Introduction
Physiological sleep plays a significant role in cardiovascular control. Cyclical sleep stages coincide with related cardiovascular variations. Blood pressure declines to the lowest values during sleep stages N3, rising again in the rapid eye movement (REM) stage. Overall blood pressure load during sleep decreases at least 10% as compared to the waking state in healthy humans. Sleep deprivation and shorter sleep time itself result in higher blood pressure and an increased risk for hypertension [1, 2]. Recurrent apnoeic episodes, a condition commonly known as sleep apnoea, provokes a lot more detrimental stimuli beyond mere sleep architecture disruption. Cessation of breathing naturally results in periods of hypoxia and hypercapnia, rapid and sustained autonomic system activity changes, and pleural pressure swings. All of these, paralleled by sequent metabolic, hormonal, and rheological alterations, add risk to the incidence of arterial hypertension, as well as early target organ damage. Experimental and epidemiological studies have shown sleep apnoea to be an independent risk factor and prognostic indicator for ischaemic heart disease, arrhythmias, and stroke.
This paper discusses obstructive sleep apnoea and its link to systemic hypertension.
Obstructive sleep apnoea
Obstructive sleep apnoea (OSA) is characterized by recurrent periods of breathing cessations during sleep caused by complete or partial upper airway collapse. Obstructive sleep apnoea has an estimated prevalence of 9 to 24% in middle-aged working women and men, respectively [3]. Attended polysomnography (PSG) has been confirmed to be a diagnostic tool for any type of sleep-disordered breathing. Simultaneous recording of electro-physiological signals allows the scoring of sleep stages as well as describing breathing events. The arbitrary cut-off value used for the distinction between physiology and disease for sleep apnoea has been set at 5 events per hour of sleep (apnoea hypopnoea index – AHI). Disease has been further classified as mild sleep apnoea (AHI 5-14.9), moderate (AHI 15-29.9) and severe (ł30 events per hour of sleep). Sleep apnoea syndrome refers to relevant PSG findings coinciding with disease symptoms, e.g. excessive daytime sleepiness, unrefreshing sleep, choking sensations during sleep, recurrent awakenings from sleep, daytime fatigue and impaired concentration [4]. Since PSG recordings are time- and money-consuming, it is also acceptable to apply polygraphic tests (no EEG, EOG, EMG) to subjects highly suspected of having OSA, both to rule in and rule out the disease. This strategy requires available pre-tests that increase the likelihood of OSA (patient’s medical history, information from a sleep-partner questionnaire) [5]. Of widely-used forms, the Berlin questionnaire (BQ) has been confirmed to be a sufficient tool to divide patients into high and low OSA probability subgroups. The BQ has been validated in primary care patients as well as atrial fibrillation patients [6, 7]. The BQ has not been proven a valuable tool for referrals to the sleep laboratory [8] (see appendix for the instructions for this tool).
Evidence of associations between obstructive sleep apnoea and arterial hypertension
A number of research studies have evidenced a link between obstructive sleep apnoea and abnormal blood pressure control. Animal experi-ments have revealed mimicked apnoeas to be a cause of elevated systemic blood pressure and development of hypertension [9]. In cross-sectional studies OSA patients demonstrate increased blood pressure and a higher incidence of hypertension as compared to controls [10-12]. On the other hand, breathing disorders during sleep are more prevalent in patients with arterial hypertension, particularly if refractory to conventional drug therapy [13-15]. Up to 83-85% of hypertensive individuals with 3 or more blood-lowering medicines may have previously undiagnosed obstructive sleep apnoea. Compelling data indicating a causative role of sleep apnoea in the pathogenesis of hypertension in humans derives from the Wisconsin Sleep Cohort Study [16]. Data analysis provided evidence of a dose-response relationship between severity of sleep-disordered breathing represented by AHI, and the odds for hypertension in a prospective four-year observation. The study was conducted among working adults and was controlled for such confounders as baseline hypertension status, BMI, neck and waist circumference, age, sex, and weekly use of stimulants. The OR for the incidence of hypertension were 2.03 with an apnoea-hypopnoea index of 5.0 to 14.9 events per hour as compared to none, and 2.89 for moderate-to-severe disease. It is worth mentioning that even a few apnoeas per hour of sleep, regarded to be within normal limits (AHI<5), conferred a risk of hypertension (OR 1.42). The strength of this association is attenuated by aging [17]. Analysis of data from a multicentre project, the Sleep Heart Health Study, has shown an independent association of OSA and hypertension, but only in a group of middle-aged subjects, whereas no such correlation was found in individuals aged over 60. Further analysis of SHHS data revealed that self-reported excessive daytime sleepiness may considerably modify risk for hypertension. Marked sleepiness strengthens the association between AHI and odds for hypertension [18]. Those findings remain consistent with results from interventional studies [19].
Since early haemodynamic alterations secondary to recurrent apnoeas are generally detectable during the night, OSA patients may not exhibit daytime hypertension [20]. It has been estimated that up to 30% of newly diagnosed OSA patients may have nighttime hypertension [21]. Furthermore, prospective observation of the Wisconsin Cohort revealed worsening of blood pressure profile in sleep apnoeic patients over time [22]. This underscores the need for ambulatory blood pressure evaluation in this group of patients [23].
Alarming signals come from studies on children whose early-age hypertension may significantly precipitate target organ damage. Although data are inconsistent and no referral scores for apnoeic events are available for children, the weight of evidence suggests obstructive sleep apnoea to be involved in excessive blood pressure load and increased risk for hypertension in youths [24-26].
Target organ damage
Obstructive sleep apnoea confers the risk of target organ damage primarily ascribed to hypertension itself. Animal and human studies suggest impaired left ventricular function and structure resulting from recurrent apnoeas [27-33]. Research testing correlations between sleep apnoea and ischaemic heart disease confirm a close relationship of those two conditions. Positive associations have been found between the incidence of ischaemic heart disease among sleep apnoea patients as well as heart disease prognosis with respect to OSA severity [34-39]. Another detrimental effect of obstructive sleep apnoea on cardiac function concerns heart rhythm control. Several observational studies have shown that OSA increases the prevalence and reoccurrence of cardiac arrhythmias [40-43]. Neurological studies have also demonstrated a link between sleep-disordered breathing and cerebrovascular disease [44]. Obstructive sleep apnoea patients are at an increased risk for both a first-time cerebrovascular event as well as a subsequently worse stroke prognosis. The latter appears to be positively influenced by continuous positive airway pressure (CPAP) therapy [45-47].
Mechanisms linking sleep apnoea to hypertension
Autonomic nervous system
Oxygen and carbon dioxide fluctuations resulting from recurrent apnoeas overstimulate the autonomic nervous system via chemoreceptors. Both sympathetic and parasympathetic activity rise progressively during the time of apnoea to be eventually enhanced by arousal. In that time increased sympathetic neural tone promotes peripheral vascular resistance, whereas heart action chiefly depends on parasympathetic overactivity [48]. The resumption of breathing coincides with constricted peripheral vasculature and rapid acceleration of heart rate, which in turn provokes a steep rise of arterial blood pressure. Apnoea termination has been evidenced to accompany systolic readings as high as 250 mm Hg, which may be true even in those individuals whose daytime resting blood pressure shows no pathology. Human observational studies using different investigative tools have also revealed higher levels of daytime sympathetic nerve activity in OSA patients [48-51]. Among the underlying recognized mechanisms responsible for increased sympathetic activity during the waking state, chemoreceptor dysfunction and impaired baroreceptor responsiveness may play a significant role [52-54]. Supportive information for this hypothesis comes from interventional studies. Introduction of CPAP therapy has been followed by marked and sustained reduction in the sympathetic drive measured both by plasma and urinary norepinephrine concentrations as well as microneurography [55, 56]. High levels of sympathetic activity are paralleled by impaired cardiovascular variability during the waking state. This alteration is marked even in OSA patients without diagnosed hypertension or heart failure. Sleep apnoeics exhibit marked increase in blood pressure variability, faster heart rate and decreased RR variability [57]. The measure of this derangement is closely linked to the disease severity. Both sympathetic overactivation and abnormal cardiovascular variability in sleep apnoea patients may contribute to the increased risk of future hypertension [58] as well as target organ damage [59].
Aldosterone
The interaction between obesity, sleep apnoea and aldosterone is vaguely elucidated. It has been suggested that the visceral adipose measure correlates with plasma aldosterone levels [60]. At the same time obesity plays a key role in sleep apnoea pathogenesis. Previous studies suggesting higher levels of plasma aldosterone and aldosterone urine excretion in OSA patients were not BMI-controlled [61, 62]. Such a correlation in a dose-response manner has been found in a fully-controlled model in subjects with resistant hypertension [63]. The authors of this paper hypothesize that hyperaldosteronism through water retention confers the risk of higher AHI. A con-trasting approach to this problem involves studies testing an inverse association. Assuming that recurrent sleep apnoeic episodes lead to a secondary increase in concentrations of plasma aldosterone, treatment with CPAP would promote a decline in hormone levels. The results of such short- or long-term observations remain very inconsistent [62-66].
Endothelin-1
Animal studies investigating the influence of either sleep deprivation or intermittent hypoxia (conditions linked to apnoeas) on endothelin-1 (ET-1) concentrations have revealed an excessive release of this potent vasoconstrictor [67, 68]. However, comparative and interventional studies in OSA patients have brought conflicting results [69-72]. One possible explanation for these discrepancies might be the different methodologies used in these studies. Another study testing a circulating precursor of ET-1 (characterized by significantly longer half-life) supports the hypothesis of impai-red hormone homeostasis further reversible by CPAP [73].
Nitric oxide
It has been evidenced that OSA patients demonstrate impaired endothelium-dependent vasodilation [74, 75]. Experiments with acetylcholine (ACH stimulates NO-mediated vasodilation) and nitroprusside (a direct donor of nitric oxide) revealed a diverse vascular response in OSA patients. The administration of a direct donor of nitric oxide results in vascular dilation comparable to controls, whereas stimulated endogenous NO release is attenuated [76]. One possible explanation for this phenomenon would be an increase in asymmetric dimethylarginine (ADMA), an endothelial nitric oxide synthase antagonist. Administration of CPAP therapy results in a decrease in ADMA levels which coincides with improvement in NO-dependent vasodilation [77].
Continuous positive airway pressure therapy
The effect of CPAP therapy on blood pressure control varies in different sleep apnoeic populations. The weight of evidence generally favours hypo-tensive action of CPAP in OSA patients. The first night with applied positive pressure results in an acute and clear-cut reduction in post-apnoeic blood pressure surges [78]. Although short-term observations are inconsistent, patients’ follow-ups reveal a statistically significant reduction in systolic and diastolic blood pressure [79-81]. Once OSA management has been started, an effort guaranteeing that no residual apnoeas are left has to be made. Interventional studies have shown no benefit in blood pressure control with subtherapeutic CPAP [82, 83]. It is also assumed that cardiovascular response to CPAP treatment varies in regard to sleep apnoea severity, initial blood pressure readings, and quantitative antihypertensive treatment [84]. Patients with advanced sleep-disordered breathing appear to receive major hypotensive benefit from CPAP therapy when compared to controls. Long-term follow-ups of subjects using CPAP devices suggest a time-related improvement in blood pressure control [85]. Another aspect of continuous positive pressure therapy is its relation to circadian blood pressure pattern. Sleep apnoea might be responsible for the previously described insufficient nocturnal decline of BP or even the increase of systemic blood pressure during the night. It has been demonstrated that CPAP therapy may at least partially overturn this detrimental condition [86]. So far, no proven hypotensive action of CPAP has been evidenced in normotensives [87] as well as hypertensive OSA patients without concomitant excessive daytime sleepiness [88]. The latter data emphasize the importance of physiological sleep architecture in cardiovascular control. Beside several demonstrated benefits for patients on CPAP therapy, adherence to this procedure remains at a poor level [89].
Conclusion
There is growing evidence of a causal and dose-dependant relationship between obstructive sleep apnoea and hypertension. Unmanaged OSA may also be implicated in a higher risk for target organ damage previously ascribed to hypertension alone. Long-term CPAP treatment attenuates neural and hormonal abnormalities relevant to circulatory control, which translates into a decrease in blood pressure load and an improved overall prognosis.
References
1. Palma BD, Gabriel A Jr, Bignotto M, Tufik S. Paradoxical sleep deprivation increases plasma endothelin levels. Braz J Med Biol Res 2002; 35: 75-9.
2. Gottlieb DJ, Redline S, Nieto FJ, et al. Association of usual sleep duration with hypertension: the Sleep Heart Health Study. Sleep 2006; 29: 1009-14.
3. Young T, Palta M, Dempsey J, Skarrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: 1230-5.
4. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999; 22: 667-89.
5. Chesson AL Jr, Berry RB, Pack A; American Academy of Sleep Medicine; American Thoracic Society; American College of Chest Physicians. Practice parameters for the use of portable monitoring devices in the investigation of suspected obstructive sleep apnea in adults. Sleep 2003; 26: 907-13.
6. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999; 131: 485-91.
7. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110: 364-7.
8. Ahmadi N, Chung SA, Gibbs A, Shapiro CM. The Berlin questionnaire for sleep apnea in a sleep clinic population: relationship to polysomnographic measurement of respiratory disturbance. Sleep Breath 2008; 12: 39-45.
9. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997; 99: 106-9.
10. Bixler EO, Vgontzas AN, Lin HM, et al. Association of hypertension and sleep-disordered breathing. Arch Intern Med 2000; 160: 2289-95.
11. 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: 1746-52.
12. Nieto FJ, Young TB, Bonnie KL, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000; 283: 1829-36.
13. Isaksson A, Svanborg E. Obstructive sleep apnea syndrome in male hypertensives, refractory to drug therapy. Nocturnal automatic blood pressure measurements – an aid to diagnosis? Clin Exp Hypertens A 1991; 13: 1195-212.
14. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007; 131: 453-9.
15. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001; 19: 2271-7.
16. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 1378-84.
17. Haas DC, Foster GL, Nieto FJ, et al. Age-dependent associations between sleep-disordered breathing and hypertension: importance of discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study. Circulation 2005; 111: 614-21.
18. Kapur VK, Resnick HE, Gottlieb DJ; Sleep Heart Health Study Group. Sleep disordered breathing and hypertension: does self-reported sleepiness modify the association? Sleep 2008; 31: 1127-32.
19. Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J 2006; 27: 1229-35.
20. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96: 1897-904.
21. Baguet JP, Lévy P, Barone-Rochette G, et al. Masked hypertension in obstructive sleep apnea syndrome. J Hypertens 2008; 26: 885-92.
22. Hla KM, Young T, Finn L, Peppard PE, Szklo-Coxe M, Stubbs M. Longitudinal association of sleep-disordered breathing and nondipping of nocturnal blood pressure in the Wisconsin Sleep Cohort Study. Sleep 2008; 31: 795-800.
23. Baguet JP, Hammer L, Lévy P, et al. Night-time and diastolic hypertension are common and underestimated conditions in newly diagnosed apnoeic patients. J Hypertens 2005; 23: 521-7.
24. Guilleminault C, Khramsov A, Stoohs RA, et al. Abnormal blood pressure in prepubertal children with sleep-disordered breathing. Pediatr Res 2004; 55: 76-84.
25. Leung LC, Ng DK, Lau MW, et al. Twenty-four-hour ambulatory BP in snoring children with obstructive sleep apnea syndrome. Chest 2006; 130: 1009-17.
26. Li AM, Au CT, Sung RY, et al. Ambulatory blood pressure in children with obstructive sleep apnoea – a community based study. Thorax 2008; 63: 803-9.
27. Parker JD, Brooks D, Kozar LF, et al. Acute and Chronic Effects of Airway Obstruction on Canine Left Ventricular Performance. Am J Respir Crit Care Med 1999; 160: 1888-96.
28. Fung JW, Li TS, Choy DK, et al. Severe obstructive sleep apnea is associated with left ventricular diastolic dysfunction. Chest 2002; 121: 422-9.
29. Alchanatis M, Tourkohoriti G, Kosmas EN, et al. Evidence for left ventricular dysfunction in patients with obstructive sleep apnoea syndrome. Eur Respir J 2002; 20: 1239-45.
30. Laaban JP, Pascal-Sebaoun S, Bloch E, Orvoën-Frija E, Oppert JM, Huchon G. Left ventricular systolic dysfunction in patients with obstructive sleep apnea syndrome. Chest 2002; 122: 1133-8.
31. Hall MJ, Ando S, Floras JS, Bradley TD. Magnitude and time course of hemodynamic responses to Mueller maneuvers in patients with congestive heart failure. J Appl Physiol 1998; 85: 1476-84.
32. Kraiczi H, Peker Y, Caidahl K, Samuelsson A, Hedner J. Blood pressure, cardiac structure and severity of obstructive sleep apnea in a sleep clinic population. J Hypertens 2001; 19: 2071-8.
33. Tanriverdi H, Evrengul H, Kaftan A, et al. Effect of obstructive sleep apnea on aortic elastic parameters – relationship to left ventricular mass and function. Circ J 2006; 70: 737-43.
34. Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990; 336: 261-4.
35. Mooe T, Rabben T, Wiklund U, Franklin KA, Eriksson P. Sleep-disordered breathing in women: occurrence and association with coronary artery disease. Am J Med 1996; 101: 251-6.
36. Peled N, Abinader EG, Pillar G, Sharif D, Lavie P. Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease effects of continuous positive air pressure treatment. J Am Coll Cardiol 1999; 34: 1744-9.
37. 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.
38. Peker Y, Kraiczi H, Hedner J, Löth S, Johansson A, Bende M. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999; 14: 179-84.
39. Peker Y, Hedner J, Kraiczi H, Löth S. Respiratory disturbance index – an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med 2000; 162: 81-6.
40. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983; 52: 490-4.
41. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110: 364-7.
42. Mehra R, Benjamin EJ, Sahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing. The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173: 910-6.
43. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003; 107: 2589-94.
44. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353: 2034-41.
45. 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.
46. 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: 375-80.
47. Martínez-García MA, Galiano-Blancart R, Román-Sánchez P, Soler-Catalun~a JJ, Cabero-Salt L, Salcedo-Maiques E. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest 2005; 128: 2123-9.
48. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96: 1897-904.
49. Dimsdale JE, Coy T, Ziegler MG, Ancoli-Israel S, Clausen J. The effect of sleep apnea on plasma and urinary catecholamines. Sleep 1995; 18: 377-81.
50. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993; 103: 1763-8.
51. Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation 1998; 98: 772-6.
52. Narkiewicz K, van de Borne PJ, Montano N, Dyken M, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 1998; 97: 943-5.
53. Parati G, Di Rienzo M, Bonsignore MR, et al. Autonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep. J Hypertens 1997; 15: 1621-6.
54. Narkiewicz K, Pesek CA, Kato M, Phillips BG, Davison DE, Somers VK. Baroreflex control of sympathetic activity and heart rate in obstructive sleep apnea. Hypertension 1998; 32: 1039-43.
55. Hedner J, Darpö B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J 1995; 8: 222-9.
56. Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999; 100: 2332-5.
57. Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98: 1071-7.
58. Singh JP, Larson MG, Tsuji H, Evans JC, O’Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension 1998; 32: 293-7.
59. Parati G, Di Rienzo M, Ulian L, et al. Clinical relevance blood pressure variability. J Hypertens 1998; 16: S25-S33.
60. Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res 1999; 7: 355-62.
61. Calhoun DA, Nishizaka MK, Zaman MA, Harding SM. Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea. Chest 2004; 125: 112-7.
62. Meston N, Davies RJ, Mullins R, Jenkinson C, Wass JA, Stradling JR. Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med 2003; 254: 447-54.
63. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007; 131: 453-9.
64. Follenius M, Krieger J, Krauth MO, Sforza F, Brandenberger G. Obstructive sleep apnea treatment: peripheral and central effects on plasma renin activity and aldosterone. Sleep 1991; 14: 211-7.
65. Mo/ller DS, Lind P, Strunge B, Pedersen EB. Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea. Am J Hypertens 2003; 16: 274-80.
66. Saarelainen S, Hasan J, Siitonen S, Seppälä E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 1996; 5: 181-5.
67. Palma BD, Gabriel A Jr, Bignotto M, Tufik S. Paradoxical sleep deprivation increases plasma endothelin levels. Braz J Med Biol Res 2002; 35: 75-9.
68. Kanagy NL, Walker BR, Nelin LD. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 2001; 37: 511-5.
69. Gjo/rup PH, Sadauskiene L, Wessels J, Nyvad O, Strunge B, Pedersen EB. Abnormally increased endothelin-1 in plasma during the night in obstructive sleep apnea: relation to blood pressure and severity of disease. Am J Hypertens 2007; 20: 44-52.
70. Jordan W, Reinbacher A, Cohrs S, Grunewald RW, Mayer G, Rüther E, Rodenbeck A. Obstructive sleep apnea: Plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure. Peptides 2005; 26: 1654-60.
71. Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G, Andreas S. Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J 2000; 15: 320-5.
72. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 1999; 17: 61-6.
73. Jordan W, Reinbacher A, Cohrs S, et al. Obstructive sleep apnea: Plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure. Peptides 2005; 26: 1654-60.
74. Carlson JT, Raa°ngemark C, Hedner JA. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens 1996; 14: 577-84.
75. Kraiczi H, Caidahl K, Samuelsson A, Peker Y, Hedner J. Impairment of vascular endothelial function and left ventricular filling. Association with the severity of apnea-induced hypoxemia during sleep. Chest 2001; 119: 1085-91.
76. Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000; 102: 2607-10.
77. Ohike Y, Kozaki K, Iijima K, et al. Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure. Possible involvement of nitric oxide and asymmetric NG,NG-Dimethylarginine. Circ J 2005; 69: 221-6.
78. Ali NJ, Davies RJ, Fleetham JA, Stradling JR. The acute effects of continuous positive airway pressure and oxygen administration on blood pressure during obstructive sleep apnea. Chest 1992; 101: 1526-32.
79. Wilcox I, Grunstein RR, Hedner JA, et al. Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep 1993; 16: 539-44.
80. Tkacova R, Logan AG, Leung RS, et al. Acute and chronic reduction of blood pressure by CPAP in patients with refractory hypertension and obstructive sleep apnea. Am J Hypertens 2000; 14 (Suppl 1): S63-S64.
81. Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007; 167: 757-64.
82. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359: 204-10.
83. Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003; 107: 68-73.
84. Börgel J, Sanner BM, Keskin F, et al. Obstructive sleep apnea and blood pressure. Interaction between the blood pressure-lowering effects of positive airway pressure therapy and antihypertensive drugs. Am J Hypertens 2004; 17: 1081-7.
85. Lies A, Nabe B, Pankow W, Kohl FV, Lohmann FW. Hypertension and obstructive sleep apnea. Ambulatory blood pressure monitoring before and with nCPAP-therapy. Z Kardiol 1996; 85 (Suppl 3): 140-2.
86. Akashiba T, Minemura H, Yamamoto H, Kosaka N, Saito O, Horie T. Nasal continuous positive airway pressure changes blood pressure "non-dippers" to "dippers" in patients with obstructive sleep apnea. Sleep 1999; 22: 849-53.
87. Barbé F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001; 134: 1015-23.
88. Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J 2006; 27: 1229-35.
89. Grote L, Hedner J, Grunstein R, Kraiczi H. Therapy with nCPAP: incomplete elimination of Sleep Related Breathing Disorder. Eur Respir J 2000; 16: 921-7.
APPENDIX
The Berlin Questionnaire (BQ)
High risk of OSA is determined by positive responses to at least 2 of the following 3 criteria:
1) symptoms at least 3 times per week for at least 2 snoring questions,
2) somnolence during daytime and/or while driving at least 3 times per week,
3) history of hypertension or BMI>30 kg/m2.
Additional information needed to be saved (gender, age, weight, height, neck circumference)
1. Has your weight changed in the last 5 years?
increased
decreased
no change
2. Do you snore?
yes
no
don’t know
If you snore:
3. Your snoring is
as loud as breathing
as loud as talking
louder than talking
very loud
4. How often do you snore?
nearly every day
3-4 times a week
1-2 times a week
1-2 times a month
never or nearly never
5. Does your snoring bother other people?
Yes
No
6. Has anyone noticed that you quit breathing during your sleep?
nearly every day
3-4 times a week
1-2 times a week
1-2 times a month
never or nearly never
7. How often do you feel tired or fatigued after your sleep?
nearly every day
3-4 times a week
1-2 times a week
1-2 times a month
never or nearly never
8. During your waking hours, do you feel tired or fatigued?
nearly every day
3-4 times a week
1-2 times a week
1-2 times a month
never or nearly never
9. Have you ever nodded off or fallen asleep while driving a vehicle?
yes
no
10. Do you have high blood pressure?
yes
no
don’t know
