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Volume 13 No. 05
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Accepted Papers





Scientific Investigations

Nocturnal Desaturation is Associated With Atrial Fibrillation in Patients With Ischemic Stroke and Obstructive Sleep Apnea

Chung-Yao Chen, MD1,2; Chien-Hui Ho, MD1; Chia-Ling Chen, MD, PhD3,4; Chung-Chieh Yu, MD2,5
1Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan; 2School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Graduate Institute of Early Intervention, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan

ABSTRACT

Study Objectives:

Both atrial fibrillation (AF) and obstructive sleep apnea (OSA) are risk factors for ischemic stroke. Previous studies suggested that OSA is associated with AF in individuals who have not had a stroke. For better secondary prevention of stroke, this study determined the association between OSA and AF among patients with ischemic stroke.

Methods:

This cross-sectional study recruited consecutive patients with subacute ischemic stroke admitted for neurorehabilitation. The baseline and clinical data were collected, and standard polysomnography was performed in a sleep center.

Results:

The 47 women and 111 men enrolled in this study were divided into two groups according to the presence of AF. The AF group (n = 26) had a significantly older age (72.2 versus 60.1 years, P = .016), significantly more disability (Barthel index: 35 versus 45, P = .045), and marginally higher mean oxygen desaturation (6.7% versus 5.6%, P = .079) compared to the non-AF group. The two groups did not significantly differ in sex, body mass index, prevalence of hyperthyroidism, and other parameters of OSA. The multivariate logistic regression analysis revealed that mean desaturation was significantly associated with AF after adjusting for age, neck circumference, Barthel index and high-density lipoprotein level (odds ratio = 1.19 (95% confidence interval 1.05–1.35), P = .008).

Conclusions:

Nocturnal hypoxia due to OSA is an independent predictor of AF in patients with subacute ischemic stroke. The use of overnight pulse oximeter to assess nocturnal hypoxia and predict paroxysmal AF in patients with cryptogenic stroke needs further evaluation.

Commentary:

A commentary on this article appears in this issue on page 667.

Citation:

Chen CY, Ho CH, Chen CL, Yu CC. Nocturnal desaturation is associated with atrial fibrillation in patients with ischemic stroke and obstructive sleep apnea. J Clin Sleep Med. 2017;13(5):729–735.


INTRODUCTION

Considerable evidence supports an independent association between obstructive sleep apnea (OSA) and atrial fibrillation (AF).15 The estimated prevalence of OSA in patients with AF is 32% to 49%.6 OSA is also a known independent risk factor for incident AF in individuals younger than 65 years.1 A significant decrease in the occurrence of paroxysmal AF has been reported by treating OSA with continuous positive airway pressure.7 The recurrence of AF after cardioversion is also reportedly higher in patients with OSA than in those without OSA.2,8 Pathogenic mechanisms of AF in patients with OSA include altered autonomic activity, proinflammation state, left ventricular dysfunction, intrathoracic pressure changes, and nocturnal desaturation.3

BRIEF SUMMARY

Current Knowledge/Study Rationale: In order to facilitate better secondary prevention of ischemic stroke, we designed this study. It determined the association between obstructive sleep apnea (OSA) and atrial fibrillation (AF) among patients with ischemic stroke.

Study Impact: We found that apnea-hypopnea index and desaturation index cannot fully represent the severity of OSA in patients with stroke. Instead, the mean desaturation value during nocturnal hypoxia must be used. After finding nocturnal hypoxia due to OSA is an independent predictor of AF in patients with subacute ischemic stroke, we conclude that the use of overnight pulse oximeter to assess nocturnal hypoxia and to predict paroxysmal AF in cryptogenic stroke patients needs further evaluation.

Interactions among OSA, AF, age, and ischemic stroke are complex and not well understood. OSA is an independent risk factor for ischemic stroke.912 Depending on patient age and other clinical features, the absolute risk of stroke varies approximately twentyfold in patients with AF.13 The attributable risk of ischemic stroke due to AF increased significantly with age.14 Additionally, OSA may have an additive causative role in the association between stroke and AF. Yaranov et al. recently reported that AF patients with OSA were 3.6 times more likely to experience a first-ever stroke than those without OSA after adjusting for age, sex, body mass index, diabetes mellitus (DM), hypertension (HTN), and coronary artery disease.15 Studies have also suggested that stroke might cause AF.16 Advanced age and history of ischemic stroke are also risk factors for both OSA17 and AF.14 Whether OSA is associated with AF in patients with stroke is not well studied. Shibazaki et al. found that severe sleep-disordered breathing (SDB) was associated with AF in patients with acute ischemic stroke by using portable polygraphy.4 Siarnik et al. also studied patients with acute ischemic stroke of minor severity using standard polysomnography (PSG) and reported that only age and desaturation index (DI), not apnea-hypopnea index (AHI) or diagnosis of OSA, were significantly associated with AF.18 In contrast, a study of patients with acute stroke by Poli et al. revealed that SDB was not an independent predictor of cardioembolic stroke after adjusting for age.19 However, patients with acute stroke are often anxious and under intensive care with regular neurologic evaluation and noise from monitors, which results in poor sleep quality. The validity of portable polygraphy therefore decreased in these clinical settings because sleep quality cannot be measured by polygraphy. In addition, central sleep apnea (CSA) and Cheyne-Stokes breathing (CSB), the common forms of SDB found in patients with acute stroke,20 were not excluded in their studies,4,18,19 which made the relationship between OSA and AF in acute stroke patients ambiguous. Because SDB severity and type change following acute stroke,20,21 the relationship between AF and SDB in patients with stroke might also change accordingly.

Elucidating the OSA characteristics that correlate with AF in subacute stroke patients may help clinicians identify the specified pathophysiologic determinants of OSA in secondary prevention of ischemic stroke. Therefore, the primary objective of this study was to use standard PSG in recruited patients with subacute ischemic stroke to determine the association between OSA and AF.

METHODS

Participants

This cross-sectional study consecutively recruited patients with recent ischemic stroke (> 1 week, within 12 months) admitted for neurorehabilitation. Ischemic stroke was diagnosed after full clinical assessment with detailed neurological examinations and neuroimaging studies, including computed tomography or magnetic resonance imaging. The exclusion criteria were unclear consciousness or unstable vital or neurologic signs, heart failure (HF), chronic obstructive pulmonary disease (COPD), chronic kidney disease stage III–V, CSB, or CSA. The local ethics committee approved this study protocol, and informed consent was obtained from all participants or their next of kin when the participant's communication was impaired.

Clinical Evaluation

During all admissions, a comprehensive history was taken, including demographic data and history of risk factors for stroke. All participants were also screened for smoking (active smokers versus nonsmokers; ex-smokers were considered nonsmokers when cessation of smoking was more than 3 months prior to this event), hyperlipidemia (history of hypercholesterolemia or fasting total cholesterol level > 200 mg/dL), HTN (history of HTN or systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg before or 2 weeks after stroke onset), and DM (history of DM or fasting blood glucose > 126 mg/dL). Initial stroke severity was taken from the relevant medical reports, as measured by the National Institutes of Health Stroke Scale (NIHSS).22 Cardiac arrhythmia was assessed by 12-lead electrocardiogram (ECG), or by 24-hour Holter ECG if stroke mechanism was unexplained after the first-line investigation. On the date of PSG examination, the Barthel index (BI)23 of current stroke severity was calculated, and the following physical parameters were recorded: neck circumference, height, and weight.

Outcome Measures

Embla N7000 (Somnologica, Iceland) was used for PSG examination at the sleep laboratory from 10:00 PM to 7:00 AM. Measurements included 6 electroencephalography channels (F3-A1, F4-A2, C3-A1, C4-A2, O1-A1, and O2-A2), an ECG, an electro-oculogram, a chin and bilateral anterior tibial surface electromyogram, airflow sensors (nasal pressure cannula and oronasal thermistor), thoracic and abdominal movement detectors (inductance plethysmography), and finger pulse oximetry.

Diagnoses of OSA were made according to 2007 American Academy of Sleep Medicine (AASM) criteria.24 In obstructive apnea, the respiratory effort was maintained, whereas in central apnea, breathing movements were absent. Apnea was defined as the absence of airflow for at least 10 seconds. A combination of central and obstructive apnea that persisted upon resumption of respiratory effort was defined as mixed apnea.25 A reduction of ≥ 50% in thoracoabdominal amplitude for at least 10 seconds with either an arousal or oxygen desaturation ≥ 3% was defined as hypopnea according to the alternative definition. The desaturation event (desaturation ≥ 3%) was recorded to calculate oxyhemoglobin DI (number of desaturation events per hour of sleep during PSG). When more than 50% of respiratory events were of obstructive or mixed types, OSA was diagnosed. Severe OSA was considered in patients with more than 30 apneas and/or hypopneas per hour of sleep (AHI > 30 events/h). When ≥ 50% of respiratory events were of the central type, CSA was diagnosed.26 Based on the updated AASM criteria in 2012,27 CSB was diagnosed. Mean SpO2 (oxyhemoglobin saturation by pulse oximetry), minimal SpO2, desaturation depth (difference between the highest and lowest SpO2 in one desaturation event), and ST90 (percent of total sleep time with oxygen saturation below 90%) were calculated. As suggested by the manufacturer and scored by proprietary software (RemLogic 2.0, Embla, Somnologica, Iceland), mean desaturation was calculated automatically as the sum of all desaturation depths divided by the total number of desaturation events. Saturation was measured by pulse oximetry every 0.1 second.

Statistics

Patients were divided into two groups according to the presence of AF. Patients with paroxysmal AF in whom a diagnosis was made before the stroke event were stratified into AF group. Statistical analyses were performed with SPSS 20.0 software (SPSS Inc., Chicago, Illinois, United States). The normality of each data distribution was assessed. The high-density lipoprotein (HDL) levels were log-transformed to achieve normality, followed by subsequent analysis with parametric tests. The Pearson χ2 test for categorical variables, unpaired t tests, or Mann-Whitney U test for continuous variables were used to assess intergroup differences. The Pearson or Spearman correlations were used to determine the relationship between the baseline continuous variables and the parameters of OSA. The potential variables were selected if they were related to AF at P ≤ .2 and were entered into a multivariate logistic regression model to determine the independent association between AF and OSA parameters. Values of P < .05 were regarded as statistically significant.

RESULTS

Forty-seven women and 111 men (mean age ± standard deviation [SD], 63.4 ± 13.3 years) were included in this study, and 26 participants were found to have AF. Thirty-nine patients were excluded due to CSA or CSB (n = 12), chronic kidney disease (n = 19), heart failure (n = 6), and COPD (n = 2), respectively. Participants in the AF group were significantly older (median age 72.2 versus 60.1 years, P = .016), had experienced significantly more severe stroke as measured by the median scores of NIHSS (13 versus 8, P = .026) and BI (35 versus 45, P = .045) than those in the non-AF group (Table 1). The median scores of mean desaturation tended to be lower in the non-AF group compared to the AF group (5.6% versus 6.7%, P = .079). Additionally, the two groups did not differ in the prevalence and severity of OSA, the time interval between the onset of stroke and the date of the PSG study, levels of high-sensitivity C-reactive protein (hs-CRP), and the prevalence of hyperthyroidism (Table 1). Table 2 shows the correlations between baseline continuous variables and parameters of OSA. Age significantly correlated with AHI (Spearman rho = 0.310, P < .001) and DI (Spearman rho = 0.276, P < .001), but did not significantly correlate with mean desaturation (Spearman rho = 0.095, P = .236). In addition, mean desaturation was highly correlated to AHI (Spearman rho = 0.618, P < .001) and DI (Spearman rho = 0.693, P < .001).

Epidemiological factors, clinical variables, and laboratory parameters stratified by the presence of atrial fibrillation.

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Table 1

Epidemiological factors, clinical variables, and laboratory parameters stratified by the presence of atrial fibrillation.

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Correlations between baseline continuous variables and parameters of obstructive sleep apnea.

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Table 2

Correlations between baseline continuous variables and parameters of obstructive sleep apnea.

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Table 3 shows that, after adjustment for age, neck circumference, BI, and levels of HDL, the multivariate logistic regression analysis revealed that mean desaturation was significantly associated with the presence of AF (odds ratio = 1.19 (95% confidence interval 1.05–1.35), P = .008).

Logistic regression models of factors associated with atrial fibrillation.

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Table 3

Logistic regression models of factors associated with atrial fibrillation.

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DISCUSSION

To our knowledge, this is the first study to evaluate the association between AF and OSA using the standard PSG examination in patients with subacute ischemic stroke. Mean desaturation, but not AHI or DI, was independently associated with AF after adjusting for common covariates. That means it is the magnitude of nocturnal desaturation, which is a crucial pathophysiological consequence of OSA, that truly has an effect on the occurrence of AF in patients with ischemic stroke.

Independent associations between OSA and AF in patients with ischemic stroke were clarified after adjusting for age, neck circumference, stroke severity, and levels of HDL. Shibazaki et al.4 and Siarnik et al.18 recruited only patients with acute stroke and relative mild severity (NIHSS, 5–6) which made their results not applicable to patients with general stroke. The severity of stroke in the patients with subacute stroke recruited in the current study (median NIHSS 9, interquartile range 5–13) was higher than that in their studies4,18 and could be more generalized to stroke patients. As other possible underlying diseases, such as CSA, heart failure, and COPD (which might cause nocturnal hypoxia) were excluded and the mean desaturation was highly correlated with AHI and DI, it is reasonable to assume that nocturnal hypoxia was mainly resulted from the pathophysiological effect of OSA in the current study. In addition, mean desaturation was marginally higher in AF groups compared to the non-AF group. The nonsignificant statistical difference in mean desaturation between the two groups may have resulted from the relatively small sample size of the AF group and may then be possible type II error. This study suggests that nocturnal hypoxia might be a contributing factor for the presence of AF in ischemic stroke patients, which concurs with the study by Siarnik et al. who reported that DI, but not AHI, was independently associated with AF in patients with acute stroke.18

Regarding AF, nocturnal mean desaturation resulting from intermittent hypoxia is a more suitable parameter than classic parameters of OSA such as AHI and DI for predicting the presence of AF and might be the primary mechanism for the pathogenesis of AF in stroke patients. Dog models show that, in the absence of inspiratory effort or arousals, apnea-induced hypoxia remarkably reduces atrial refractory periods and lowers the threshold for development of AF.28 In addition, the left ventricular diastolic dysfunction induced by apnea-related hypoxia29 may increase left atrial pressure and size, which is a well-known AF risk factor. Our results also agree with two large-scale longitudinal studies1,5 that suggested that nocturnal desaturation instead of AHI is a putative mechanism of the link between OSA and the development of AF in stroke-free subjects younger than 65 years. As DI is a rate calculated as the number of desaturation events per hour of sleep, it cannot fully express the duration and degree of nocturnal intermittent hypoxia caused by OSA. That is, the effect of intermittent hypoxia with deep and long oxygen desaturation should not be equal to that of shallow and short oxygen desaturation. Therefore, new indexes such as ST90 and integrated area of desaturation have gained attention because of their direct reflection of the duration and severity of hypoxia.3032 Because ST90 did not differ between patients with and without AF, this study suggests that the degree of hypoxia is more important than the duration of hypoxia in the pathogenesis of AF. Studies have suggested that circulating CRP was a marker of vascular inflammation, and its level reportedly correlated with AF stability and predicted postoperative AF despite of the debatable causal relationship.33 In the current study, the finding that hs-CRP level did not correlate with severity of OSA, and did not significantly differ between stroke patients with and without AF, suggests that vascular inflammation has a minor role in the complex relationship between OSA, AF, and ischemic stroke.

Nocturnal hypoxia is independently associated with AF not only in young patients, but also in the elderly. Gami et al. found that the incidence of AF was significant associated with nocturnal hypoxia and HF in individuals younger than 65 years and those 65 years or older, respectively.1 Mehra et al. found that AF was most substantially associated with CSA in older men.34 As HF and CSA can also cause nocturnal hypoxia, excluding patients with underlying CSA and HF in this study might be the main reason for the different findings from aforementioned studies.1,34 Aging has a strong association with AF risk and SDB risk,3 which might be the reason why previous studies on patients with acute stroke did not support the independent role of SDB in predicting cardioembolic stroke after adjusting for age.19 Mean desaturation was not significantly correlated with age in the current study, which made mean desaturation independently associated with the presence of AF after adjusting for covariates and may be a predictor for AF in patients with ischemic stroke.

The AHI level does not indicate the full extent and degree of nocturnal intermittent hypoxia due to OSA and is not independently associated with the presence of AF in patients with stroke. The best method by which to score hypopnea events and whether or not AHI is the best parameter to measuring the severity of OSA are debatable.3537 Currently, the oxygen desaturation threshold (ODT) levels for hypopnea can be 3% or 4% based on different definitions proved by the AASM in 2013.38 Myllymaa et al. studied middle-aged subjects and found that the number of patients with AHI ≥ 15 decreased by approximately 44% when hypopnea was classified according to ODT4% (AASM 2007) instead of ODT3% (AASM 2012).39 Punjabi et al. analyzed data from the Sleep Heart Health Study and found that only hypopneas with a desaturation > 4% had an independent correlation with cardiovascular disease, with no association found for hypopneas with mild desaturations or arousals.40 Recent studies also found the correlation of severe consequence of OSA and the parameters with AHI was only moderate35 and overnight oxygen saturation may better predict older men at risk for stroke than apnea frequency.41 Elderly patients are also known to have an increased frequency of spontaneous arousal.42 Therefore, the alternative definition of hypopnea applied in this study may not fully represent the degree of intermittent hypoxia due to OSA, and further studies to determine the optimal desaturation threshold for defining hypopnea in stroke patients are required.

This study has several limitations. One limitation is selection bias because this study only recruited patients admitted for inpatient stroke rehabilitation. Patients with strokes of mild severity undergoing rehabilitation on an outpatient basis and with severe strokes and impaired consciousness were not recruited for this study. Therefore, our findings cannot be generalized to these patients. Another potential limitation is that the presence of undetermined factors other than OSA that could cause desaturation during sleep may have affected our conclusions; however, we did exclude patients with common underlying diseases such as CSA, heart failure, and COPD. Misclassification of AF status could not be ruled out given that cardiac rhythm monitoring beyond 30 days was not used in this study. Finally, a causal relationship between nocturnal hypoxia and AF was not established in this cross-sectional study. Further prospective studies of the incidence of newly diagnosed AF in cryptogenic ischemic stroke patients with prominent nocturnal hypoxia due to OSA are needed.

CONCLUSIONS

Nocturnal oxygen desaturation due to OSA is an independent predictor of AF in ischemic stroke patients admitted for neurorehabilitation. Nocturnal desaturation may also be a predictor of paroxysmal AF and is a potential treatment target for cryptogenic stroke. The role of overnight pulse oximeter for assessing nocturnal hypoxia and for predicting paroxysmal AF in cryptogenic stroke patients remains to be determined.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. This was not an industry supported study. The authors have indicated no financial conflicts of interest. This study was funded by the Chang Gung Medical Research Council under Contract No. CMRPG2E0012.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

AF

atrial fibrillation

AHI

apnea-hypopnea index

BI

Barthel index

BMI

body mass index

CI

conference interval

COPD

chronic obstructive pulmonary disease

CSA

central sleep apnea

CSB

Cheyne-Stokes breathing

DI

desaturation index

DM

diabetes mellitus

ECG

electrocardiogram

ESS

Epworth Sleepiness Scale

HDL

high-density lipoprotein

HF

heart failure

hs-CRP

high-sensitivity C-reactive protein

HTN

hypertension

IQR

interquartile range

LDL

low-density lipoprotein

NIHSS

National Institutes of Health Stroke Scale

ODT

oxygen desaturation threshold

OR

odds ratio

OSA

obstructive sleep apnea

PSG

polysomnography

SD

standard deviation

SDB

sleep-disordered breathing

SpO2

oxyhemoglobin saturation by pulse oximetry

ST90

percent of total sleep time with oxygen saturation below 90%

ACKNOWLEDGMENTS

The authors thank Ted Knoy for his editorial assistance.

REFERENCES

1 

Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol. 2007;49(5):565–571. [PubMed]

2 

Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589–2594. [PubMed]

3 

Maan A, Mansour M, Anter E, et al. Obstructive sleep apnea and atrial fibrillation: pathophysiology and implications for treatment. Crit Pathw Cardiol. 2015;14(2):81–85. [PubMed]

4 

Shibazaki K, Kimura K, Uemura J, et al. Atrial fibrillation is associated with severe sleep-disordered breathing in patients with ischaemic stroke and transient ischaemic attack. Eur J Neurol. 2013;20(2):266–270. [PubMed]

5 

Cadby G, McArdle N, Briffa T, et al. Severity of OSA is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort. Chest. 2015;148(4):945–952. [PubMed]

6 

Gami AS, Friedman PA, Chung MK, Caples SM, Somers VK. Therapy insight: interactions between atrial fibrillation and obstructive sleep apnea. Nat Clin Pract Cardiovasc Med. 2005;2(3):145–149. [PubMed]

7 

Abe H, Takahashi M, Yaegashi H, et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels. 2010;25(1):63–69. [PubMed]

8 

Szymanski FM, Filipiak KJ, Platek AE, et al. Presence and severity of obstructive sleep apnea and remote outcomes of atrial fibrillation ablations - a long-term prospective, cross-sectional cohort study. Sleep Breath. 2015;19(3):849–856. [PubMed Central][PubMed]

9 

Marin JM, Carrizo SJ, Vicente E, Agusti AGN. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;36(9464):1046–1053.

10 

Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke. 2006;37(9):2317–2321. [PubMed]

11 

Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–2041. [PubMed]

12 

Valham F, Mooe T, Rabben T, Stenlund H, Wiklund U, Franklin KA. Increased risk of stroke in patients with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation. 2008;118(9):955–960. [PubMed]

13 

Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546–554. [PubMed]

14 

Bjorck S, Palaszewski B, Friberg L, Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin therapy revisited: a population-based study. Stroke. 2013;44(11):3103–3108. [PubMed]

15 

Yaranov DM, Smyrlis A, Usatii N, et al. Effect of obstructive sleep apnea on frequency of stroke in patients with atrial fibrillation. Am J Cardiol. 2015;115(4):461–465. [PubMed]

16 

Sposato LA, Riccio PM, Hachinski V. Poststroke atrial fibrillation: cause or consequence? Critical review of current views. Neurology. 2014;82(13):1180–1186. [PubMed]

17 

Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med. 2010;6(2):131–137. [PubMed Central][PubMed]

18 

Siarnik P, Kollar B, Carnicka Z, Sutovsky S, Klobucnikova K, Turcani P. Characteristics of sleep-disordered breathing in etiologic subtypes of minor-to-moderate acute ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24(5):1087–1093. [PubMed]

19 

Poli M, Philip P, Taillard J, et al. Atrial fibrillation is a major cause of stroke in apneic patients: a prospective study. Sleep Med. 2017;30:251–254. [PubMed]

20 

Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med. 2000;161:375–380. [PubMed]

21 

Harbison J, Ford GA, James OF, Gibson GJ. Sleep-disordered breathing following acute stroke. QJM. 2002;95(11):741–747. [PubMed]

22 

Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864–870. [PubMed]

23 

Shah S, Vanclay F, Cooper B. Improving the sensitivity of the Barthel Index for stroke rehabilitation. J Clin Epidemiol. 1989;42(8):703–709. [PubMed]

24 

Iber C, Ancoli-Israel S, Chesson A, Quan SF; for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007.

25 

Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667–689. [PubMed]

26 

Aaronson JA, van Bennekom CA, Hofman WF, et al. Obstructive sleep apnea is related to impaired cognitive and functional status after stroke. Sleep. 2015;38(9):1431–1437. [PubMed Central][PubMed]

27 

Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8(5):597–619. [PubMed Central][PubMed]

28 

Ghias M, Scherlag BJ, Lu Z, et al. The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol. 2009;54(22):2075–2083. [PubMed]

29 

Kraiczi H, Caidahl K, Samuelsson A, Peker Yk, Hedner J. Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep. Chest. 2001;119(4):1085–1091. [PubMed]

30 

van Oosten EM, Hamilton A, Petsikas D, et al. Effect of preoperative obstructive sleep apnea on the frequency of atrial fibrillation after coronary artery bypass grafting. Am J Cardiol. 2014;113(6):919–923. [PubMed]

31 

Asano K, Takata Y, Usui Y, et al. New index for analysis of polysomnography, ‘integrated area of desaturation’, is associated with high cardiovascular risk in patients with mild to moderate obstructive sleep apnea. Respiration. 2009;78(3):278–284. [PubMed]

32 

Yamaguchi T, Takata Y, Usui Y, et al. Nocturnal intermittent hypoxia is associated with left ventricular hypertrophy in middle-aged men with hypertension and obstructive sleep apnea. Am J Hypertens. 2016;29(3):372–378. [PubMed]

33 

Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: causes of ‘not-so-lone atrial fibrillation’. Europace. 2008;10(6):668–673. [PubMed]

34 

Mehra R, Stone KL, Varosy PD, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med. 2009;169(12):1147–1155. [PubMed Central][PubMed]

35 

Kulkas A, Tiihonen P, Julkunen P, Mervaala E, Toyras J. Novel parameters indicate significant differences in severity of obstructive sleep apnea with patients having similar apnea-hypopnea index. Med Biol Eng Comput. 2013;51(6):697–708. [PubMed]

36 

Wu MN, Lai CL, Liu CK, et al. More severe hypoxemia is associated with better subjective sleep quality in obstructive sleep apnea. BMC Pulm Med. 2015;15:117[PubMed Central][PubMed]

37 

Muraja-Murro A, Kulkas A, Hiltunen M, et al. Adjustment of apnea-hypopnea index with severity of obstruction events enhances detection of sleep apnea patients with the highest risk of severe health consequences. Sleep Breath. 2014;18(3):641–647. [PubMed]

38 

Berry RB, Brooks R, Gamaldo CE, et al; for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Version 2.0.2. Darien, IL: American Academy of Sleep Medicine; 2013.

39 

Myllymaa S, Myllymaa K, Kupari S, et al. Effect of different oxygen desaturation threshold levels on hypopnea scoring and classification of severity of sleep apnea. Sleep Breath. 2015;19(3):947–954. [PubMed]

40 

Punjabi NM, Newman AB, Young TB, Resnick HE, Sanders MH. Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med. 2008;177(10):1150–1155. [PubMed Central][PubMed]

41 

Stone KL, Blackwell TL, Ancoli-Israel S, et al. Sleep disordered breathing and risk of stroke in older community-dwelling men. Sleep. 2016;39(3):531–540. [PubMed Central][PubMed]

42 

Redline S, Kirchner HL, Quan SF, Gottlieb DJ, Kapur V, Newman A. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med. 2004;164(4):406–418. [PubMed]