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(Chest. 2005;127:731-737.)
© 2005 American College of Chest Physicians

Low Plasma Orexin-A Levels Were Improved by Continuous Positive Airway Pressure Treatment in Patients With Severe Obstructive Sleep Apnea-Hypopnea Syndrome*

Shigeru Sakurai, MD, PhD; Tsuguo Nishijima, MD, PhD; Susumu Takahashi, MD, PhD; Kohei Yamauchi, MD, PhD; Zenei Arihara, MD, PhD and Kazuhiro Takahashi, MD, PhD

* From the Third Department of Internal Medicine (Drs. Sakurai, Nishijima, S. Takahashi, and Yamauchi), Iwate Medical University School of Medicine, Morioka, Japan; the Division of Nephrology, Endocrinology, and Vascular Medicine (Dr. Arihara), Department of Medicine, and the Department of Molecular Biology and Applied Physiology (Dr. K. Takahashi), Tohoku University School of Medicine, Sendai, Japan.

Correspondence to: Shigeru Sakurai, MD, PhD, Third Department of Internal Medicine, Iwate Medical University School of Medicine, 19–1, Uchimaru, Morioka, 020-8505, Japan; e-mail; ssakurai{at}iwate-med.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: We have previously shown that plasma levels of orexin-A, a neuropeptide with an arousal-stimulating action, were decreased in parallel with the severity of the disease in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS).

Objective: To clarify the effects of nasal continuous positive airway pressure (nCPAP) treatment on plasma orexin-A levels in patients with this syndrome.

Method: Sleep tests and blood sample collections were conducted at the sleep-related respiratory disorders clinic and the sleep laboratory of the Iwate Medical University Hospital. We studied 27 patients with OSAHS (apnea-hypopnea index [AHI], ≥ 20 by polysomnography) who were treated with nCPAP for 3 to 6 months. These patients were divided into the following two groups according to the arousal index (AI): group A (n = 11), ≥ 60; group B (n = 16), < 60. Plasma samples were obtained before and after the nCPAP treatment for 3 to 6 months. Plasma immunoreactive (IR)-orexin-A concentrations were measured by radioimmunoassay after the extraction using cartridges.

Results: Plasma IR-orexin-A concentrations were inversely correlated with the AI (r = –0.807; p < 0.0001) and AHI (r = –0.661; p < 0.0001) in 27 patients before the nCPAP treatment. Mean (± SEM) plasma IR-orexin-A concentrations were significantly lower in group A (1.0 ± 0.3 pmol/L) than in group B (4.6 ± 0.4 pmol/L). Mean plasma IR-orexin-A concentrations were significantly increased after the nCPAP treatment in group A (to 3.4 ± 1.2 pmol/L; p = 0.0069), whereas they were not significantly changed in group B. The increases in plasma IR-orexin-A concentrations after the nCPAP treatment were in parallel with the improvements in AI and Epworth sleepiness scale (a marker of severity of daytime excessive sleepiness) score in group A.

Conclusions: The low plasma orexin-A levels were increased by the nCPAP treatment in patients with severe OSAHS, suggesting that orexin-A is a plasma marker that reflects the severity of OSAHS and the response to treatment.

Key Words: adherence • arousal index • continuous positive airway pressure • neuropeptides • orexin • sleep apnea hypopnea syndrome


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a disease in which sleep fragmentation is caused by apnea or hypopnea during sleep, thereby resulting in excessive daytime sleepiness.12 It is a common disorder with a prevalence of 2 to 4% in the population. Its diagnosis and the assessment of its clinical severity are generally based on the apnea-hypopnea index (AHI), which measures the frequency of respiratory disturbance, and Epworth sleepiness scale (ESS) score,3 which measures the severity of daytime excessive sleepiness. The treatment of first choice for OSAHS is currently nasal continuous positive airway pressure (nCPAP). The risk of hypertension and ischemic heart disease is decreased by the nCPAP treatment.456

OSAHS closely correlates with obesity. Obesity increases the risk of OSAHS by approximately 10-fold, within a range of 2 to 4% in the general adult population, to up to 20 to 40% in obese subjects with a body mass index of > 30.7 Plasma levels of leptin, an adipocyte-derived peptide hormone with an appetite-suppressing action, are elevated in obese patients.8 It has been reported, however, that plasma leptin levels were still high in OSAHS patients even after the body weight was decreased.9 On the other hand, plasma leptin levels have been reported to be lowered by the nCPAP treatment,9 suggesting that the improvement of OSAHS by nCPAP treatment was associated with the change in neuroendocrinologic factors. Furthermore, leptin has a stimulatory action on respiration in animals.1011

Orexin-A is a neuropeptide with an appetite-stimulating action and an arousal-stimulating action.121314 We have previously shown15 that plasma levels of immunoreactive (IR)-orexin-A were decreased in parallel with the arousal index (AI), the AHI, and the ESS score in patients with OSAHS. In the present study, we wished to examine the effects of nCPAP treatment on plasma IR-orexin-A concentrations in patients with OSAHS.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The subjects consisted of 27 patients who had visited the Third Department of Internal Medicine, Iwate Medical University School of Medicine, in whom OSAHS had been diagnosed by polysomnography testing. All of the patients had received the nCPAP treatment for a period of 3 to 6 months (mean [± SE] duration, 4.1 ± 0.3 months). We included patients with good adherence to therapy based on the modified definition by Kribbs et al16 in the present study (subjects received nCPAP treatment for at least 4 h per night on 70% of the days and with symptomatic improvement). Patients with endocrine diseases, chronic obstructive respiratory diseases, renal diseases, or a history of the use of hypnotics were excluded from this study. All of the patients gave written informed consent to be included into the present study.

The subjects were divided into two groups according to the AI. Patients with an AI of ≥ 60 events per hour were likely to have disturbed daytime cognitive function,17 and were therefore placed into group A (n = 11). The other patients were placed into group B (AI, < 60 events per hour; n = 16) [Table 1 ].


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  		Table 1. Clinical Characteristics and Polysomnographic Findings Before and After the nCPAP Treatment in Patients With OSAHS*

 
Samples
Blood samples were collected from the cubital vein by using a vacuum blood-collecting tube containing ethylenediaminetetraacetic acid at approximately 6:00 AM after undergoing the first polysomnography testing. Plasma samples were separated and stored at –40°C until the measurement. The nCPAP treatment was performed in all 27 patients for 3 to 6 months, and then blood samples were collected similarly just after the second polysomnography test.

Polysomnography Test
Overnight polysomnography testing was performed in every subject before and after the nCPAP treatment. Polysomnography was performed between 8:00 PM and 6:00 AM by using a digital polysomnography system (SomnoStar-{alpha}; SensorMedics; Yorba Linda, CA), which can simultaneously record a total of 14 channels (4 channels of EEG, and 10 channels consisting of ECG, movements of the chest and abdominal walls, oronasal airflow by a thermistor sensor, arterial oxygen saturation, and pulse rate by a pulse oximeter, electrooculogram, frontal electromyography, submental electromyography, and snoring sounds). AHI and AI were measured according to the criteria of the American Academy of Sleep Medicine18 and were evaluated visually on a personal computer display.

ESS
The severity of subjective excessive daytime sleepiness was assessed using the ESS.3

Plasma IR-Orexin-A Concentrations
Plasma IR-orexin-A concentrations were measured by radioimmunoassay after extraction (Sep-Pak C18 cartridges; Waters Associates; Milford, MA), as previously reported.19 Briefly, 2 mL plasma was acidified with 2 mL 0.75 mol/L acetic acid containing 0.5% (w/v) casein, and was loaded onto a cartridge (Sep-Pak C18), which was pretreated with 10 mL acetonitrile, 10 mL methanol, and then 10 mL 0.75 mol/L acetic acid. The adsorbed peptides were eluted with 2 mL 60% (v/v) acetonitrile containing 0.1% trifluoroacetic acid. The plasma extract was reconstituted in 500 µL assay buffer, and aliquots (200 µL) were assayed in duplicate, as previously reported.1920 The antiserum against human orexin-A was raised in a rabbit. Human orexin-A was used as a standard. 125I-orexin-A prepared by the chloramines-T method was used as a radioligand. The assay could detect mean (± SD) changes of 0.97 ± 0.21 fmol per tube (n = 14) from zero at 95% confidence. The cross-reaction was 0.017% with human orexin-B, and < 0.003% with other peptides, including neuropeptide Y, endothelin-1, vasoactive intestinal polypeptide, corticotropin-releasing hormone, and atrial natriuretic peptide. Intraassay and interassay coefficients of variation were 5.2% and 14.2%, respectively. The rate of recovery of orexin-A following the extraction procedure was 66.7%.

Statistical Analysis
The data are shown as the mean ± SE, unless otherwise stated. Statistical analyses were performed by using commercially available software (StatView 5.0; Abacus Concepts; Berkeley, CA). Data between the two groups were compared by one-way analysis of variance. Frequency analysis was performed with the Fisher exact test. Linear regression analysis of the data was performed by the least squares method.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The nCPAP treatment significantly decreased AHI and AI, and significantly increased the percentages of stage 3 + 4 sleep and rapid eye movement sleep in both group A and group B (Table 1). There was no significant difference in the total sleep time and stage 1 sleep between the time periods before and after nCPAP treatment.

Plasma IR-orexin-A concentrations showed significant inverse correlations with the AHI (r = – 0.661; p < 0.0001) [Fig 1 , top, A], AI (r = – 0.807; p < 0.0001) [Fig 1, middle, B], and ESS (r = – 0.453; p < 0.05) [Fig 1, bottom, C], which is consistent with our previous report.15 Mean plasma IR-orexin-A concentrations were significantly lower in group A (1.0 ± 0.3 pmol/L) than in group B (4.6 ± 0.4 pmol/L) before the nCPAP treatment. Mean plasma IR-orexin-A concentrations were significantly increased after the nCPAP treatment in group A (from 1.0 ± 0.3 to 3.4 ± 1.2 pmol/L; p = 0.0069) [Fig 2 , top, A), whereas they were not significantly changed in group B (from 4.6 ± 0.4 to 4.6 ± 0.5 pmol/L; p = 0.91) [Fig 2, bottom, B].



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  		Figure 1. Correlation between plasma IR-orexin-A concentrations and (top, A) the AHI, (middle, B) the AI, and (bottom, C) the ESS in 27 patients with OSAHS.

 


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  		Figure 2. Plasma IR-orexin-A concentrations before and after nCPAP treatment in (top, A) group A and (bottom, B) group B. * = F(1, 20) = 9.056 (p = 0.0069); # = F(1, 30) = 0.011 (p = 0.9181).

 
We then studied the relationship between the changes in plasma IR-orexin-A concentrations after the nCPAP treatment and the improvement of OSAHS. There was a significant negative correlation between the changes in plasma IR-orexin-A concentrations after nCPAP treatment and those of AI and ESS in 11 patients in group A ({Delta}AI: r = – 0.609; p = 0.0456; {Delta}ESS: r = – 0.751; p = 0.0059) [Fig 3 , top, A], but not in the 16 patients of group B ({Delta}AI: r = 0.341; p = 0.1925; {Delta}ESS: r = – 0.329; p = 0.2174) [Fig 3, bottom, B]. There was no significant correlation between the changes in plasma IR-orexin-A concentrations after nCPAP treatment and those in AHI (group A: r = – 0.314; p = 0.358; group B: r = – 0.043; p = – 0.878).



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  		Figure 3. Correlations between the changes in plasma IR-orexin-A concentration ({Delta}Orexin-A) after nCPAP treatment, and those of the {Delta}AI (left side) and the {Delta}ESS (right side). Top, A: group A ({Delta}AI: r = – 0.609; p = 0.0456; {Delta}ESS: r = – 0.751; p = 0.0059). Bottom, B: group B ({Delta}AI: r = 0.341; p = 0.1925; {Delta}ESS: r = – 0.329; p = 0.2174). {Delta}Orexin-A = (plasma IR-orexin-A concentrations after nCPAP) – (plasma IR-orexin-A concentrations before nCPAP). {Delta}AI = ({Delta}AI after nCPAP) – ({Delta}AI before nCPAP). {Delta}ESS = ({Delta}ESS after nCPAP) – ({Delta}ESS before nCPAP).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Patients with OSAHS have a higher incidence of various diseases, such as hypertension,2122 abnormal lipid metabolism, type 2 diabetes mellitus, and obesity,232425 which influence morbidity and mortality. Furthermore, OSAHS patients are likely to have cognitive executive and learning dysfunctions, which might be associated with a higher incidence of automobile accidents.2627 The nCPAP treatment improves not only nocturnal hypoxia but also excessive daytime sleepiness. Plasma concentrations of cortisol, catecholamines, atrial natriuretic peptide, antidiuretic hormone, leptin, and ghrelin were elevated in patients with OSAHS.282930 Plasma concentrations of catecholamines, leptin, and ghrelin were decreased after CPAP treatment. Particularly, it has been reported931 that plasma leptin levels lowered independently of obesity when the AHI is improved by nCPAP.

We have previously shown that plasma levels of IR-orexin-A were decreased in parallel with the severity of OSAHS.15 It is therefore plausible that a low level of plasma IR-orexin-A may be a marker for severe OSAHS. In the present study, we have shown that nCPAP treatment improved not only the clinical parameters, such as AI and AHI, but also the low plasma levels of IR-orexin-A in patients with severe OSAHS (AI, ≥ 60 events per hour). On the other hand, nCPAP treatment had no significant effects on plasma levels of IR-orexin-A in patients with mild OSAHS (AI, < 60 events per hour) despite their clinical improvement. Plasma IR-orexin-A concentrations were rather elevated in patients with mild OSAHS, particularly in patients with an AHI of < 20 events per hour, or an AI of < 20 events per hour, suggesting that hypothalamic orexin-A secretion is increased in patients with mild OSAHS. Furthermore, plasma IR-orexin-A concentrations were decreased after nCPAP treatment in about half of the subjects in the group B (Fig 2, bottom, B). Thus, the state of the hypothalamic orexin-neurons may be different depending on the severity of OSAHS. On the other hand, orexin-A is expressed not only in the hypothalamus, but also in peripheral tissues, such as those in the GI tract and pancreas,3233 although the tissue concentrations of orexin-A in the peripheral tissues are much lower than those in the brain. It is therefore also possible that the negative results in patients with mild OSAHS (group B) was due to the contribution of peripheral orexin-A to the plasma concentrations.

We then studied the relationship between the change in plasma IR-orexin-A concentrations after nCPAP treatment and the improvement in OSAHS. The increases in plasma IR-orexin-A concentrations after nCPAP treatment were in parallel with the improvement of AI and ESS in OSAHS patients with AI values of > 60 events per hour (group A). These findings suggested that the nCPAP improved the secretion of orexin-A neurons in the hypothalamus, which may be related to the improvement of daytime cognitive executive function. On the other hand, we did not observe a significant correlation between the increase in plasma IR-orexin-A concentrations after nCPAP treatment and the improvement in AHI in both the groups. The effects of apnea or hypopnea may act indirectly on the activity of orexin neurons in the hypothalamus via the alteration of other neurotransmitters, such as catecholamines. On the other hand, it is tempting to speculate that the activity of orexin neurons may be related more closely to arousal during sleep and sleepiness during the daytime. These may explain the absence of a significant correlation between the increase in plasma IR-orexin-A concentrations after nCPAP treatment and the improvement in AHI. Further studies in a larger number of subjects with OSAHS may be required, however, to clarify the relationship between plasma IR-orexin-A concentrations and AHI. Moreover, we could not deny the possibility that the polysomnography test underestimated the number of these respiratory events due to the technical reasons (ie, thermistor technology).

Orexin-A has a stimulatory effect on arousal. The defect in orexin-A or the orexin type 2 receptor results in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, cataplexy sleep paralysis, and hypnagogic hallucinations.3435363738 Orexin-A concentrations in the spinal fluid were remarkably decreased in most of the patients with narcolepsy.36 We could not obtain samples of spinal fluid for the measurement of orexin-A from patients with OSAHS for ethical reasons. If the plasma level of orexin-A reflects the neuronal activity of the orexin neurons in the hypothalamus, the plasma orexin-A level would be a good marker of orexin-A secretion from the hypothalamic orexin-neurons. If the plasma level of orexin-A reflects the severity of OSAHS and correlates with the successful treatment of this syndrome, this would be of great value. The low plasma levels of orexin-A in patients with severe OSAHS may be a result of the hypofunction of the orexin-neurons in the hypothalamus, which may be caused by frequent arousals and/or hypoxia during sleep, and may result in daytime sleepiness in these patients.

Igarashi et al39 have reported elevated plasma levels of IR-orexin-A in patients with OSAHS, which is entirely contrary to our findings.1540 In the present study, we have confirmed the findings in our previous studies,1540 which showed that plasma IR-orexin-A levels were decreased in parallel with the severity of OSAHS. One possible reason for this discrepancy may be the difference in the methods used for measurement.41 We measured plasma IR-orexin-A concentrations by a specific radioimmunoassay developed by Arihara et al1920 after extraction using cartridges (Sep-Pak C18), whereas Igarashi et al39 used a radioimmunoassay kit (Peninsula Laboratories; San Carlos CA) without extraction. In our preliminary studies,41 however, a good correlation was found between the data obtained by these two different methods, although the levels obtained by the radioimmunoassay kit without extraction were about 10-fold higher than those using the method of Arihara et al.1920 The difference in the methods of the measurement is therefore unlikely to explain this discrepancy. Another possibility may be differences in the populations studied.41 In our studies, plasma IR-orexin-A concentrations were rather elevated in patients with mild OSAHS,15 and in some of these patients, plasma levels decreased after nCPAP treatment (Fig 2, bottom, B). If the study had included a larger number of such patients with mild OSAHS, discrepant results in plasma IR-orexin-concentrations might have occurred. Decreased plasma levels of IR-orexin-A were observed particularly in OSAHS patients with an AI of > 60 events per hour in our studies.15 On the other hand, Igarashi et al39 studied only one patient with an AI of > 60 events per hour among the 30 patients with OSAHS who were studied.

In conclusion, we have demonstrated that nCPAP treatment improved the low plasma levels of IR-orexin-A in patients with severe OSAHS. This observation may reflect an improved activity of orexin neurons in the hypothalamus as a result of treatment, which is related to the improvement of daytime cognitive executive function in patients with OSAHS.


   Footnotes
 
Abbreviations: AHI = apnea-hypopnea index; AI = arousal index; ESS = Epworth sleepiness scale; IR = immunoreactive; nCPAP = nasal continuous positive airway pressure; OSAHS = obstructive sleep apnea-hypopnea syndrome

Received for publication March 2, 2004. Accepted for publication October 27, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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