnormal blood coagulation and platelet profiles (24). Intermittent hypoxia during sleep, which is frequently observed in patients with OSA, may induce atherogenic stimuli such as oxidative stress (3). Moreover, OSA activates several inflammatory cascades mediated through multifactorial processes including hypoxia, increased sympathetic activation, and transient blood pressure surges, which lead to vascular damage (3). These findings suggest that vascular inflammation progresses rapidly during sleep in patients with OSA and may contribute to the initiation of acute
Address for reprint requests and other correspondence: H. Watanabe, Dept. of Cardiovascular and Respiratory Medicine, Akita Univ. Graduate School of Medicine, Hondoh1-1-1, Akita, 010-8543, Japan (e-mail: [email protected]. akita-u.ac.jp). http://www.jappl.org
coronary syndrome, resulting in midnight or early morning cardiovascular events. An elevated serum C-reactive protein (CRP) level is a useful prognostic marker in patients with acute coronary syndrome (4). Pentraxin3 (PTX3) has recently emerged as a specific biomarker of vascular inflammation. Although PTX3 and CRP belong to the pentraxin superfamily, their respective origins and manner of induction differ. Serum CRP, a classical short pentraxin, is produced primarily in the liver in response to interleukin-6 stimulation (13). However, CRP does not immediately reflect inflammatory responses in patients with OSA. Mills et al. (18) reported that the mean serum CRP levels in patients with OSA were significantly higher during the day than during the night and that elevated daytime CRP levels occurred as a result of nighttime carryover arousal responses. PTX3 is primarily produced in neutrophils, macrophages, smooth muscle cells, and endothelial cells stimulated by interleukin-1 or tumor necrosis factor-␣ (13). PTX3, but not CRP, is considered to be a rapid release, vascular-specific inflammatory biomarker because of its short half-life and rapid clearance rate (5). Furthermore, PTX3 is elevated in patients with OSA (9) and in patients with coronary artery disease (10). However, the difference between evening and morning levels of PTX3 in patients with OSA are unknown. Moreover, it was not fully evaluated whether PTX3 is a more sensitive marker of OSArelated acute inflammation than CRP. Continuous positive airway pressure (CPAP) therapy is an effective therapeutic approach for hypoxia and cessation of breathing in patients with OSA. A previous observational study found that CPAP therapy was associated with a reduced incidence of vascular events in patients with OSA (16). Thus CPAP therapy is suitable for the investigation of biomarker sensitivity to OSArelated acute inflammation. We investigated the hypothesis that the morning PTX3 level is a useful biomarker for OSA-related acute vascular inflammation in patients with OSA. METHODS
Study design. We enrolled 61 consecutive patients who had OSArelated symptoms, including episodes of loud snoring, excessive daytime sleepiness, nocturnal dyspnea, and restless sleep, between April of 2008 and March of 2012. The patients were divided into two groups according to the results of polysomnography (PSG): moderateto-severe OSA [apnea-hypopnea index (AHI) score ⱖ15/h; n ⫽ 41] and non-to-mild OSA (AHI score ⬍15/h; n ⫽ 20). Patients with moderate-to-severe OSA were fitted with a CPAP device during the initial 7 days of treatment to determine whether they would be able to continue CPAP therapy. Some patients refused CPAP therapy because of the discomfort of wearing a mask or because of the positive airway pressure. Thus the patients with moderate-to-severe sleep-disordered breathing (SDB) were further divided into CPAP-treated (n ⫽ 21) and non-CPAP-treated (n ⫽ 20) groups. Figure 1 shows a flow chart of the study protocol. Patients were excluded from the study if they had any
8750-7587/14 Copyright © 2014 the American Physiological Society
1141
1142
Acute Inflammation in OSA Enrolled patients (n = 61) PSG, Blood Sampling
AHI≥15
AHI
