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Reevaluating Obstructive Sleep Apnea as a Risk Factor for Cerebrovascular Disease
Editorial
Reevaluating Obstructive Sleep Apnea as a Risk Factor for Cerebrovascular Disease Hrayr Attarian, MD
Over the past quarter century, multiple studies have firmly established an association between obstructive sleep apnea syndrome (OSAS) and stroke. Case reports,1-3 case series,2,4,5 and case-control studies6-8 have demonstrated an 70% prevalence of OSAS in stroke survivors. Furthermore, the severity of OSAS (Apnea Hypopnea Index [AHI] of .30/hour) is much higher in stroke patients than in controls.6-8 In many cases, the symptoms of OSAS precede the occurrence of stroke, suggesting a cause-andeffect relationship.4 Early large-scale risk ratio studies showed a strong association between snoring and cerebral infarction, with a risk ratio of 10.3;9 the more habitual the snoring, the greater the risk of stroke. Specifically, persistent snoring is an independent risk factor for cerebrovascular events, with a risk ratio of 3.16, especially for events occurring during sleep or shortly after awakening.10 Adding obesity and daytime sleepiness to habitual snoring more than doubles the risk. With apnea added, the risk is 7-fold greater.11 Subjects diagnosed with OSAS (AHI $ 5) have a 1.58 relative odds of prevalent stroke, with a hazard ratio of 2.89.12 After stratifying for severity, mild OSAS ($ 5 AHI , 15) carries a 2.44-fold greater risk of cerebrovascular events, whereas moderate ($ 15 AHI , 30) or severe OSAS (AHI $ 30) carries a 3.56-fold greater risk.13 One of the seminal articles on this subject was published by Arzt et al14 in 2005. The authors followed a population of 1475 subjects aged 30-60 years for 12
From the Department of Neurology Stritch School of Medicine Loyola University, Chicago. Received April 13, 2010; accepted May 21, 2010. Address correspondence to Hrayr Attarian, MD, Department of Neurology Stritch School of Medicine Loyola University, 2160 S 1st Ave Maywood, IL 60153, Chicago. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2010 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2010.05.005
years. Subjects with an AHI of $ 20 per hour on baseline polysomnography had an odds ratio (OR) for stroke of 3.83 after controlling for other confounding variables. A subset of 1189 subjects were followed prospectively for 12 years, and an AHI of 20/hour at baseline was associated with increased incidence of cerebrovascular events at 4, 8, and 12 years, with an overall OR of 4.48. This was the first study to show that in addition to being prevalent in stroke sufferers, OSAS preceded stroke, making it a potential risk factor.14 OSAS is associated with a significant risk of composite transient ischemic attack (TIA), stroke, and death over a span of 6 years (hazard ratio [HR], 1.97; 95% confidence interval CI, 1.12-3.48; P 5 .01) even after adjusting for age, sex, race, smoking, weight, hypertension, diabetes, atrial fibrillation, and hyperlipidemia. The severity of OSAS also affects this risk,15 with severe OSAS (AHI $ 30) associated with an HR of 2.52.16 Thus, OSAS appears to be an independent risk factor for cerebrovascular disease, considering that the foregoing studies controlled for all cardiovascular variables associated with OSAS. In addition, OSAS precedes stroke, according to a recently published meta-analysis of 29 articles published before December 2008.17 When specifically evaluating OSAS as a risk factor for TIA, the results are conflicting. A small study (13 subjects) showed a significantly higher prevalence of TIA in subjects with OSAS versus controls,7 but a similarly designed larger study with 86 subjects did not duplicate those findings.18 It is also well established that OSAS worsens disability and increases morbidity and mortality from stroke.2 Hospital stay tends to be longer and functional disability higher in stroke victims with OSAS,19 as does mortality at both 5 and 10 years out.20-22 The use of continuous positive airway pressure (CPAP) reduces mortality,21,23 but patient adherence to and compliance with CPAP after stroke, although possible,24 has proven to be fraught with difficulty.24-26
Journal of Stroke and Cerebrovascular Diseases, Vol. 19, No. 5 (September–October), 2010: pp 337-339
337
H. ATTARIAN
338
The exact pathophysiology of OSAS-induced cerebrovascular events remains unknown. The most likely theory is that hypoxia- and hypercarbia-induced elevation in sympathetic nerve activity (SNA) together with diminished thoracic stretch receptor activity,2,27 lead to persistent hypertension, which in turn can cause cerebrovascular morbidity. SNA can increase by up to 246% during a single 10-second apneic episode. This leads to a persistent increase in mean blood pressure, especially during rapid eye movement sleep, when SNA is already higher than usual and apneic episodes are more frequent because of atonia.27 This is the same mechanism that leads to an increased prevalence of atrial fibrillation in OSAS,28 which in turn is a risk factor for stroke.29 Worsening of OSAS in REM sleep, the related increased SNA, elevated catecholamine levels,30 and hemodynamic instability worsen the early morning hypercoagulable state31 that is characterized by low fibrinolytic activity, increased blood viscosity, and platelet aggregability.32 Levels of proinflammatory (and platelet-activation) proteins CD40 ligand and soluble P-selectin are elevated in patients with silent stroke, as well as those with moderate to severe OSAS. The prevalence of silent stroke was found to be 25% in subjects with moderate to severe OSAS versus 6.7% in controls.33 CPAP therapy significantly reduced the levels of both proteins.33 Finally, OSAS has been implicated in increased intracranial pressure, which can further reduce cerebral blood flow, contributing to cerebral ischemia.34,35 Tracheostomy is the only proven treatment for preventing cerebrovascular morbidity in patients with OSAS. The prevalence of stroke in OSAS patients treated solely with a weight-loss regimen was found to be almost 4.5-fold (5.2% vs 1.2%) that of patients treated with tracheostomy over a 7-year period. 36,37 Those studies were conducted at a time when CPAP was still not widely available, however. To date, no studies have investigated the effectiveness of CPAP or other treatment modalities, such as oral appliances and uvulopalatopharyngeoplasty procedures, in preventing cerebrovascular events. The use of CPAP in stroke patients with OSAS has been shown to reduce 5-year mortality from all causes, as well as improve overall functional recovery;38-40 however, there have been no treatment studies evaluating the role of currently prescribed OSAS treatments in the primary prevention of stroke. In addition, although CPAP has been shown to reduce the risk of cardiovascular events after stroke in patients with OSAS, to date no studies have specifically evaluated CPAP as a way to prevent recurrent stroke. OSAS has been shown to be a modifiable risk factor for cardiac disease; its treatment with CPAP clearly can prevent the occurrence of both fatal and nonfatal cardiac events.41 Treatment of OSAS is included in the American Heart Association’s guidelines for primary prevention of coronary artery disease.42 As pointed out by Bradley and Floras in 2009,43 these conclusions are based primarily on
small randomized trials, and larger randomized trials are needed to determine definitively whether treating OSAS improves cardiovascular outcomes. Because CPAP clearly prevents cardiac morbidity and mortality in patients with OSAS,44-47 studies examining its impact on preventing stroke-related morbidity and mortality are overdue. Because of issues with CPAP compliance in patients with stroke, the heterogeneity of the population with cereberovascular disorders, and problems with selection bias, designing an exploratory observational or cross-sectional trial is difficult; however, this is a necessary step before the initiation of a randomized study to investigate the role of CPAP as a primary prevention method.
References 1. Tikare SK, Chaudhary BA, Bandisode MS. Hypertension and stroke in a young man with obstructive sleep apnea syndrome. Postgrad Med 1985;78:59-60. 2. Dyken ME, Im KB. Obstructive sleep apnea and stroke. Chest 2009;136:1668-1677. 3. Tilkian AG, Guilleminault C, Schroeder JS, et al. Hemodynamics in sleep-induced apnea: Studies during wakefulness and sleep. Ann Intern Med 1976;85:714-719. 4. Good DC, Henkle JQ, Gelber D, et al. Sleep-disordered breathing and poor functional outcome after stroke. Stroke 1996;27:252-259. 5. Kapen S, Park A, Goldberg J, et al. The incidence and severity of obstructive sleep apnea in ischemic cerebrovascular disease. Neurology 1991;41(Suppl):125. 6. Hudgel DW, Devadatta P, Quadri M, et al. Mechanism of sleep-induced periodic breathing in convalescing stroke patients and healthy elderly subjects. Chest 1993; 104:1503-1510. 7. Bassetti C, Aldrich MS, Chervin RD, et al. Sleep apnea in patients with transient ischemic attack and stroke: A prospective study of 59 patients. Neurology 1996;47:1167-1173. 8. Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 1996;27:401-407. 9. Partinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;11:1325-1326. 10. Palomaki H, Partinen M, Juvela S, et al. Snoring as a risk factor for sleep-related brain infarction. Stroke 1989; 20:1311-1315. 11. Palomaki H. Snoring and the risk of ischemic brain infarction. Stroke 1991;22:1021-1025. 12. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: Cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19-25. 13. Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: A 10-year follow-up. Circulation 2008;118:955-960. 14. Arzt M, Young T, Finn L, et al. Association of sleepdisordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005;172:1447-1451. 15. 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. 16. 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.
REEVALUATING OBSTRUCTIVE SLEEP APNEA AS A RISK FACTOR FOR CEREBROVASCULAR DISEASE 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. McArdle N, Riha RL, Vennelle M, et al. Sleep-disordered breathing as a risk factor for cerebrovascular disease: A case-control study in patients with transient ischemic attacks. Stroke 2003;34:2916-2921. 19. 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. 20. 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. 21. Hardie K, Jamrozik K, Hankey GJ, et al. Trends in fiveyear survival and risk of recurrent stroke after first-ever stroke in the Perth Community Stroke Study. Cerebrovasc Dis 2005;19:179-185. 22. 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. 23. Martinez-Garcia MA, Soler-Cataluna JJ, EjarqueMartinez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: A 5-year follow-up study. Am J Respir Crit Care Med 2009;180:36-41. 24. Disler P, Hansford A, Skelton J, et al. Diagnosis and treatment of obstructive sleep apnea in a stroke rehabilitation unit: A feasibility study. Am J Phys Med Rehabil 2002; 81:622-625. 25. Bassetti CL, Milanova M, Gugger M. Sleep-disordered breathing and acute ischemic stroke: Diagnosis, risk factors, treatment, evolution, and long-term clinical outcome. Stroke 2006;37:967-972. 26. Strollo PJ Jr, Sanders MH, Atwood CW. Positive pressure therapy. Clin Chest Med 1998;19:55-68. 27. Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904. 28. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-367. 29. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119:e21-e181. 30. Fletcher EC, Miller J, Schaaf JW, et al. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987;10:35-44. 31. Geiser T, Buck F, Meyer BJ, et al. In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 2002;69:229-234. 32. Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk
33.
34. 35.
36.
37.
38. 39.
40.
41.
42.
43. 44.
45. 46.
47.
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of myocardial infarction and sudden cardiac death. N Engl J Med 1987;316:1514-1518. Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med 2007;175:612-617. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest 1989;95:279-283. Klingelhofer J, Hajak G, Sander D, et al. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke 1992;23:1427-1433. Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients: Mortality. Chest 1988;94:1200-1204. Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest 1990;97:27-32. Palombini L, Guilleminault C. Stroke and treatment with nasal CPAP. Eur J Neurol 2006;13:198-200. Martinez-Garcia MA, Galiano-Blancart R, RomanSanchez P, et al. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest 2005;128:2123-2129. 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. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoeahypopnoea with or without treatment with continuous positive airway pressure: An observational study. Lancet 2005;365:1046-1053. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: An American Heart Association/ American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing Council. Circulation 2008;118:1080-1111. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82-93. Abe H, Takahashi M, Yaegashi H, et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels 2010;25:63-69. Butt M, Dwivedi G, Khair O, et al. Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 2010;139:7-16. Moro JA, Almenar L, Fernandez-Fabrellas E, et al. Hypertension and sleep apnea-hypopnea syndrome: Changes in echocardiographic abnormalities depending on the presence of hypertension and treatment with CPAP. Sleep Med 2009;10:344-352. Dernaika TA, Kinasewitz GT, Tawk MM. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med 2009;5:103-107.
Reevaluating Obstructive Sleep Apnea as a Risk Factor for Cerebrovascular Disease Hrayr Attarian, MD
Over the past quarter century, multiple studies have firmly established an association between obstructive sleep apnea syndrome (OSAS) and stroke. Case reports,1-3 case series,2,4,5 and case-control studies6-8 have demonstrated an 70% prevalence of OSAS in stroke survivors. Furthermore, the severity of OSAS (Apnea Hypopnea Index [AHI] of .30/hour) is much higher in stroke patients than in controls.6-8 In many cases, the symptoms of OSAS precede the occurrence of stroke, suggesting a cause-andeffect relationship.4 Early large-scale risk ratio studies showed a strong association between snoring and cerebral infarction, with a risk ratio of 10.3;9 the more habitual the snoring, the greater the risk of stroke. Specifically, persistent snoring is an independent risk factor for cerebrovascular events, with a risk ratio of 3.16, especially for events occurring during sleep or shortly after awakening.10 Adding obesity and daytime sleepiness to habitual snoring more than doubles the risk. With apnea added, the risk is 7-fold greater.11 Subjects diagnosed with OSAS (AHI $ 5) have a 1.58 relative odds of prevalent stroke, with a hazard ratio of 2.89.12 After stratifying for severity, mild OSAS ($ 5 AHI , 15) carries a 2.44-fold greater risk of cerebrovascular events, whereas moderate ($ 15 AHI , 30) or severe OSAS (AHI $ 30) carries a 3.56-fold greater risk.13 One of the seminal articles on this subject was published by Arzt et al14 in 2005. The authors followed a population of 1475 subjects aged 30-60 years for 12
From the Department of Neurology Stritch School of Medicine Loyola University, Chicago. Received April 13, 2010; accepted May 21, 2010. Address correspondence to Hrayr Attarian, MD, Department of Neurology Stritch School of Medicine Loyola University, 2160 S 1st Ave Maywood, IL 60153, Chicago. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2010 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2010.05.005
years. Subjects with an AHI of $ 20 per hour on baseline polysomnography had an odds ratio (OR) for stroke of 3.83 after controlling for other confounding variables. A subset of 1189 subjects were followed prospectively for 12 years, and an AHI of 20/hour at baseline was associated with increased incidence of cerebrovascular events at 4, 8, and 12 years, with an overall OR of 4.48. This was the first study to show that in addition to being prevalent in stroke sufferers, OSAS preceded stroke, making it a potential risk factor.14 OSAS is associated with a significant risk of composite transient ischemic attack (TIA), stroke, and death over a span of 6 years (hazard ratio [HR], 1.97; 95% confidence interval CI, 1.12-3.48; P 5 .01) even after adjusting for age, sex, race, smoking, weight, hypertension, diabetes, atrial fibrillation, and hyperlipidemia. The severity of OSAS also affects this risk,15 with severe OSAS (AHI $ 30) associated with an HR of 2.52.16 Thus, OSAS appears to be an independent risk factor for cerebrovascular disease, considering that the foregoing studies controlled for all cardiovascular variables associated with OSAS. In addition, OSAS precedes stroke, according to a recently published meta-analysis of 29 articles published before December 2008.17 When specifically evaluating OSAS as a risk factor for TIA, the results are conflicting. A small study (13 subjects) showed a significantly higher prevalence of TIA in subjects with OSAS versus controls,7 but a similarly designed larger study with 86 subjects did not duplicate those findings.18 It is also well established that OSAS worsens disability and increases morbidity and mortality from stroke.2 Hospital stay tends to be longer and functional disability higher in stroke victims with OSAS,19 as does mortality at both 5 and 10 years out.20-22 The use of continuous positive airway pressure (CPAP) reduces mortality,21,23 but patient adherence to and compliance with CPAP after stroke, although possible,24 has proven to be fraught with difficulty.24-26
Journal of Stroke and Cerebrovascular Diseases, Vol. 19, No. 5 (September–October), 2010: pp 337-339
337
H. ATTARIAN
338
The exact pathophysiology of OSAS-induced cerebrovascular events remains unknown. The most likely theory is that hypoxia- and hypercarbia-induced elevation in sympathetic nerve activity (SNA) together with diminished thoracic stretch receptor activity,2,27 lead to persistent hypertension, which in turn can cause cerebrovascular morbidity. SNA can increase by up to 246% during a single 10-second apneic episode. This leads to a persistent increase in mean blood pressure, especially during rapid eye movement sleep, when SNA is already higher than usual and apneic episodes are more frequent because of atonia.27 This is the same mechanism that leads to an increased prevalence of atrial fibrillation in OSAS,28 which in turn is a risk factor for stroke.29 Worsening of OSAS in REM sleep, the related increased SNA, elevated catecholamine levels,30 and hemodynamic instability worsen the early morning hypercoagulable state31 that is characterized by low fibrinolytic activity, increased blood viscosity, and platelet aggregability.32 Levels of proinflammatory (and platelet-activation) proteins CD40 ligand and soluble P-selectin are elevated in patients with silent stroke, as well as those with moderate to severe OSAS. The prevalence of silent stroke was found to be 25% in subjects with moderate to severe OSAS versus 6.7% in controls.33 CPAP therapy significantly reduced the levels of both proteins.33 Finally, OSAS has been implicated in increased intracranial pressure, which can further reduce cerebral blood flow, contributing to cerebral ischemia.34,35 Tracheostomy is the only proven treatment for preventing cerebrovascular morbidity in patients with OSAS. The prevalence of stroke in OSAS patients treated solely with a weight-loss regimen was found to be almost 4.5-fold (5.2% vs 1.2%) that of patients treated with tracheostomy over a 7-year period. 36,37 Those studies were conducted at a time when CPAP was still not widely available, however. To date, no studies have investigated the effectiveness of CPAP or other treatment modalities, such as oral appliances and uvulopalatopharyngeoplasty procedures, in preventing cerebrovascular events. The use of CPAP in stroke patients with OSAS has been shown to reduce 5-year mortality from all causes, as well as improve overall functional recovery;38-40 however, there have been no treatment studies evaluating the role of currently prescribed OSAS treatments in the primary prevention of stroke. In addition, although CPAP has been shown to reduce the risk of cardiovascular events after stroke in patients with OSAS, to date no studies have specifically evaluated CPAP as a way to prevent recurrent stroke. OSAS has been shown to be a modifiable risk factor for cardiac disease; its treatment with CPAP clearly can prevent the occurrence of both fatal and nonfatal cardiac events.41 Treatment of OSAS is included in the American Heart Association’s guidelines for primary prevention of coronary artery disease.42 As pointed out by Bradley and Floras in 2009,43 these conclusions are based primarily on
small randomized trials, and larger randomized trials are needed to determine definitively whether treating OSAS improves cardiovascular outcomes. Because CPAP clearly prevents cardiac morbidity and mortality in patients with OSAS,44-47 studies examining its impact on preventing stroke-related morbidity and mortality are overdue. Because of issues with CPAP compliance in patients with stroke, the heterogeneity of the population with cereberovascular disorders, and problems with selection bias, designing an exploratory observational or cross-sectional trial is difficult; however, this is a necessary step before the initiation of a randomized study to investigate the role of CPAP as a primary prevention method.
References 1. Tikare SK, Chaudhary BA, Bandisode MS. Hypertension and stroke in a young man with obstructive sleep apnea syndrome. Postgrad Med 1985;78:59-60. 2. Dyken ME, Im KB. Obstructive sleep apnea and stroke. Chest 2009;136:1668-1677. 3. Tilkian AG, Guilleminault C, Schroeder JS, et al. Hemodynamics in sleep-induced apnea: Studies during wakefulness and sleep. Ann Intern Med 1976;85:714-719. 4. Good DC, Henkle JQ, Gelber D, et al. Sleep-disordered breathing and poor functional outcome after stroke. Stroke 1996;27:252-259. 5. Kapen S, Park A, Goldberg J, et al. The incidence and severity of obstructive sleep apnea in ischemic cerebrovascular disease. Neurology 1991;41(Suppl):125. 6. Hudgel DW, Devadatta P, Quadri M, et al. Mechanism of sleep-induced periodic breathing in convalescing stroke patients and healthy elderly subjects. Chest 1993; 104:1503-1510. 7. Bassetti C, Aldrich MS, Chervin RD, et al. Sleep apnea in patients with transient ischemic attack and stroke: A prospective study of 59 patients. Neurology 1996;47:1167-1173. 8. Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 1996;27:401-407. 9. Partinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985;11:1325-1326. 10. Palomaki H, Partinen M, Juvela S, et al. Snoring as a risk factor for sleep-related brain infarction. Stroke 1989; 20:1311-1315. 11. Palomaki H. Snoring and the risk of ischemic brain infarction. Stroke 1991;22:1021-1025. 12. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: Cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19-25. 13. Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: A 10-year follow-up. Circulation 2008;118:955-960. 14. Arzt M, Young T, Finn L, et al. Association of sleepdisordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005;172:1447-1451. 15. 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. 16. 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.
REEVALUATING OBSTRUCTIVE SLEEP APNEA AS A RISK FACTOR FOR CEREBROVASCULAR DISEASE 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. McArdle N, Riha RL, Vennelle M, et al. Sleep-disordered breathing as a risk factor for cerebrovascular disease: A case-control study in patients with transient ischemic attacks. Stroke 2003;34:2916-2921. 19. 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. 20. 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. 21. Hardie K, Jamrozik K, Hankey GJ, et al. Trends in fiveyear survival and risk of recurrent stroke after first-ever stroke in the Perth Community Stroke Study. Cerebrovasc Dis 2005;19:179-185. 22. 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. 23. Martinez-Garcia MA, Soler-Cataluna JJ, EjarqueMartinez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: A 5-year follow-up study. Am J Respir Crit Care Med 2009;180:36-41. 24. Disler P, Hansford A, Skelton J, et al. Diagnosis and treatment of obstructive sleep apnea in a stroke rehabilitation unit: A feasibility study. Am J Phys Med Rehabil 2002; 81:622-625. 25. Bassetti CL, Milanova M, Gugger M. Sleep-disordered breathing and acute ischemic stroke: Diagnosis, risk factors, treatment, evolution, and long-term clinical outcome. Stroke 2006;37:967-972. 26. Strollo PJ Jr, Sanders MH, Atwood CW. Positive pressure therapy. Clin Chest Med 1998;19:55-68. 27. Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904. 28. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-367. 29. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119:e21-e181. 30. Fletcher EC, Miller J, Schaaf JW, et al. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987;10:35-44. 31. Geiser T, Buck F, Meyer BJ, et al. In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 2002;69:229-234. 32. Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk
33.
34. 35.
36.
37.
38. 39.
40.
41.
42.
43. 44.
45. 46.
47.
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of myocardial infarction and sudden cardiac death. N Engl J Med 1987;316:1514-1518. Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med 2007;175:612-617. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest 1989;95:279-283. Klingelhofer J, Hajak G, Sander D, et al. Assessment of intracranial hemodynamics in sleep apnea syndrome. Stroke 1992;23:1427-1433. Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients: Mortality. Chest 1988;94:1200-1204. Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest 1990;97:27-32. Palombini L, Guilleminault C. Stroke and treatment with nasal CPAP. Eur J Neurol 2006;13:198-200. Martinez-Garcia MA, Galiano-Blancart R, RomanSanchez P, et al. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest 2005;128:2123-2129. 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. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoeahypopnoea with or without treatment with continuous positive airway pressure: An observational study. Lancet 2005;365:1046-1053. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: An American Heart Association/ American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing Council. Circulation 2008;118:1080-1111. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82-93. Abe H, Takahashi M, Yaegashi H, et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels 2010;25:63-69. Butt M, Dwivedi G, Khair O, et al. Obstructive sleep apnea and cardiovascular disease. Int J Cardiol 2010;139:7-16. Moro JA, Almenar L, Fernandez-Fabrellas E, et al. Hypertension and sleep apnea-hypopnea syndrome: Changes in echocardiographic abnormalities depending on the presence of hypertension and treatment with CPAP. Sleep Med 2009;10:344-352. Dernaika TA, Kinasewitz GT, Tawk MM. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med 2009;5:103-107.