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Sleep-disordered breathing in Eisenmenger Syndrome
International Journal of Cardiology 214 (2016) 23–24
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Sleep-disordered breathing in Eisenmenger Syndrome☆ Cristel S. Hjortshøj a,⁎, Annette S. Jensen a, Julie A.E. Christensen b, Poul Jennum b, Lars Søndergaard a a b
Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Copenhagen University Hospital, Rigshospitalet Glostrup, Copenhagen, Denmark
a r t i c l e
i n f o
Article history: Received 12 February 2016 Accepted 19 March 2016 Available online 26 March 2016 Keywords: Sleep-disordered breathing Obstructive sleep apnoea Cyanotic congenital heart disease Pulmonary arterial hypertension Eisenmenger Syndrome
Sleep-disordered breathing (SDB) including obstructive sleep apnoea (OSA) is an independent risk factor for cardiovascular morbidity and mortality in the general population. SDB is a common finding in patients with pulmonary arterial hypertension (PAH) and contributes to increased morbidity [1,2]. Despite new treatment options such as advanced therapy in Eisenmenger Syndrome (ES), ES patients still have a high morbidity and mortality. Therefore, identifying and treating possible comorbidities is of great importance. In the general population the estimated prevalence of SDB is 5–25% [3]. The prevalence of SDB in ES have only been examined in two small studies and none of the two studies found evidence of SDB in ES patients [4,5]. The prevalence of SDB, however, increases with older age and the previous studies only examined young ES patients. Thus we aimed with this study to examine the prevalence of SDB in middle-aged patients with ES. We performed a cross-sectional, single-centre study in 20 middleaged patients with ES and compared the results of the polysomnography with healthy controls from a historic cohort. The controls were matched 1:1 according to age, gender, and BMI. The study was conducted according to the Declaration of Helsinki. Informed consent was obtained from all patients and the study was approved by the Regional Ethics Committee (www.regionh.dk/vek, H-2-2012-168).
☆ All authors takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Dept. Cardiology B, 2013, Blegdamsvej 9, Rigshospitalet, 2100 Copenhagen, Denmark. E-mail address: [email protected] (C.S. Hjortshøj).
http://dx.doi.org/10.1016/j.ijcard.2016.03.108 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
ES patients from our out-patient clinic were prospectively invited to participate in the study without pre-selection for symptoms of SDB. From May 2013 to February 2015 20 clinical stabile patients (defined as no hospitalization or change in medications within the last three months), were included. Patients underwent clinical examination, 6-minute walking distance test (6MWD), spirometry, venous blood sampling, and polysomnography (PSG). All testing were done according to recommended clinical standards. PSG was performed with an oronasal thermal sensor using standard techniques and scored in accordance with the American Academy of Sleep Medicine (AASM) standards [6]. Total recording time, total sleep time, sleep stages, apnoea–hypopnea index (AHI), periodic leg movement and arousals were determined [7]. Sleep architecture refers to the structural organization of normal sleep in rapid eye movement (REM) and non-REM sleep. AHI was calculated as the number of apnoeas and hypopneas per hour of sleep. An apnoea was defined as a drop in nasal flow ventilation of ≥ 90% lasting ≥ 10 s. If persistent respiratory effort was present, the apnoea was categorized as obstructive. Hypopnoea was defined as a respiratory reduction of ≥30% lasting ≥10 s followed by a ≥3% desaturation or an arousal. SDB was defined as mild if AHI 5–15/h, moderate if AHI 15–25/h and severe if AHI N25/h. The apnoea type was categorized OSA if more than 50% of the events were obstructive [6]. Statistical comparisons between categories were made using appropriate non-parametric testing. Multivariate relations between SDB and independent predefined variables were analysed by multiple regression. Two-sided p b 0.05 was considered statistically significant. Analysis was performed using SPSS 22 (IBM SPSS Inc., Chicago, IL). The male:female ratio was 1:2.3. The majority of the patients (80%) had ES due to a ventricular septum defect; the remaining had atrial septum defect (10%) and Tetralogy of Fallot (10%). All except one patient received advanced therapy; this patient however, as the only in the study, received nocturnal supplemental oxygen therapy. Demographics are shown in Table 1. Controls were healthy individuals from a historic cohort; median age 51 years (IQR 48.0–56.5), median BMI 23.5 kg/m2 (IQR 21.6–25.4 kg/m2), and 70% female, equivalent to the patient group. Total sleep time in ES patients was equal to the controls, but the patients had significantly lower sleep efficiency (minutes of sleep divided by minutes in bed). This is not believed to influence the sleep architecture, which was normal in both groups. Results of the polysomnography are presented in Table 2. Three ES patients (15%) had AHI ≥ 5, one with severe OSA and two with moderate OSA. Although median AHI amongst ES patients and controls were comparable, 25% of the controls had OSA.
24
Correspondence
Table 1 Patient demographics. Data from the full patient cohort and in the subgroups of patients with and without OSA are presented.
Age (years) Body mass index 6MWD (m) Saturation, rest (%) Blood tests Haemoglobin (g/dl) Haematocrit NTproBNP (pmol/l) Pulmonary function test DLCOc (%pred) FEV1/FVC (%pred)
All patients Median (IQR)
OSA, n = 3 Median (range)
non-OSA, n = 17 Median (range)
P-value: OSA/non-OSA
50.0 (48.0–56.0) 23.0 (21.2–25.6) 460.0 (412.5–460.0) 82.5 (79.0–86.0)
61.0 (56.0–70.0) 30.8 (24.7–31.3) 482.0 (420.0–482.0) 81.0 (79.0–83.0)
49.0 (38.0–64.0) 22.2 (16.8–27.1) 456.0 (310.0–575.0) 83.0 (70.0–91.0)
0.006 0.003 NS NS
20.5 (18.5–21.3) 0.60 (0.54–0.65) 94.7 (17.5–159.0)
19.2 (18.5–20.8) 0.6 (0.55–0.6) 111.0 (18.3–135.0)
20.8 (17.1–22.7) 0.6 (0.5–0.7) 92.1 (5.9–622.0)
NS NS NS
61.7 (56.4–67.7) 71.3 (61.2–77.0)
66.4 (56.7–69.8) 72.0 (70.6–77.6)
61.5 (40.7–80.4) 69.1 (53.8–85.4)
NS NS
OSA: Obstructive sleep apnoea, 6MWD: 6 minute walking distance, DLCOc: haemoglobin-corrected diffusion capacity of the lung for carbon monoxide, %pred: % of predicted, FEV1/FVC: Forced expiratory volume to forced vital capacity ratio. p b 0.05.
OSA was significantly related to BMI (p = 0.003) and age (p = 0.006), but it did not correlate with the type of shunt, resting oxygen saturation, level of haemoglobin, haematocrit, N-terminal pro-type B natriuretic peptide, or 6MWD, Table 1. Transcutaneous pCO2 was normal. All ES patients diagnosed with OSA were offered CPAP treatment and repeated PSG for evaluation of treatment effect. However none accepted due to the extensive impact of CPAP on daily life and minimal subjective symptoms of OSA. In this study, the prevalence of SDB in ES was 15%, which is equal to the estimated prevalence in the general population. The ES patients examined in the two previous studies were, with a median age of 24–43 years, considerable younger than the ES patients in this study, which could explain why no patients in the previous studies had SDB. More than 2/3 of the patients were women, who are known to have a lower prevalence of SDB. This might impact the statistical analysis reducing the chances to prove differences between groups. However, Ramakrishnan et al. did not find a higher prevalence despite 72% of included patients were men [4]. Opposed to predicted [8,9], but similar to previous findings in ES patients [4] sleep architecture was not altered, and the allocation of non-REM and REM sleep was equivalent to the distribution in the control group. These findings suggest that ES patients may develop
some adaptation in sleep regulation. Corroborating this hypothesis a lower arousal-index in ES patients compared to controls were also found, which could suggest that arousability from brain-stem regions may be suppressed. These findings need further validation, but recent studies of other physiological factors e.g. hypoglycaemia show that these stimuli may suppress nocturnal arousability [10]. In conclusion, we found that the prevalence of SDB in ES patients is similar to SDB in the general population. SDB in ES patients was not related to factors of hypoxemia, but solely to well-known risk factors such as age and BMI. Finally, the sleep architecture in patients with ES was normal.
Table 2 Results of the polysomnography.
References Patients
ESS score TST (min) Sleep efficiency (%) Sleep latency (min) REM latency (min) Sleep architecture % of TST in N1 % of TST in N2 % of TST in N3 % of TST in REM Arousal index (n/h) LM index (n/h) PLMS Mean SpO2 (%) Minimum SpO2(%) ΔSpO2 (%) Mean pCO2 (mm Hg) AHI Mild 5–15 pr. hour (n) Moderate 15–25 pr. hour (n) Severe N 25 (n)
Controls
6.0 (4.0–8.8) 3.5 (2.8–8.3) 392.0 (303.0–409.5) 427.0 (379.6–462.0) 85.0 (63.4–88.2) 91.6 (81.4–94.2) 6.8 (4.0–20.7) 5.5 (3.1–11.3) 86.5 (60.8–183.8) 79.3 (56.5–103.1) 6.5 (4.0–11.5) 49.5 (43.0–57.0) 20.5 (16.3–26.8) 21.0 (15.3–24.8)
8.5 (5.0–11.5) 51.0 (44.0–59.8) 20.0 (8.3–23.0) 22.5 (20.3–28.0)
7.8 (4.9–13.1) 31.9 (4.0–47.2) 7.0 (0.3–12.0) 84.0 (82.0–85.5) 79.0 (74.0–81.5) 5.0 (4.0–9.0) 38.0 (36.0–44.5) 0.2 (0.0–1.5) 0 2 1
15.3 (9.6–21.8) 18.3 (8.9–27.9) 7.0 (1.0–17.0) 96.0 (94.3–96.0) 89.5 (85.3–91.8) 6.0 (4.3–9.8) – 1.4 (0.0–9.3) 2 2 1
P-value NS NS 0.009 NS NS
NS
NS
0.013 NS NS b0.001 b0.001 NS NS
NS
NS
Values expressed as median (IQR). ESS: Epworth Sleepiness Scale, TST: Total sleep time, LM: Leg movements, PLMS: Periodic leg movements, SpO2: Oxygen saturation, pCO2: Transcutaneous carbon dioxide, AHI: Apnoea–Hypopnoea index.
Conflict of interest C S Hjortshøj has received an educational grant from Actelion Pharmaceuticals. A S Jensen has received a speaker fee from Actelion Pharmaceuticals. J A E Christensen reports no relationships that could be construed as a conflict of interest. P Jennum reports no relationships that could be construed as a conflict of interest. L Søndergaard has received research grant, speaker fee, and consultant fee from Actelion Pharmaceuticals.
[1] M. Minic, J.T. Granton, C.M. Ryan, Sleep disordered breathing in group 1 pulmonary arterial hypertension, J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 10 (2014) 277–283. [2] D.L. Prisco, A.L. Sica, A. Talwar, M. Narasimhan, K. Omonuwa, B. Hakimisefat, et al., Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing, Sleep Breath 15 (2010) 633–639. [3] T. Young, M. Palta, J. Dempsey, J. Skatrud, S. Weber, S. Badr, The occurrence of sleep-disordered breathing among middle-aged adults, N Engl J Med 328 (1993) 1230–1235. [4] S. Ramakrishnan, R. Juneja, N. Bardolei, A. Sharma, G. Shukla, M. Bhatia, et al., Nocturnal hypoxaemia in patients with eisenmenger syndrome: a cohort study, BMJ Open 3 (2013). [5] S. Legault, P. Lanfranchi, J. Montplaisir, T. Nielsen, A. Dore, P. Khairy, et al., Nocturnal breathing in cyanotic congenital heart disease, Int J Cardiol 128 (2008) 197–200. [6] R.B. Berry, R. Brooks, C.E. Gamaldo, S.M. Harding, R.M. Lloyd, C.L. Marcus, et al., The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.0, American Academy of Sleep Medicine, 2012. [7] American Academy of Sleep Medicine, The International Classification of Sleep Disorders (ICSD)-Diagnostic and Coding Manual, 2 ed., 2005. [8] P.L. Johnson, N. Edwards, K.R. Burgess, C.E. Sullivan, Sleep architecture changes during a trek from 1400 to 5000 m in the Nepal Himalaya, J Sleep Res 19 (2010) 148–156. [9] K. Ray, A. Dutta, U. Panjwani, L. Thakur, J.P. Anand, S. Kumar, Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture, Neurochem Int 58 (2011) 112–118. [10] P. Jennum, K. Stender-Petersen, R. Rabøl, N.R. Jørgensen, P.-L. Chu, S. Madsbad, The impact of nocturnal hypoglycemia on sleep in subjects with type 2 diabetes, Diabetes Care (2015), dc150907.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Sleep-disordered breathing in Eisenmenger Syndrome☆ Cristel S. Hjortshøj a,⁎, Annette S. Jensen a, Julie A.E. Christensen b, Poul Jennum b, Lars Søndergaard a a b
Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Copenhagen University Hospital, Rigshospitalet Glostrup, Copenhagen, Denmark
a r t i c l e
i n f o
Article history: Received 12 February 2016 Accepted 19 March 2016 Available online 26 March 2016 Keywords: Sleep-disordered breathing Obstructive sleep apnoea Cyanotic congenital heart disease Pulmonary arterial hypertension Eisenmenger Syndrome
Sleep-disordered breathing (SDB) including obstructive sleep apnoea (OSA) is an independent risk factor for cardiovascular morbidity and mortality in the general population. SDB is a common finding in patients with pulmonary arterial hypertension (PAH) and contributes to increased morbidity [1,2]. Despite new treatment options such as advanced therapy in Eisenmenger Syndrome (ES), ES patients still have a high morbidity and mortality. Therefore, identifying and treating possible comorbidities is of great importance. In the general population the estimated prevalence of SDB is 5–25% [3]. The prevalence of SDB in ES have only been examined in two small studies and none of the two studies found evidence of SDB in ES patients [4,5]. The prevalence of SDB, however, increases with older age and the previous studies only examined young ES patients. Thus we aimed with this study to examine the prevalence of SDB in middle-aged patients with ES. We performed a cross-sectional, single-centre study in 20 middleaged patients with ES and compared the results of the polysomnography with healthy controls from a historic cohort. The controls were matched 1:1 according to age, gender, and BMI. The study was conducted according to the Declaration of Helsinki. Informed consent was obtained from all patients and the study was approved by the Regional Ethics Committee (www.regionh.dk/vek, H-2-2012-168).
☆ All authors takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Dept. Cardiology B, 2013, Blegdamsvej 9, Rigshospitalet, 2100 Copenhagen, Denmark. E-mail address: [email protected] (C.S. Hjortshøj).
http://dx.doi.org/10.1016/j.ijcard.2016.03.108 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
ES patients from our out-patient clinic were prospectively invited to participate in the study without pre-selection for symptoms of SDB. From May 2013 to February 2015 20 clinical stabile patients (defined as no hospitalization or change in medications within the last three months), were included. Patients underwent clinical examination, 6-minute walking distance test (6MWD), spirometry, venous blood sampling, and polysomnography (PSG). All testing were done according to recommended clinical standards. PSG was performed with an oronasal thermal sensor using standard techniques and scored in accordance with the American Academy of Sleep Medicine (AASM) standards [6]. Total recording time, total sleep time, sleep stages, apnoea–hypopnea index (AHI), periodic leg movement and arousals were determined [7]. Sleep architecture refers to the structural organization of normal sleep in rapid eye movement (REM) and non-REM sleep. AHI was calculated as the number of apnoeas and hypopneas per hour of sleep. An apnoea was defined as a drop in nasal flow ventilation of ≥ 90% lasting ≥ 10 s. If persistent respiratory effort was present, the apnoea was categorized as obstructive. Hypopnoea was defined as a respiratory reduction of ≥30% lasting ≥10 s followed by a ≥3% desaturation or an arousal. SDB was defined as mild if AHI 5–15/h, moderate if AHI 15–25/h and severe if AHI N25/h. The apnoea type was categorized OSA if more than 50% of the events were obstructive [6]. Statistical comparisons between categories were made using appropriate non-parametric testing. Multivariate relations between SDB and independent predefined variables were analysed by multiple regression. Two-sided p b 0.05 was considered statistically significant. Analysis was performed using SPSS 22 (IBM SPSS Inc., Chicago, IL). The male:female ratio was 1:2.3. The majority of the patients (80%) had ES due to a ventricular septum defect; the remaining had atrial septum defect (10%) and Tetralogy of Fallot (10%). All except one patient received advanced therapy; this patient however, as the only in the study, received nocturnal supplemental oxygen therapy. Demographics are shown in Table 1. Controls were healthy individuals from a historic cohort; median age 51 years (IQR 48.0–56.5), median BMI 23.5 kg/m2 (IQR 21.6–25.4 kg/m2), and 70% female, equivalent to the patient group. Total sleep time in ES patients was equal to the controls, but the patients had significantly lower sleep efficiency (minutes of sleep divided by minutes in bed). This is not believed to influence the sleep architecture, which was normal in both groups. Results of the polysomnography are presented in Table 2. Three ES patients (15%) had AHI ≥ 5, one with severe OSA and two with moderate OSA. Although median AHI amongst ES patients and controls were comparable, 25% of the controls had OSA.
24
Correspondence
Table 1 Patient demographics. Data from the full patient cohort and in the subgroups of patients with and without OSA are presented.
Age (years) Body mass index 6MWD (m) Saturation, rest (%) Blood tests Haemoglobin (g/dl) Haematocrit NTproBNP (pmol/l) Pulmonary function test DLCOc (%pred) FEV1/FVC (%pred)
All patients Median (IQR)
OSA, n = 3 Median (range)
non-OSA, n = 17 Median (range)
P-value: OSA/non-OSA
50.0 (48.0–56.0) 23.0 (21.2–25.6) 460.0 (412.5–460.0) 82.5 (79.0–86.0)
61.0 (56.0–70.0) 30.8 (24.7–31.3) 482.0 (420.0–482.0) 81.0 (79.0–83.0)
49.0 (38.0–64.0) 22.2 (16.8–27.1) 456.0 (310.0–575.0) 83.0 (70.0–91.0)
0.006 0.003 NS NS
20.5 (18.5–21.3) 0.60 (0.54–0.65) 94.7 (17.5–159.0)
19.2 (18.5–20.8) 0.6 (0.55–0.6) 111.0 (18.3–135.0)
20.8 (17.1–22.7) 0.6 (0.5–0.7) 92.1 (5.9–622.0)
NS NS NS
61.7 (56.4–67.7) 71.3 (61.2–77.0)
66.4 (56.7–69.8) 72.0 (70.6–77.6)
61.5 (40.7–80.4) 69.1 (53.8–85.4)
NS NS
OSA: Obstructive sleep apnoea, 6MWD: 6 minute walking distance, DLCOc: haemoglobin-corrected diffusion capacity of the lung for carbon monoxide, %pred: % of predicted, FEV1/FVC: Forced expiratory volume to forced vital capacity ratio. p b 0.05.
OSA was significantly related to BMI (p = 0.003) and age (p = 0.006), but it did not correlate with the type of shunt, resting oxygen saturation, level of haemoglobin, haematocrit, N-terminal pro-type B natriuretic peptide, or 6MWD, Table 1. Transcutaneous pCO2 was normal. All ES patients diagnosed with OSA were offered CPAP treatment and repeated PSG for evaluation of treatment effect. However none accepted due to the extensive impact of CPAP on daily life and minimal subjective symptoms of OSA. In this study, the prevalence of SDB in ES was 15%, which is equal to the estimated prevalence in the general population. The ES patients examined in the two previous studies were, with a median age of 24–43 years, considerable younger than the ES patients in this study, which could explain why no patients in the previous studies had SDB. More than 2/3 of the patients were women, who are known to have a lower prevalence of SDB. This might impact the statistical analysis reducing the chances to prove differences between groups. However, Ramakrishnan et al. did not find a higher prevalence despite 72% of included patients were men [4]. Opposed to predicted [8,9], but similar to previous findings in ES patients [4] sleep architecture was not altered, and the allocation of non-REM and REM sleep was equivalent to the distribution in the control group. These findings suggest that ES patients may develop
some adaptation in sleep regulation. Corroborating this hypothesis a lower arousal-index in ES patients compared to controls were also found, which could suggest that arousability from brain-stem regions may be suppressed. These findings need further validation, but recent studies of other physiological factors e.g. hypoglycaemia show that these stimuli may suppress nocturnal arousability [10]. In conclusion, we found that the prevalence of SDB in ES patients is similar to SDB in the general population. SDB in ES patients was not related to factors of hypoxemia, but solely to well-known risk factors such as age and BMI. Finally, the sleep architecture in patients with ES was normal.
Table 2 Results of the polysomnography.
References Patients
ESS score TST (min) Sleep efficiency (%) Sleep latency (min) REM latency (min) Sleep architecture % of TST in N1 % of TST in N2 % of TST in N3 % of TST in REM Arousal index (n/h) LM index (n/h) PLMS Mean SpO2 (%) Minimum SpO2(%) ΔSpO2 (%) Mean pCO2 (mm Hg) AHI Mild 5–15 pr. hour (n) Moderate 15–25 pr. hour (n) Severe N 25 (n)
Controls
6.0 (4.0–8.8) 3.5 (2.8–8.3) 392.0 (303.0–409.5) 427.0 (379.6–462.0) 85.0 (63.4–88.2) 91.6 (81.4–94.2) 6.8 (4.0–20.7) 5.5 (3.1–11.3) 86.5 (60.8–183.8) 79.3 (56.5–103.1) 6.5 (4.0–11.5) 49.5 (43.0–57.0) 20.5 (16.3–26.8) 21.0 (15.3–24.8)
8.5 (5.0–11.5) 51.0 (44.0–59.8) 20.0 (8.3–23.0) 22.5 (20.3–28.0)
7.8 (4.9–13.1) 31.9 (4.0–47.2) 7.0 (0.3–12.0) 84.0 (82.0–85.5) 79.0 (74.0–81.5) 5.0 (4.0–9.0) 38.0 (36.0–44.5) 0.2 (0.0–1.5) 0 2 1
15.3 (9.6–21.8) 18.3 (8.9–27.9) 7.0 (1.0–17.0) 96.0 (94.3–96.0) 89.5 (85.3–91.8) 6.0 (4.3–9.8) – 1.4 (0.0–9.3) 2 2 1
P-value NS NS 0.009 NS NS
NS
NS
0.013 NS NS b0.001 b0.001 NS NS
NS
NS
Values expressed as median (IQR). ESS: Epworth Sleepiness Scale, TST: Total sleep time, LM: Leg movements, PLMS: Periodic leg movements, SpO2: Oxygen saturation, pCO2: Transcutaneous carbon dioxide, AHI: Apnoea–Hypopnoea index.
Conflict of interest C S Hjortshøj has received an educational grant from Actelion Pharmaceuticals. A S Jensen has received a speaker fee from Actelion Pharmaceuticals. J A E Christensen reports no relationships that could be construed as a conflict of interest. P Jennum reports no relationships that could be construed as a conflict of interest. L Søndergaard has received research grant, speaker fee, and consultant fee from Actelion Pharmaceuticals.
[1] M. Minic, J.T. Granton, C.M. Ryan, Sleep disordered breathing in group 1 pulmonary arterial hypertension, J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 10 (2014) 277–283. [2] D.L. Prisco, A.L. Sica, A. Talwar, M. Narasimhan, K. Omonuwa, B. Hakimisefat, et al., Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing, Sleep Breath 15 (2010) 633–639. [3] T. Young, M. Palta, J. Dempsey, J. Skatrud, S. Weber, S. Badr, The occurrence of sleep-disordered breathing among middle-aged adults, N Engl J Med 328 (1993) 1230–1235. [4] S. Ramakrishnan, R. Juneja, N. Bardolei, A. Sharma, G. Shukla, M. Bhatia, et al., Nocturnal hypoxaemia in patients with eisenmenger syndrome: a cohort study, BMJ Open 3 (2013). [5] S. Legault, P. Lanfranchi, J. Montplaisir, T. Nielsen, A. Dore, P. Khairy, et al., Nocturnal breathing in cyanotic congenital heart disease, Int J Cardiol 128 (2008) 197–200. [6] R.B. Berry, R. Brooks, C.E. Gamaldo, S.M. Harding, R.M. Lloyd, C.L. Marcus, et al., The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.0, American Academy of Sleep Medicine, 2012. [7] American Academy of Sleep Medicine, The International Classification of Sleep Disorders (ICSD)-Diagnostic and Coding Manual, 2 ed., 2005. [8] P.L. Johnson, N. Edwards, K.R. Burgess, C.E. Sullivan, Sleep architecture changes during a trek from 1400 to 5000 m in the Nepal Himalaya, J Sleep Res 19 (2010) 148–156. [9] K. Ray, A. Dutta, U. Panjwani, L. Thakur, J.P. Anand, S. Kumar, Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture, Neurochem Int 58 (2011) 112–118. [10] P. Jennum, K. Stender-Petersen, R. Rabøl, N.R. Jørgensen, P.-L. Chu, S. Madsbad, The impact of nocturnal hypoglycemia on sleep in subjects with type 2 diabetes, Diabetes Care (2015), dc150907.