Accepted Manuscript Sleep Apnea and Stroke Owen D. Lyons, MB, MRCPI, Clodagh M. Ryan, MD, FRCPC PII:
S0828-282X(15)00203-2
DOI:
10.1016/j.cjca.2015.03.014
Reference:
CJCA 1626
To appear in:
Canadian Journal of Cardiology
Received Date: 17 November 2014 Revised Date:
27 February 2015
Accepted Date: 1 March 2015
Please cite this article as: Lyons OD, Ryan CM, Sleep Apnea and Stroke, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.03.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Lyons and Ryan, Sleep Apnea and Stroke
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Sleep Apnea and Stroke Owen D. Lyons, MB, MRCPI
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Clodagh M. Ryan, MD, FRCPC. Affiliation
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Centre for Sleep Health and Research,
Corresponding Author: Clodagh M. Ryan 9N-967 Toronto General Hospital,
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University of Toronto / Toronto General Hospital & Toronto Rehabilitation Institute, Canada
Telephone: 416-340-4719
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Fax: 416-340-4197
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Toronto, Ontario, M5G 2N2, Canada.
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[email protected] Keywords: obstructive sleep apnea, central sleep apnea, stroke,
Total Word Count: 7068
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Brief Summary Sleep apnea has been postulated as a significant causative intermediary mechanism of stroke. It
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evidence exploring the relationship between sleep apnea and stroke.
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is prevalent in the post-stroke population. In this article we will provide a synopsis of current
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Abstract
Stroke is the second leading cause of death worldwide and often has devastating consequences for affected individuals in terms of chronic disability. Traditional risk factors such as age, male sex, ethnicity, hypertension and atrial fibrillation explain 60-80% of the risk of stroke.
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Obstructive sleep apnea (OSA) is highly prevalent in the post-stroke population and its emerging role as a potential modifiable risk factor for stroke has been recognised in the most recent American Heart Association stroke guidelines which recommend consideration of both screening
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for and treatment of OSA in this regard. In this paper we provide an overview of the current evidence based knowledge relating to stroke and sleep apnea. The main focus of this paper is to
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consider key pathophysiological mechanisms by which obstructive sleep apnea may increase the risk for stroke. The effect of OSA on stroke outcomes and the efficacy of treatment of OSA on these outcomes is also considered.
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Introduction The personal, societal and economic consequences of stroke are colossal. Stroke affects
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16.9 million individuals each year and is the second leading cause of death worldwide. Although the incidence of stroke is falling in high-income countries, the absolute numbers sustaining a stroke, mortality from stroke, survivors and those with disability are rising 1. The majority
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(approximately 85%) of strokes are ischemic, rather than hemorrhagic and result from a transient or permanent reduction in cerebral blood flow to a specific territory of brain. Subsequent brain
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injury with disruption of the brain-blood barrier initiates a cascade of inflammation, oxidative stress, excitotoxicity and apoptosis 2. Sequelae from hemorrhagic stroke are similar to ischemic stroke with the added insult caused by compression of surrounding brain tissue, and the cytotoxic effect of blood and vasospasm in those with subarachnoid hemorrhage. Clinical research continues on efforts to recover perfusion and understand vascular remodeling 3, reduce
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inflammation and enhance neuroplasticity 4. Both the high recurrence rate and mortality rate in stroke suggests that more aggressive primary and secondary measures need to be instituted 5. In this paper we will provide an overview of the current literature relating to the role of sleep
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explored.
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apnea(SA) in stroke.. Additionally, the intermediary links between stroke and SA will be
Sleep and Health
Sleep is a biological imperative for all humans, and is usually a period of rest and
inactivity, conferring protection against acute cardiovascular events 6. Upon wakening elevations in blood pressure and heart rate cerebrovascular events
7,8
may explain the
early morning surge of cardiac and
. However, heightened cardiovascular activity during sleep as may
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occur as a result of SA or sleep-wake disorders, may predispose to adverse cardiovascular and cerebrovascular events occurring between 12am and 6am9. Moreover, the sleep-wake cycle is regulated by a complex interplay of mechanisms located mainly in the brainstem, hypothalamus
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and thalamus. Any lesion, such as an acute stroke, which directly affects these areas, has the potential to disrupt the sleep-wake cycle and lead to sleep disturbances. Sleep disturbance caused by SA may be associated with adverse health outcomes including obesity, metabolic disorders,
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hypertension, anxiety and depression. Hence, adequate sleep quality and quantity may be critical
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to those at risk of stroke and for those post-stroke to ensure optimum recovery.
Stroke and Sleep Apnea
Stroke risk is evaluated on an individual and societal basis on the presence of both modifiable (e.g. hypertension, atrial fibrillation) and non-modifiable risk factors (e.g. male sex, 10
.
Within the general population these factors account for 60-80% of risk
11
.
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age, ethnicity)
The emerging role of SA, in particular obstructive sleep apnea (OSA) as a modifiable risk factor for stroke is compelling. The recommendation for consideration of both screening for and
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treatment of SA in the most recent updated American Heart Association guidelines in patients following stroke or transient ischemic attack, reflects the increasing body of available evidence
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in support of the connection between SA and future stroke
12
. SA is an umbrella term that
encompasses both OSA and central sleep apnea (CSA). It is characterized by intermittent complete or partial cessation of airflow during sleep, referred to as apneas and hypopneas, respectively. When present, these events occur multiple times per hour, each at least 10 seconds in duration. OSA results from the narrowing and collapse of the pharyngeal upper airway. CSA results from a transient abolition of central respiratory drive to the respiratory muscles leading to
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cessation of airflow. During an obstructive apnea, respiratory efforts continue; this contrasts to central events where there is no respiratory effort. SA within both the general and stroke population is usually due to OSA. Screening questionnaires, such as the Berlin Questionnaire or
as subjective sleepiness and snoring may be absent
13,14
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the Epworth sleepiness scale, are poor predictors of those with SA in the post-stroke population, . At present, screening for SA in this
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population requires overnight in-laboratory polysomnography or portable polygraphy 15.
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Stroke and OSA
The prevalence of OSA within the general population is 3-7% 16. This is in stark contrast to a prevalence of 30 to 70% in post-stroke subjects
17
. This high prevalence rate fuelled the
exploration of the relationship between SA and stroke (Table 1). The community based Sleep
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Heart Health Study (SHHS) showed an increased risk of self-reported unadjusted prevalent stroke for those with a respiratory disturbance index ≥ 11 events/hour. The association was not significant following adjustment for hypertension and body mass index (BMI)
18
. Subsequent
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results from the population based Wisconsin cohort study demonstrated a 3-fold increased adjusted risk of prevalent stroke in those with an AHI ≥20 events/hour
19
. This included
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adjustment for age, sex, BMI, alcohol, smoking, hypertension and diabetes. Further analysis of 4 and 8 year follow-up data from both the Wisconsin and SHHS epidemiology studies, respectively, demonstrated a 2 to 3-fold increased risk for incident stroke in those with moderate to severe OSA (see eS1)
19-23
. This relationship between OSA and stroke was confirmed in a
recent meta-analysis of 12 prospective cohort studies encompassing 25,760 subjects whereby the
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relative risk of incident fatal and non-fatal stroke for severe OSA compared to no SA was 2.15 (95% CI: 1.42 to 3.24) 24.
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Stroke Outcomes in OSA In the post-stroke period OSA causes poorer functional outcomes at 3 and 12 months, longer hospitalisations and rehabilitation
25
, increased stroke recurrence
26
and increased
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mortality 27,28. In stroke patients both with and without OSA followed for a 10 year period and following adjustment for multiple confounders the presence of moderate OSA (AHI ≥ 15
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events/hour) increased the risk of death by 75%.29. An increased mortality for those with moderate-severe OSA (AHI ≥ 20 events/hr) post-stroke was demonstrated in a 5 year follow-up observational study30.
The 7 year follow-up data of this cohort with ischemic stroke showed
increased recurrent stroke independent of other cardiovascular risk factors, age and sex.
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Importantly, the efficacy of CPAP in attenuating cardiovascular events in those stroke subjects with moderate-severe OSA was also shown 31. Efficacy of Treatment in OSA and Stroke
However, the evidence for outcomes related to treatment of OSA is
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recurrent stroke.
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Clearly the evidence supports post-stroke OSA as a risk factor of all-cause mortality and
inconclusive. The “gold standard” for the treatment of OSA is continuous positive airway pressure (CPAP).
CPAP has been shown to be feasible in both the acute
chronic phase of stroke
34,35
32
, subacute
33
and
. Unfortunately, adherence with CPAP in the stroke population has
been poor, varying from 15 to 80%27,33,36. Factors implicated in this often dismal adherence include an absence of symptoms altered
cognition, post-stroke depression, and physical
disabilities which prevent the application of the CPAP interface
37
. For most patients the 6
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motivation to adhere to CPAP therapy is driven by the desire to reduce the risk of future strokes 38
.
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Observational studies of 5-7 years duration suggest efficacy of CPAP therapy in reducing mortality and morbidity30,31. There have been 5 randomized controlled studies examining the effect of CPAP on stroke outcomes (Table 2). The majority of these randomized controlled
27,33,34,36,39,40
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studies were of short duration with small sample size and often with poor adherence to treatment . In the largest of these studies, Parra and colleagues randomized 140 acute stroke
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subjects with OSA (AHI ≥ 20). Of those randomized to CPAP 28% refused to use it. A perprotocol analysis of those randomized to CPAP compared to conventional treatment, showed a significant improvement in neurological recovery at one month and a delay in the occurrence of subsequent cardiovascular events, but no significant change in quality of life or mortality at 24 months
27
.
A subsequent 68 month follow-up of this group demonstrated a significantly
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increased cardiovascular survival (p = 0.015), and a higher cardiovascular event-free survival (p = 0.059) in the CPAP compared to the control group
40
. Results from the other four studies
suggest that in those stroke patients who comply with CPAP treatment early improvements in
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motor function and fewer depressive symptoms occur (see eS2). Other treatment modalities for
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OSA (e.g. dental appliances, weight reduction, avoidance of sleep in the supine position) have undergone limited or no assessment in the stroke population and therefore their efficacy is uncertain at this time41.
The true impact of OSA treatment in the stroke population is difficult to determine due to
the confounding factors of stroke heterogeneity, diverse comorbid medical conditions, relatively minute study populations and short study time.
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OSA as a precursor of Stroke In a small percentage of stroke cases the vascular injury to the respiratory and upper42,43
. Currently, the principal belief is that
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airway muscles brain centres may cause de novo SA
OSA is a precursor of stroke in the majority of individuals. The presence of OSA preceding stroke is supported by a body of evidence which includes 1) the known overlap between the risk
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factors for OSA (which include obesity, male sex, hypertension) 44 and those for stroke 10; 2) the high prevalence of OSA in patients with TIA, which is a known precursor of stroke
45
; 3)the
those without OSA
46
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presence of pre-existing anatomical factors in those with acute stroke and OSA compared to ; 4) the high frequency of OSA in those with recurrent strokes and the
persistence of OSA following neurological recovery
17
; 5) evidence from epidemiology and
longitudinal studies of the general population discussed above, demonstrating the increased risk
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associated with pre-existent OSA.
Potential Mediators between OSA and Stroke
The mechanisms by which OSA causes stroke have not been fully expounded. Certainly,
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traditional risk factors for stroke including hypertension, hyperlipidemia, diabetes mellitus, smoking, atrial fibrillation and obesity are prevalent in OSA patients but they do not fully 19
. OSA elicits both acute and chronic pathogenic effects which have been
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explain the risk
proposed as the intermediary processes predisposing an individual to a stroke. Acutely, OSA causes intermittent and repetitive hypoxia during sleep, recurrent arousals and the generation of negative intrathoracic pressure
47
.
The sequelae of this cascade may include sympathetic
activation and catecholamine release leading to post-apneic surges in blood pressure and heart rate, increased sleep fragmentation and intermittent reductions in cerebral blood flow 47,48. As a consequence of the acute effects a downstream cascade of deleterious effects including a) 8
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arrhythmias, b) reactive oxidative stress, endothelial dysfunction and atherosclerosis, c) altered cerebral blood flow, d) hypertension, e) autonomic dysfunction and f) hypercoagulability may predispose to stroke. Other factors such as the presence of a patent foramen ovale may heighten
A)
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stroke risk in those with OSA (Figure 1). We will review in greater detail these factors.
Arrhythmias: Atrial fibrillation is a major risk factor for stroke. Approximately 1 in 6
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strokes and a significant percentage of cryptogenic strokes are attributed to atrial fibrillation 49. In OSA, the generation of negative intrathoracic pressure will cause stretch and remodeling of
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the atria and pulmonary vein ostia predisposing to conduction abnormalities. OSA is a strong predictor for prevalent 50 and incident atrial fibrillation 51, and the prevalence rises in those with moderate to severe compared to mild OSA50,52.
In a case-control study of patients with both
OSA and first time ischemic stroke there was a 5.34 fold increased risk of atrial fibrillation following adjustment for confounders53.
While not conclusive, the current evidence is
B)
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suggestive of an intermediary role of atrial fibrillation between OSA and stroke.
Reactive Oxidative Stress, Endothelial Dysfunction and Atherosclerosis: Oxidative stress
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may be the unifying mechanism between OSA and endothelial dysfunction/atherosclerosis. As
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a result of periodic intermittent hypoxia an oxygenation/reoxygenation injury is generated, which in turn provokes the production of reactive oxygen species (ROS), a precursor of oxidative stress. Oxidative stress by altering sundry redox-sensitive signaling pathways in endothelial cells key to gene and protein expression 54, sympathetic activation and promotion of inflammation induces endothelial dysfunction. ROS causes lipid peroxidation
56
55
a potential instigator or
aggravator of insulin resistance and may alter the homeostatic balance in favor of the development of atherosclerosis. The chronic intermittent hypoxia may also cause activation of 9
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the renin angiotensin aldosterone system (RAAS) 57, leading to increased ROS production 58 and contributing to elevations in blood pressure
59
, a risk factor for stroke. Furthermore, the
intermittent hypoxia of OSA modulates the activity of the various isoforms of nitric oxide
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synthases (NOS) that synthesize NO, thus reducing circulating NO and increasing oxidative stress. NO alters vascular reactivity, inhibits platelet aggregation and attenuates adhesion of both platelets and white blood cells to vessel walls and acts as a neurotransmitter. Jelic et al
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demonstrated reduced endothelial NOS (eNOS), but increased inducible NOS (iNOS) and reduced vascular reactivity in OSA subjects compared to controls, with improvements following
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CPAP treatment independent of obesity 60,61. Contrary to this, Patt et al showed increased eNOS and peroxynitrate 62. While contradictory, these findings may be explained by the Kaczmarek study that demonstrated low or high eNOS in OSA compared to controls, dependent on the severity of associated hypoxia 63. These studies highlight the intricate relationship between NO
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homeostasis/oxidative stress and OSA and endothelial function.
Oxidative stress may predispose the brain to stroke via a number of possible mechanisms. Firstly, the brain and cerebral vasculature are highly susceptible to oxidative damage due to the
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paucity of its antioxidant system and large oxygen dependency injury by ROS may predispose to stroke
66,67
. Secondly, direct neuronal
. Thirdly, the oxidative stress of OSA may cause
elevated levels of matrix metalloproteinase (MMP)-9
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64,65
68
, known to be associated with plaque
rupture69 and disruption of the blood brain barrier in those with stroke 70. The blood brain barrier is critical for the maintenance of cerebral homeostasis and the degree of disruption is correlated with functional outcomes from stroke
71
.
Fourthly, oxidative stress induces inflammatory
cytokines such as IL-6, a pro-atherogenic marker in OSA and stroke compared to those without
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OSA
72
.
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Lastly, the increased ROS promotes endothelial dysfunction a precursor of
atherosclerosis. Atherosclerosis is a marker of incident stroke 73. Drager and colleagues have shown that
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compared to controls otherwise healthy OSA patients had early signs of atherosclerosis
74
.
Moreover, the degree of atherosclerosis was similar when comparisons were made between OSA and hypertensive subjects, but augmented in those OSA subjects with concomitant hypertension (Figure 2). Four months of CPAP treatment for OSA in a randomized controlled trial
attenuated the subclinical atherosclerosis
76
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75
. The above findings have been confirmed in other
77,78
.
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cross-sectional studies suggesting that OSA may be an independent predictor of atherosclerosis Severe OSA in those following an ischemic stroke is an independent risk factor of
atherosclerotic artery disease 79 and is robustly associated with both increased arterial stiffness 80 and with extracranial artery disease 81.
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In summary, impaired endothelial vascular function may result in perturbation of the cerebral circulation (including cerebral blood flow and vascular reactivity), increasing the risk of stroke in OSA subjects. Conversely, in some instances hypoxic preconditioning as a result of
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OSA/intermittent hypoxia, may protect the cerebrovascular system from injury. Preconditioning
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is probably related to cell adaptation to the intermittent hypoxia 55. This is most likely to occur in those with mild to moderate OSA and may explain discrepant results and outcomes in some following cardio/cerebrovascular events. Recent animal work, demonstrating a dichotomous response to chronic intermittent hypoxia further supports this concept82.
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OSA and Control of brain blood flow: In order to meet its metabolic demands the brain is
highly dependent on an adequate cerebral blood flow Altered cerebrovascular reactivity (the cerebral blood flow response to changes in PaCO2) occurs in patients with stroke 84
and also
. In view of the recurrent nocturnal
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predicts stroke risk in patients with carotid artery disease
83
hypoxia and intermittent hypercapnia in OSA, protection of the brain is dependent on the ability to modulate the cerebrovascular response. An inadequate cerebrovascular response may result in
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brain hypoperfusion and an increased risk of cerebral ischemia and stroke (see eS3). In most studies, increased cerebral blood flow velocity has been noted during the apneas, often with a
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reduction below baseline on termination of the apnea 48 (Figure 3). In OSA compared to normal subjects there is a reduction in cerebral blood flow velocity during both wakefulness and sleep85,86. Therefore, in OSA the intermittent hypoxia, possible increases in perfusion pressure or shear stress, or inadequate cerebrovascular responses are the mediators of potential ischemic
D)
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brain injury and stroke.
Hypertension: Through the remodelling of systemic and cerebral blood vessels and the 87
, hypertension increases the risk of stroke 3 to 4 fold
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ensuing atherosclerosis
88
. In particular,
exaggerated nocturnal dipping, non-dipping or reverse dipping are associated with increased 89
. Treatment that reduces blood pressure significantly alleviates stroke risk
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incident stroke
90
.
Due to the occurrence of OSA during sleep, typically it is associated with elevated nocturnal, non-dipping and greater variability in blood pressure. In OSA, hypertension may result from sympathetic and RAAS activation
91
, altered chemoreceptor sensitivity
92
and endothelial
dysfunction. The greater burden of evidence espouses OSA as a cause of hypertension. This includes the association between prevalent hypertension and OSA
95,96
; the dose-dependent
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linear relationship between elevated arterial blood pressure and OSA 93; blood pressure reduction induced by CPAP treated OSA 94,95 and the reduced risk of hypertension in OSA subjects treated with CPAP
96
. Studies on the relationship between incident hypertension and OSA are 99
. Overall,
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conflicting97,98 and the efficacy of treatment in those with mild OSA is not proven
the evidence favours OSA as contributing to hypertension and subsequent risk of stroke. The presence of OSA in those with acute stroke is associated with greater blood pressure variability
E)
Autonomic Dysfunction:
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and with higher 24 hour blood pressure 101.
Peripheral and central chemoreceptor stimulation in OSA
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100
results in sympathetic nervous system activation, reduced baroreflex sensitivity and heart rate variability and augmented blood pressure variability
102
. There is extensive innervation of the
cerebral vasculature and the elevated SNA may perturb cerebral autoregulation and blood flow 103
.
In fact elevated SNA in post-stroke subjects is an
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predisposing to cerebral ischemia
independent predictor of poor outcome at 12 months. 104.
Hypercoagulability: Hypercoagulability may predispose to acute thrombosis and
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F)
subsequent cerebrovascular events 106,107
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mechanisms in OSA
105
.
Altered hypercoagulability occurs by a variety of
and may peak during the night
108
. Furthermore, treatment of OSA
with CPAP is successful in reducing coagulation markers 109.
G) PFO
Patent foramen ovale (PFO): Cryptogenic strokes occur more frequently in those with
110
. The reported prevalence of PFO in OSA is variable (26.9 to 68.8%), with 2 studies
suggesting increased prevalence compared to the general population
111,112
. Most PFOs are
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benign and not associated with shunting. In OSA the negative intrathoracic pressure which occurs during apnea episodes, leads to increased venous return to the right heart which favours right to left shunting 112
. This is particularly evident in those with obstructive apneas of long
and may be associated with more severe nocturnal oxygen desaturation. The
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duration
113
intermittent hypoxia associated with the obstructive events may also cause pulmonary vasoconstriction, which acutely elevates the systolic transmural pulmonary artery pressure
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contributing to right to left shunting 114. Theoretically, the combination of a PFO and OSA may predispose to increased stroke risk, by potentially causing increased right to left shunting and
PFO-associated ischemic strokes
115
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paradoxical embolism. It is recognised that wake-up strokes are independently associated with and there is an increased reported frequency of wake-up
strokes in severe OSA 115 giving credence to the role of PFO in those with OSA.
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Stroke and CSA
CSA has been observed in patients with acute stroke where the reported prevalence is approximately 6-24% 100,116 . The stroke location associated with hypercapnic CSA is the nucleus
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tractus solitarius region of the medulla responsible for diaphragmatic function 117,118. Most recent studies have found no relationship between the site, size or type of stroke and the presence of 25,119
. The CSA usually dissipates over time in the majority of cases. The presence of
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CSA
underlying occult cardiac dysfunction may be present in a subset of patients116. The clinical significance of CSA in patients with stroke is unclear.
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Conclusion The significant burden of stroke on the individual and society is undisputed. SA is frequent both
rationalization of the connection between stroke and SA.
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within the general and post-stroke population. Current research provides a persuasive Ongoing research is imperative: 1)
for the stratification and phenotyping of individuals at greatest risk from SA and those in whom
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treatment will be most critical; 2) to determine the correct timing and modality of treatment; and 3) to understand the interplay between vascular remodeling, neuroplasticity and SA, particularly
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OSA. A more sophisticated, personalized approach is required. Whilst conceding that there are substantial knowledge gaps and further research is required, strategies for comprehensive acute, chronic and preventive care of stroke, should be complemented with evaluation and screening for
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OSA and consideration given to treatment.
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References
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1 Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 19902010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383:245-254 2 Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22:391-397 3 Ip HL, Liebeskind DS. The future of ischemic stroke: flow from prehospital neuroprotection to definitive reperfusion. Interv Neurol 2014; 2:105-117 4 Majid A. Neuroprotection in stroke: past, present, and future. ISRN Neurol 2014; 2014:515716 5 Aarnio K, Haapaniemi E, Melkas S, et al. Long-term mortality after first-ever and recurrent stroke in young adults. Stroke 2014; 45:2670-2676 6 Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79:733-743 7 Marler JR, Price TR, Clark GL, et al. Morning increase in onset of ischemic stroke. Stroke 1989; 20:473476 8 Turin TC, Kita Y, Rumana N, et al. Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990-2003. Eur J Neurol 2009; 16:843-851 9 Martinez Garcia MA, Galiano Blancart R, Cabero Salt L, et al. [Prevalence of sleep-disordered breathing in patients with acute ischemic stroke: influence of onset time of stroke]. Arch Bronconeumol 2004; 40:196-202 10 Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:517-584 11 Allen CL, Bayraktutan U. Risk factors for ischaemic stroke. Int J Stroke 2008; 3:105-116 12 Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2160-2236 13 Arzt M, Young T, Peppard PE, et al. Dissociation of obstructive sleep apnea from hypersomnolence and obesity in patients with stroke. Stroke 2010; 41:e129-134 14 Srijithesh PR, Shukla G, Srivastav A, et al. Validity of the Berlin Questionnaire in identifying obstructive sleep apnea syndrome when administered to the informants of stroke patients. J Clin Neurosci 2011; 18:340-343 15 Kuna ST, Gurubhagavatula I, Maislin G, et al. Noninferiority of functional outcome in ambulatory management of obstructive sleep apnea. Am J Respir Crit Care Med 2011; 183:1238-1244 16 Duran J, Esnaola S, Rubio R, et al. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med 2001; 163:685689 17 Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med 2010; 6:131-137 18 Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: crosssectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19-25 19 Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005; 172:1447-1451 20 Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010; 182:269-277
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21 Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nunez N, et al. Role of sleep apnea and continuous positive airway pressure therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014; 189:1544-1550 22 Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke 2006; 37:2317-2321 23 Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353:2034-2041 24 Wang X, Ouyang Y, Wang Z, et al. Obstructive sleep apnea and risk of cardiovascular disease and allcause mortality: a meta-analysis of prospective cohort studies. Int J Cardiol 2013; 169:207-214 25 Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep 2003; 26:293-297 26 Rola R, Jarosz H, Wierzbicka A, et al. Sleep disorderd breathing and recurrence of cerebrovascular events, case-fatality, and functional outcome in patients with ischemic stroke or transient ischemic attack. J Physiol Pharmacol 2008; 59 Suppl 6:615-621 27 Parra O, Sanchez-Armengol A, Bonnin M, et al. Early treatment of obstructive apnoea and stroke outcome: a randomised controlled trial. Eur Respir J 2011; 37:1128-1136 28 Yan-fang S, Yu-ping W. Sleep-disordered breathing: impact on functional outcome of ischemic stroke patients. Sleep Med 2009; 10:717-719 29 Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke: a 10-year follow-up. Arch Intern Med 2008; 168:297-301 30 Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5year follow-up study. Am J Respir Crit Care Med 2009; 180:36-41 31 Martinez-Garcia MA, Campos-Rodriguez F, Soler-Cataluna JJ, et al. Increased incidence of non-fatal cardiovascular events in stroke patients with sleep apnoea. Effect of CPAP treatment. Eur Respir J 32 Scala R, Turkington PM, Wanklyn P, et al. Acceptance, effectiveness and safety of continuous positive airway pressure in acute stroke: a pilot study. Respir Med 2009; 103:59-66 33 Ryan CM, Bayley M, Green R, et al. Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke 2011; 42:1062-1067 34 Sandberg O, Franklin KA, Bucht G, et al. Nasal continuous positive airway pressure in stroke patients with sleep apnoea: a randomized treatment study. Eur Respir J 2001; 18:630-634 35 Wessendorf TE, Wang YM, Thilmann AF, et al. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J 2001; 18:623-629 36 Hsu CY, Vennelle M, Li HY, et al. Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure. J Neurol Neurosurg Psychiatry 2006; 77:1143-1149 37 Palombini L, Guilleminault C. Stroke and treatment with nasal CPAP. Eur J Neurol 2006; 13:198-200 38 Matthias MS, Chumbler NR, Bravata DM, et al. Challenges and motivating factors related to positive airway pressure therapy for post-TIA and stroke patients. Behav Sleep Med 2014; 12:143-157 39 Bravata DM, Concato J, Fried T, et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep 2011; 34:1271-1277 40 Parra O, Sanchez-Armengol A, Capote F, et al. Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial. J Sleep Res 2014 41 Svatikova A, Chervin RD, Wing JJ, et al. Positional therapy in ischemic stroke patients with obstructive sleep apnea. Sleep Med 2011; 12:262-266 42 Dyken ME, Im KB. Obstructive sleep apnea and stroke. Chest 2009; 136:1668-1677
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43 Brown DL, McDermott M, Mowla A, et al. Brainstem infarction and sleep-disordered breathing in the BASIC sleep apnea study. Sleep Med 2014; 15:887-891 44 Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004; 291:2013-2016 45 Chan W, Coutts SB, Hanly P. Sleep apnea in patients with transient ischemic attack and minor stroke: opportunity for risk reduction of recurrent stroke? Stroke 2010; 41:2973-2975 46 Brown DL, Bapuraj JR, Mukherji SK, et al. MRI of the pharynx in ischemic stroke patients with and without obstructive sleep apnea. Sleep Med 2010; 11:540-544 47 Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009; 373:82-93 48 Balfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med 1994; 150:1587-1591 49 Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014; 370:2467-2477 50 Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173:910-916 51 Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007; 49:565-571 52 Tanigawa T, Yamagishi K, Sakurai S, et al. Arterial oxygen desaturation during sleep and atrial fibrillation. Heart 2006; 92:1854-1855 53 Mansukhani MP, Calvin AD, Kolla BP, et al. The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. Sleep Med 2013; 14:243-246 54 Dworakowski R, Alom-Ruiz SP, Shah AM. NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype. Pharmacol Rep 2008; 60:21-28 55 Lavie L. Oxidative stress in obstructive sleep apnea and intermittent hypoxia - Revisited - The bad ugly and good: Implications to the heart and brain. Sleep Med Rev 2014 56 Barcelo A, Miralles C, Barbe F, et al. Abnormal lipid peroxidation in patients with sleep apnoea. Eur Respir J 2000; 16:644-647 57 Foster GE, Hanly PJ, Ahmed SB, et al. Intermittent hypoxia increases arterial blood pressure in humans through a Renin-Angiotensin system-dependent mechanism. Hypertension 2010; 56:369-377 58 Touyz RM. Oxidative stress and vascular damage in hypertension. Curr Hypertens Rep 2000; 2:98-105 59 Nicholl DD, Hanly PJ, Poulin MJ, et al. Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med 2014; 190:572-580 60 Jelic S, Lederer DJ, Adams T, et al. Vascular inflammation in obesity and sleep apnea. Circulation 2010; 121:1014-1021 61 Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 2008; 117:2270-2278 62 Patt BT, Jarjoura D, Haddad DN, et al. Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am J Respir Crit Care Med 2010; 182:1540-1545 63 Kaczmarek E, Bakker JP, Clarke DN, et al. Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. PLoS One 2013; 8:e70559 64 Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38:357-366 65 Butterfield D, Castegna A, Pocernich C, et al. Nutritional approaches to combat oxidative stress in Alzheimer's disease. J Nutr Biochem 2002; 13:444 18
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66 Wang Y, Zhang SX, Gozal D. Reactive oxygen species and the brain in sleep apnea. Respir Physiol Neurobiol 2010; 174:307-316 67 Nair D, Dayyat EA, Zhang SX, et al. Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS One 2011; 6:e19847 68 Chuang LP, Chen NH, Lin SW, et al. Increased matrix metalloproteinases-9 after sleep in plasma and in monocytes of obstructive sleep apnea patients. Life Sci 2013; 93:220-225 69 Heo SH, Cho CH, Kim HO, et al. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of matrix metalloproteinases 2 and 9. J Clin Neurol 2011; 7:69-76 70 Mun-Bryce S, Rosenberg GA. Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 1998; 18:1163-1172 71 Bektas H, Wu TC, Kasam M, et al. Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction. Stroke 2010; 41:2539-2544 72 Medeiros CA, de Bruin VM, Andrade GM, et al. Obstructive sleep apnea and biomarkers of inflammation in ischemic stroke. Acta Neurol Scand 2011 73 Polak JF, Pencina MJ, O'Leary DH, et al. Common Carotid Artery Intima-Media Thickness Progression as a Predictor of Stroke in Multi-Ethnic Study of Atherosclerosis. Stroke 2011 74 Drager LF, Bortolotto LA, Lorenzi MC, et al. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172:613-618 75 Drager LF, Bortolotto LA, Maki-Nunes C, et al. The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome. Atherosclerosis 2010; 208:490495 76 Drager LF, Bortolotto LA, Krieger EM, et al. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension 2009; 53:64-69 77 Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest 2011; 140:534-542 78 Ali SS, Oni ET, Warraich HJ, et al. Systematic review on noninvasive assessment of subclinical cardiovascular disease in obstructive sleep apnea: new kid on the block! Sleep Med Rev 2014; 18:379-391 79 Dziewas R, Ritter M, Usta N, et al. Atherosclerosis and obstructive sleep apnea in patients with ischemic stroke. Cerebrovasc Dis 2007; 24:122-126 80 Cereda CW, Tamisier R, Manconi M, et al. Endothelial dysfunction and arterial stiffness in ischemic stroke: the role of sleep-disordered breathing. Stroke 2013; 44:1175-1178 81 Nachtmann A, Stang A, Wang YM, et al. Association of obstructive sleep apnea and stenotic artery disease in ischemic stroke patients. Atherosclerosis 2003; 169:301-307 82 Jackman KA, Zhou P, Faraco G, et al. Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury. Stroke 2014; 45:1460-1467 83 Stevenson SF, Doubal FN, Shuler K, et al. A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke 2010; 41:e434-442 84 Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:457-467 85 Nasr N, Traon AP, Czosnyka M, et al. Cerebral autoregulation in patients with obstructive sleep apnea syndrome during wakefulness. Eur J Neurol 2009; 16:386-391 86 Urbano F, Roux F, Schindler J, et al. Impaired cerebral autoregulation in obstructive sleep apnea. J Appl Physiol (1985) 2008; 105:1852-1857 87 Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol 2002; 12:358-370 88 Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPE. Lancet Neurol 2002; 1:149156 19
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89 Kario K, Pickering TG, Matsuo T, et al. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001; 38:852-857 90 Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Bmj 2009; 338:b1665 91 Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897-1904 92 Cooper VL, Pearson SB, Bowker CM, et al. Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia - a mechanism for promoting hypertension in obstructive sleep apnoea. J Physiol 2005; 568:677-687 93 Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157:1746-1752 94 Alajmi M, Mulgrew AT, Fox J, et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007; 185:67-72 95 Bazzano LA, Khan Z, Reynolds K, et al. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007; 50:417-423 96 Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 2012; 307:2169-2176 97 O'Connor GT, Caffo B, Newman AB, et al. Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009; 179:1159-1164 98 Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384 99 Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012; 307:2161-2168 100 Turkington PM, Bamford J, Wanklyn P, et al. Effect of upper airway obstruction on blood pressure variability after stroke. Clin Sci (Lond) 2004; 107:75-79 101 Selic C, Siccoli MM, Hermann DM, et al. Blood pressure evolution after acute ischemic stroke in patients with and without sleep apnea. Stroke 2005; 36:2614-2618 102 Horner RL, Brooks D, Kozar LF, et al. Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol 1995; 79:151-162 103 Kamba M, Suto Y, Ohta Y, et al. Cerebral metabolism in sleep apnea. Evaluation by magnetic resonance spectroscopy. Am J Respir Crit Care Med 1997; 156:296-298 104 Sander D, Winbeck K, Klingelhofer J, et al. Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke. Neurology 2001; 57:833-838 105 Wiklund PG, Nilsson L, Ardnor SN, et al. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts. Stroke 2005; 36:1661-1665 106 Guardiola JJ, Matheson PJ, Clavijo LC, et al. Hypercoagulability in patients with obstructive sleep apnea. Sleep Med 2001; 2:517-523 107 Nobili L, Schiavi G, Bozano E, et al. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000; 22:21-27 108 Wessendorf TE, Thilmann AF, Wang YM, et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000; 162:2039-2042 109 Phillips CL, McEwen BJ, Morel-Kopp MC, et al. Effects of continuous positive airway pressure on coagulability in obstructive sleep apnoea: a randomised, placebo-controlled crossover study. Thorax 2012; 67:639-644 20
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110 Gu X, He Y, Li Z, et al. Comparison of Frequencies of Patent Foramen Ovale and Thoracic Aortic Atherosclerosis in Patients With Cryptogenic Ischemic Stroke Undergoing Transesophageal Echocardiography. Am J Cardiol 2011 111 Lau EM, Jaijee SK, Melehan KL, et al. Prevalence of patent foramen ovale and its impact on oxygen desaturation in obstructive sleep apnea. Int J Cardiol 2011 112 Beelke M, Angeli S, Del Sette M, et al. Obstructive sleep apnea can be provocative for right-to-left shunting through a patent foramen ovale. Sleep 2002; 25:856-862 113 Guchlerner M, Kardos P, Liss-Koch E, et al. PFO and right-to-left shunting in patients with obstructive sleep apnea. J Clin Sleep Med 2012; 8:375-380 114 Schafer H, Hasper E, Ewig S, et al. Pulmonary haemodynamics in obstructive sleep apnoea: time course and associated factors. Eur Respir J 1998; 12:679-684 115 Hsieh SW, Lai CL, Liu CK, et al. Obstructive sleep apnea linked to wake-up strokes. J Neurol 2012; 259:1433-1439 116 Nopmaneejumruslers C, Kaneko Y, Hajek V, et al. Cheyne-Stokes respiration in stroke: relationship to hypocapnia and occult cardiac dysfunction. Am J Respir Crit Care Med 2005; 171:1048-1052 117 Devereaux MW, Keane JR, Davis RL. Automatic respiratory failure associated with infarction of the medulla. Report of two cases with pathologic study of one. Arch Neurol 1973; 29:46-52 118 Levin BE, Margolis G. Acute failure of automatic respirations secondary to a unilateral brainstem infarct. Ann Neurol 1977; 1:583-586 119 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
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Legends Figure 1:
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Pathophysiological effects of OSA on the cerebrovascular system. The black lines indicate deleterious effects. The brown lines indicate the possible protective mechanism of ischemic preconditioning.
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Abbreviations: -ITP, negative intrathoracic pressure; IH, intermittent hypoxia; OSA, obstructive sleep apnea; ↑ SNA, increased sympathetic nervous activity; ↑ BP, hypertension; CBF, cerebral
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blood flow; IPC, ischemic preconditioning; A. Fib, atrial fibrillation; PFO, patent foramen ovale; HTN, hypertension. Figure 2:
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Carotid Intimal media thickness in Controls, Obstructive sleep apnea (OSA), Hypertension (HTN), and OSA and HTN subjects. Reprinted with permission from Drager et al,
Figure 3:
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Hypertension. 2009; 53: 64-69
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Typical changes of mean arterial pressure and cerebral blood flow velocity during and after a 23s apnea. The dashed line represents baseline values. Reprinted with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society. Balfour et al, 1994 Am J of Respir and Crit Care Med.150: 1587-1591 Official Journal of the American Thoracic Society. Abbreviations: MAP, mean arterial pressure; CBFV, cerebral blood flow velocity; PtcCO2, transcutaneous carbon dioxide; SpO2, pulse oxygen saturation. 22
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Table 1: Abbreviations: AHI, Apnea-hypopnea index; SA, sleep apnea; CNS, Canadian neurological
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scale; CVS, cardiovascular; BI, Barthel index; SF-36, short –form 36; QoL, quality of life; NIHSS, NIH Stroke Scale; NEADL, Nottingham extended activities of daily living; ESS, Epworth sleepiness scale; MADRS, Montgomery-Asberg Depression Rating Scale; ADL,
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activities of daily living; MMSE, mini-mental state examination; FIM, functional independence measure, SSS, Stanford sleepiness scale, 6MWD, six minute walk distance; SART, sustained
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attention to response test; BBS, Berg balance scale, CMM, Chedoke McMaster scale; BDI, Beck Depression Inventory.
Table 2:
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Abbreviations: AHI, Apnea-hypopnea index; A, age; AF, atrial fibrillation; Al, alcohol; BMI,
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status.
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body mass index; D, diabetes; HTN, hypertension; Meds, medications; S, sex; SS, smoking
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OSA
Altered CBF
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Hypercoagulability
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PFO
Paradoxical embolism
Arousals
Oxidative Stress
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- ITP
IPC
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Endothelial Dysfunction
Atherosclerosis
SSTROKE
HTN
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Intima Media Thickness (μm)
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Controls OSA
HTN
OSA & HTN
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Figure 3
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Table 1: Summary of Clinical studies evaluating OSA and stroke risk Design
Patients (n)
Adjusted confounding variables
Primary Outcome
Result
Shahar 2001 18
Cross-sectional
6424
A, S, SS, D, race
Prevalent stroke comparing lowest quartile with the highest quartile
OR: 1.58;95%CI:1.022.46, p = 0.03
Arzt 2005 19
Cross-sectional
1475
A, S, SS, BMI, Al
Observational cohort
1189
A, S, BMI
Prevalent stroke comparing AHI >20 to AHI 20 to AHI19 in 8.7 years Incident stroke in women with untreated AHI >19 in 8.7 years
HR: 2.86;95%CI:1.1017.39, p = 0.016 HR: 1.21;95%CI:0.6562.54, p = 0.693
Yaggi 2005 21
Observational cohort
1022
A, S,SS,BMI, D, HTN, AF,Al,L,race
Incident stroke or death in those with OSA
HR:2.24;95%CI:1.3033.86,p=-0.004
Munoz 2006 22
Observational cohort
394
Incident stroke in patients 70100 years with AHI ≥30 in 6 years
HR:2.52;95%CI:1.044046.1,p=-0.04
CamposRodriguez 2014 23
Observational cohort
268
Incident stroke in women with untreated AHI ≥10 over 6.8 years Incident stroke in women with treated AHI ≥10 over 6.8 years
HR: 6.44; 95%CI: 1.46-28.3
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S
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Redline 2010 20
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Study
A, BMI, D, HTN, AF
HR: 0.76; 95%CI:0.02 1.57
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Table 2: Summary of Randomized Controlled Trials evaluating CPAP treatment in stroke patients with OSA Timing Post Stroke
Numbers Randomized
Assessment Period
Compliance
Primary Outcome
Secondary Outcome
Result
Parra 2011 27
Acute
140
1,3,12,24 months
5.3 hr/night Per-protocol
CNS , Rankin,BI, SF-36 QoL at 1 month
Mortality and new cardiovascular events at 24 months
⬆ Early neurological improvement
CVS morbidity & mortality at 68 months
⬆ CVS survival at 68months (per protocol)
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Study
2014 40
Subacute
5.1hr/night
SA prevalence CPAP compliance
NIHSS
High prevalence SA ⬇Stroke severity
30
2 & 6 months
1.4 hr/night
NEADL
NIHSS, BI, ESS
Negative
7 & 28 days
4.1 hr/night
MADRS,
Barthel-ADL, MMSE
⬇Depressive symptoms
1 month
5.0 hr/night
CNS, 6MWD, SART, Digit/Spatial span backwards
FIM, ESS, SSS, BBS,Purdue Pegboard test, CMM, BDI, Grip strength
Early neurological improvement ⬇sleepiness Improved motor function
(AHI ≥ 30/hr) Sandberg 2001 34
Subacute
63
(AHI ≥ 15/hr) Ryan 2011 33
Subacute (AHI ≥ 15/hr)
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(Auto-CPAP) Hsu 2006 36
5.3hr/night Per-protocol
55
48
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Bravata 2011 39
68 months
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eS1: A 4 year analysis of the Wisconsin cohort, excluding those with prior stroke, controlling for age and sex, subjects with a baseline AHI ≥ 20 had a 4-fold increased risk for an incident stroke. However, following adjustment for BMI, although there was a 3-fold increased risk of stroke, it failed to maintain statistical significance. The study’s statistical power was limited by the small number of strokes. In the SHHS of untreated OSA and incident stroke in 5422 subjects without prior stroke over a period of 8 years1, there was an almost 3-fold increased risk of stroke in men in whom the obstructive AHI was > 25. Furthermore, for every one unit increase in the obstructive AHI in men there was a 6% increase in stroke risk. In women, the increased stroke risk was not observed until the obstructive AHI was > 25. In both men and women there was an association with increasing age, systolic blood pressure, use of antihypertensive medications and atrial fibrillation. However, a Spanish prospective observational clinic study in women, referred for assessment of OSA, but without cardiac disease or previous stroke, demonstrated that untreated OSA had a strong association with incident stroke (HR, 6.44; 95% CI 1.46 – 28.34) following adjustment for age, BMI, hypertension, atrial fibrillation, and type 2 diabetes mellitus 2 . Follow-up period was 6.8 years, and compared to the SHHS, these women were of younger age, but had higher BMI, and had a higher percentage of comorbid diseases.
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In a North American observational clinic cohort study 1022 subjects both with and without OSA were followed for a median time of 3.3 (no sleep apnea) or 3.4 (with sleep apnea) years 3. In the OSA group the incidence of stroke or death was 3.48 per 100 person-years and in the control group 1.60 per 100 person-years. Following adjustment for sex, race, smoking status, alcohol, BMI, presence of diabetes mellitus, hyperlipidaemia, atrial fibrillation and hypertension, OSA remained a significant independent predictor of stroke or death. There was also a significant trend with increasing OSA severity. The Vitoria Sleep Project, examined the risk of ischemic stroke in an elderly Spanish population with untreated OSA 4. There were 20 ischemic strokes in 394 subjects, verified during the mean follow-up period of 4.5 years, for an incidence of 11.28 per 1000 person-years. This also demonstrated a significant association between severe OSA and ischemic stroke (hazard ratio 2.52).
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eS2: Bravata et al, randomized stroke patients to auto-titrating (auto)-CPAP or conventional therapy, and showed at 30 days a significant improvement in stroke severity in the treatment arm. The greatest improvements were observed in those patients most compliant with CPAP (≥ 4 hours for 75% of the time) 5. Hsu et al, performed a randomized trial in 30 patients with OSA (AHI ≥ 30) with subacute stroke (14 – 19 days post stroke) 6. At 3 months follow-up no significant difference in functional outcomes or depressive symptoms was demonstrated between conventional therapy and CPAP arms. However, the overall average compliance with CPAP was very low at 1.4 hours per night. Sandberg et al, randomized 59 patients with subacute stroke to CPAP or conventional therapy. Those randomized to CPAP had fewer depressive symptoms, but no change in outcome compared to the conventional group 7. Ryan and colleagues, in a randomized study of 44 patients with subacute stroke undergoing rehabilitation showed significant improvements in motor function and the affective component of the depression score, but not in neurocognitive function following one month of CPAP 8.
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eS3: Impaired cerebrovascular reactivity may also exaggerate the accumulation and washout of
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References:
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carbon dioxide from central chemoreceptors causing breathing instability during sleep. Limitations in, and different modalities of assessment techniques of the cerebral vasculature, timing of assessment (day versus night), differing patient profiles, and severity of OSA, failure to adequately integrate blood pressure changes, have led to sometimes discrepant results regarding both cerebral blood flow and cerebrovascular reactivity in this group 9. In most studies, increased cerebral blood flow velocity has been noted during the apneas, often with a reduction below baseline on termination of the apnea 10 (Figure 3). In OSA compared to normal subjects there is a reduction in cerebral blood flow velocity during both wakefulness and sleep 11,12. A large population based study of OSA subjects has also demonstrated impaired daytime hypercapnic cerebrovascular reactivity in a continuum from mild to severe OSA 13. Continuous positive airway pressure may alter the hypercapnic cerebrovascular reactivity in OSA subjects, suggesting a potential for improvement in some individuals 14. Newer diagnostic imaging techniques in OSA have shown reductions in regional cerebral blood flow to major sensory and motor fiber systems 15, reduced cerebrovascular reactivity to autonomic challenges 16, leukoaraiosis compared to controls 17 in addition to regional grey matter loss in OSA subjects 18,19 . Leukoaraiosis is a strong predictor of both stroke risk and outcome from stroke 20 and, interestingly, recent studies have suggested that it may result from white matter infarction in some instances 21. Therefore, current evidence suggests that in OSA, the intermittent hypoxia, possible increases in perfusion pressure or shear stress, or inadequate cerebrovascular responses are the mediators of potential ischemic brain injury and stroke.
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1 Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010; 182:269-277 2 Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nunez N, et al. Role of sleep apnea and continuous positive airway pressure therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014; 189:1544-1550 3 Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353:2034-2041 4 Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke 2006; 37:2317-2321 5 Bravata DM, Concato J, Fried T, et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep 2011; 34:1271-1277 6 Hsu CY, Vennelle M, Li HY, et al. Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure. J Neurol Neurosurg Psychiatry 2006; 77:1143-1149
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7 Sandberg O, Franklin KA, Bucht G, et al. Nasal continuous positive airway pressure in stroke patients with sleep apnoea: a randomized treatment study. Eur Respir J 2001; 18:630-634 8 Ryan CM, Bayley M, Green R, et al. Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke 2011; 42:1062-1067 9 Willie CK, Tzeng YC, Fisher JA, et al. Integrative regulation of human brain blood flow. J Physiol 2014; 592:841-859 10 Balfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med 1994; 150:1587-1591 11 Nasr N, Traon AP, Czosnyka M, et al. Cerebral autoregulation in patients with obstructive sleep apnea syndrome during wakefulness. Eur J Neurol 2009; 16:386-391 12 Urbano F, Roux F, Schindler J, et al. Impaired cerebral autoregulation in obstructive sleep apnea. J Appl Physiol (1985) 2008; 105:1852-1857 13 Morgan BJ, Reichmuth KJ, Peppard PE, et al. Effects of Sleep Disordered Breathing on Cerebrovascular Regulation: A Population-Based Study. Am J Respir Crit Care Med 2010; 182:1445 - 1452 14 Diomedi M, Placidi F, Cupini LM, et al. Cerebral hemodynamic changes in sleep apnea syndrome and effect of continuous positive airway pressure treatment. Neurology 1998; 51:1051-1056 15 Yadav SK, Kumar R, Macey PM, et al. Regional cerebral blood flow alterations in obstructive sleep apnea. Neurosci Lett 2013; 555:159-164 16 Macey PM, Kumar R, Ogren JA, et al. Global brain blood-oxygen level responses to autonomic challenges in obstructive sleep apnea. PLoS One 2014; 9:e105261 17 Macey PM, Kumar R, Woo MA, et al. Brain structural changes in obstructive sleep apnea. Sleep 2008; 31:967-977 18 Morrell MJ, Jackson ML, Twigg GL, et al. Changes in brain morphology in patients with obstructive sleep apnoea. Thorax 2010; 65:908-914 19 Canessa N, Castronovo V, Cappa SF, et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 2011; 183:14191426 20 Smith EE. Leukoaraiosis and stroke. Stroke 2010; 41:S139-143 21 Conklin J, Silver FL, Mikulis DJ, et al. Are acute infarcts the cause of leukoaraiosis? Brain mapping for 16 consecutive weeks. Ann Neurol 2014