New Data About Sleep Apnea and Stroke
Sleep is one of the pillars of good health along with a balanced diet and sufficient exercise. When sleep is fragmented, not deep enough, or short in duration, a chain of events is released that leads to failing health. Sleep apnea is arguably the most common offender of sleep and health among the close to 100 codified sleep disorders. Sleep apnea has emerged as a significant risk factor for vascular disease. It has been associated with atherosclerosis, and cardio- and cerebrovascular morbidity. Recent research has made important inroads in the pathophysiology that links sleep apnea and stroke.
Atherosclerosis, Vascular Inflammation, and Endothelial Disease.
Chronic intermittent hypoxia (CIH) is a key factor in initiating pro-atherogenic activity and a likely link for the close association between sleep apnea and vascular disease. Experiments in mice 1 subjected to eight hours of cyclic hypoxia every 90 seconds, equivalent to a pO2 of 40mmHg and consistent with levels seen in patients with sleep apnea, led to elevations of arterial pressure after 35 days of CIH. Chronic intermittent hypoxia activates the transcription factor hypoxia inducible factor 1 (HIF-1), which induces the expression of endothelin-1(ET1), a HIF-1 inducible gene.2 Endothelin-1 activates a signaling cascade that culminates in superoxide production. In turn, superoxide leads to vascular oxidative stress, which inactivates nitric oxide in cerebral blood vessels, a condition that alters cerebrovascular regulation, reducing cerebrovascular reserves and rendering the brain more susceptible to ischemic injury.3
It has been hypothesized 4 that CIH in patients with sleep apnea can initiate complex metabolic molecular and cellular changes that promote development of vascular inflammation leading to atherosclerosis and endothelial disease. Elevated markers of vascular inflammation, such as oxidized LDL, C-reactive protein, hypercoagulability and fibrinolytic system markers, adhesion molecules, pro-inflammatory cytokines and transcription factors have been shown to be altered in patients with sleep apnea. Increased oxidative stress, vascular inflammation and endothelial dysfunction triggered by CIH are potential links between sleep apnea and stroke. Paradoxically, CIH may also activate adaptive mechanisms, such as increased vascular collateralization and recruitment of bone marrow-derived endothelial progenitor cells, which can provide protection to post-ischemic injured tissues. The balance between pro-atherogenic and protective mechanisms may determine the predisposition of sleep apnea patients to stroke.5
Autonomic Alterations in Sleep Apnea
A significant increase in sympathetic activity, influencing heart rate and blood pressure, has been observed in patients with sleep apnea. Increased sympathetic activity in sleep apnea patients may be induced through a variety of different mechanisms that include the arousal response as well as chemoreflex stimulation by hypoxia and hypercapnia, impairment in venous return to the heart, and alterations in cardiac output.6 Sleep apnea influences heart rate variability not only during sleep, but also during wakefulness. Cortelli et al.7 have shown that normotensive sleep apnea patients have higher heart rate at rest during wakefulness and a higher blood pressure response to head-up tilt than controls, suggesting sympathetic overactivity. When performing cardiovascular reflex tests, sleep apnea patients show significantly lower values of respiratory arrhythmia and greater decrease in heart rate induced by cold face testing, indicating normal or increased cardiac vagal efferent activity. A significant improvement of autonomic modulation and cardiovascular variability is observed in patients with sleep apnea treated successfully with continuous positive airway pressure (CPAP).8
Atrial fibrillation is a major risk factor for stroke that has been associated with sleep apnea. The prevalence of atrial fibrillation in the United States has been estimated at 3.03 million persons in 20059 and has been increasing as more individuals survive into old age.10 Epidemiological studies and clinical data suggest that sleep apnea increases the risk of new-onset atrial fibrillation. A large study 11 evaluating 3542 patients without atrial fibrillation followed subjects for an average of five years. All patients underwent polysomnogaphy. The study revealed that clinically significant nocturnal oxygen desaturation predicted new-onset atrial fibrillation in patients less than 65-years-old. Sleep apnea may also confer a poorer prognosis for recovery following atrial fibrillation interventions. In a study of 424 patients undergoing ablation, sleep apnea more than doubled the risk of acute intra-procedural failure 12. Prospective randomized controlled trials will be necessary to determine the effect of sleep apnea therapy on atrial fibrillation outcomes.
Patent Foramen Ovale
In the general population,13 patent foramen ovale (PFO) occurs with a range of 10%-30% depending on the diagnostic method used. In one study, 27% of sleep apnea patients and only 15% of control subjects had PFO (p < 0.05).14. It has been hypothesized that sleep apnea in patients with PFO could augment the risk of paradoxical embolism and stroke, particularly in individuals who develop pulmonary hypertension as a result of nocturnal hypoxemia.15 In a prospective study of 335 patients with stroke and TIA,16, 202 (60%) had at least one long obstructive sleep apnea event and 116 (35%) a right to left shunting episode by contrast transcranial Doppler examination; 69 (21%) had both. There were significantly more wake-up strokes and TIAs in subjects with right to left shunting plus long obstructive sleep apnea events than in those without this association (27/69 vs. 70/266; OR 1.91, 95% CI 1.08 to 3.38; p=0.03). The authors concluded that the combination of long obstructive sleep apnea events and right to left shunting could be a major and potentially treatable risk for cerebrovascular ischemic events. Further studies are warranted.
- Coleman CG, Wang G, Park L, Anrather J, Delagrammatikas GJ, Chan J, Zhou J, Iadecola C, Pickel VM. Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. J Neurosci 2010;30:12103-12.
- Capone C, Faraco G, Coleman C, Young CN, Pickel VM, Anrather J, Davisson RL, Iadecola C. Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia. Hypertension 2012;60:106-13.
- Lavie L. Oxidative stress--a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis 2009; 51: 303-12.
- Lavie L. Sleep apnea syndrome, endothelial dysfunction, and cardiovascular morbidity. Sleep 2004; 27:1053-5.
- Berger S and Lavie L. Sleep apnea, oxidative stress, proinflammatory vascular risk factors, and endothelial disease. In: Sleep, Stroke and Cardiovascular Disease. Culebras A, editor. Cambridge University Press, New York, 2013, pp. 11-32.
- Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-904.
- Cortelli P, Parchi P, Sforza E, et al. Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome. Clin Auton Res 1994;4: 57-62.
- Noda A, Nakata S, Koike Y, et al. Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome. Hypertens Res 2007;30:669-76.
- Naccarelli GV, Varker H, Lin J, Schulman KL.Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104:1534-9.
- Miyasaka Y, Barnes ME, Gersh BJ, et al.Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119-25.
- Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565-71.
- Sauer WH, McKernan ML, Lin D, Gerstenfeld EP, Callans DJ, Marchlinski FE. Clinical predictors and outcomes associated with acute return of pulmonary vein conduction during pulmonary vein isolation for treatment of atrial fibrillation. Heart Rhythm 2006;3:1024-8.
- Lynch JJ, Schuchard GH, Gross CM, Wann LS.Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography. Am J Cardiol 1984;53:1478-806.
- Beelke M, Angeli S, Del Sette M, Gandolfo C, Cabano ME, Canovaro P, et al. Prevalence of patent foramen ovale in subjects with obstructive sleep apnea: a transcranial Doppler ultrasound study. Sleep Med 2003;4:219-23.
- Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157:2483-7.
- Ciccone A, Proserpio P, Roccatagliata DV, Nichelatti M, Gigli GL, Parati G, Lombardi C, Pizza F, Cirignotta F, Santilli IM, Silani V, Sterzi R, Nobili L; DARIA (Detection of Sleep Apnea as Risk Factor in Acute Stroke) Investigators. Wake-up stroke and TIA due to paradoxical embolism during long obstructive sleep apnoeas: a cross-sectional study. Thorax 2013;68:97-104.
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