Obstruktive Schlaf-Apnoe und kardiovaskuläre Erkrankungen - Hypothese pathophysiologischer Zusammenhänge

Einleitung

Kardiovaskuläre Erkrankungen bei obstruktiver Schlaf-Apnoe (OSA) sind in den Mittelpunkt des Interesses gerückt, da hierauf im allgemeinen die erhöhte Mortalität unbehandelter OSA-Patienten zurückgeführt wird [1] [2]. Der kausale Zusammenhang zwischen kardiovaskulären Erkrankungen und OSA wird jedoch von vielen Autoren immer noch angezweifelt [3] [4]. Angeführt wird in diesem Zusammenhang vor allem, dass OSA-Patienten häufig an weiteren Erkrankungen leiden, die per se das kardiovaskuläre Risiko erhöhen können (z. B. Adipositas, Diabetes mellitus, Hyperlipidämie).

Quasi in Antwort auf diese Kritik sind in den letzten Jahren mehrere Arbeiten publiziert worden, die einen direkten Zusammenhang zwischen OSA und kardiovaskulären Erkrankungen immer wahrscheinlicher machen. Diese Arbeiten haben einerseits einen epidemiologischen Ansatz verfolgt (Übersicht z. B. bei [5]), andererseits wächst aber auch das Verständnis für den pathophysiologischen Zusammenhang von OSA und kardiovaskulären Erkrankungen auf der biochemischen bzw. zellbiologischen Ebene. Ziel der vorliegenden Übersichtsarbeit ist es, den letzteren Aspekt detaillierter darzustellen.

Literatur

• 1 Hedner J, Grote L. Cardiovascular consequences of obstructive sleep apnoea.  Eur Respir Mon. 1998;  10 227-265
• 2 Weiss J W, Launois S, Anand A, Garpestad E. Cardiovascular morbidity in obstructive sleep apnea.  Progr Cardiovasc Dis. 1999;  41 367-376
• 3 Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence.  BMJ. 1997;  314 851-860
• 4 Stradling J, Davies R JO. Sleep apnea and hypertension - what a mess!.  Sleep. 1997;  20 789-793
• 5 Young T, Peppard P. Sleep-disordered breathing and cardiovascular disease: epidemiologic evidence for a relationship.  Sleep. 2000;  23 S122-S126
• 6 Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing.  Bull Eur Physiopathol Respir. 1972;  8 1159-1172
• 7 Guilleminault C, Connolly S J, Winkle R A. Cardiac arrhythmias and conduction disturbances during sleep in 400 patients with sleep apnea syndrome.  Am J Cardiol. 1983;  52 490-494
• 8 Flemons W W, Remmers J E, Gillis A M. Sleep apnea and cardiac arrhythmias. Is there a relationship?.  Am Rev Respir Dis. 1993;  148 618-621
• 9 Guilleminault C, Conolly S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome. Mechanisms, and usefulness of 24 h electrocardiography as a screening technique.  Lancet. 1984;  1 (8369) 126-131
• 10 Becker H F, Koehler U, Stammnitz A, Peter J H. Heart block in patients with sleep apnoea.  Thorax. 1998;  53 S29-32
• 11 Shepard J W, Garrison M W, Grither D A, Dolan G F. Relationship of ventricular ectopy to oxyhemoglobin desaturation in patients with obstructive sleep apnea.  Chest. 1985;  88 335-340
• 12 Bonsignore M R, Marrone O, Insalaco G, Bonsignore G. The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenic mechanisms.  Eur Respir J. 1994;  7 786-805
• 13 Carlson J, Hedner J, Ejnell H, Peterson L. High prevalence of hypertension in sleep apnea patients independent of obesity.  Am J Respir Crit Care Med. 1994;  150 72-77
• 14 Olson L G, King M T, Hensley M J, Saunders N A. A community of snoring and sleep-disordered breathing. Health outcomes.  Am J Respir Crit Care Med. 1995;  152 717-720
• 15 Young T, Peppard P, Palta M, Hla M, Finn L, Morgan B, Skatrud J. Population-based study of sleep-disordered breathing as a risk factor for hypertension.  Arch Intern Med. 1997;  157 1746-1752
• 16 Peppard P E, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension.  N Engl Med. 2000;  342 1378-1384
• 17 Nieto F J, Young T B, Lind B K, Shahar E, Samet J M, Redline S, D'Agostino R B, Newman A B, Lebowitz M D, Pickering T G. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study.  JAMA. 2000;  283 1829-1836
• 18 Kessler R, Chaouat A, Weitzenblum E, Oswald M, Ehrhart M, Apprill M, Krieger J. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.  Eur Respir J. 1996;  9 787-794
• 19 Steiner S, Perings C. Pulmonalarterielle Hypertonie und Cor pulmonale bei obstruktiver Schlafapnoe.  Internist. 1999;  40 739-746
• 20 Maekawa M, Shiomi T, Usui K, Sasanabe R, Kobayashi T. Prevalence of ischemic heart disease among patients with sleep apnea syndrome.  Psychiatry Clin Neurosci. 1998;  52 219-220
• 21 Schulz R, Olschewski H, Grimminger F, Seeger W. Prävalenz von Schlaganfall und transitorischer ischämischer Attacke (TIA) bei obstruktiver Schlaf-Apnoe: eine retrospektive Erhebung an 187 konsekutiven Patienten.  Pneumologie. 2000;  54 575-579
• 22 Hung J, Whitford E G, Parsons R W, Hillmann D R. Association of sleep apnea with myocardial infarction in men.  Lancet. 1990;  336 261-264
• 23 Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients.  Chest. 1990;  97 27-32
• 24 Shahar E, Whitney C W, Redline S, Lee E T, Newman A B, Nieto F J, O'Connor G T, Boland L L, Schwartz J E, Samet J M. 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
• 25 Carlson J T, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin B G. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea.  Chest. 1993;  103 1763-1768
• 26 Somers V K, Dyken M E, Clary M P, Abboud F M. Sympathetic neural mechanisms in obstructive sleep apnea.  J Clin Invest. 1995;  96 1897-1904
• 27 Narkiewicz K, van de Borne P J, Cooley R L, Dyken M E, Somers V K. Sympathetic activity in obese subjects with and without obstructive sleep apnea.  Circulation. 1998;  98 772-776
• 28 Hedner J, Darpo 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;  8 222-229
• 29 Waradekar N V, Sinoway L I, Zwillich C W, Leuenberger U A. Influence of treatment on muscle sympathetic nerve activity in sleep apnea.  Am J Respir Crit Care Med. 1996;  153 1333-1338
• 30 Carlson J T, Rangemark C, Hedner J A. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea.  J Hypertens. 1996;  14 577-584
• 31 Duchna H W, Guilleminault C, Stoohs R A, Faul J L, Moreno H, Hoffmann B B, Blaschke T F. Vascular reactivity in obstructive sleep apnea syndrome.  Am J Respir Crit Care Med. 2000;  161 187-191
• 32 Kato M, Roberts-Thomson P, Phillips B G, Haynes W G, Winnicki M, Accurso V, Somers V K. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea.  Circulation. 2000;  102 2607-2610
• 33 Schulz R, Schmidt D, Mayer K, Blum A, Olschewski H, Grimminger F, Seeger W. Plasma levels of NOx in obstructive sleep apnea before and after CPAP therapy.  Am J Respir Crit Care Med. 1998;  157 A777
• 34 Schulz R, Schmidt D, Blum A, Lopes-Ribeiro X, Lücke C, Mayer K, Olschewski H, Seeger W, Grimminger F. Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy.  Thorax. 2000;  55 1046-1051
• 35 Ip M S, Lam B, Chan L Y, Zheng L, Tsang F W, Fung P C, Lam W K. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure.  Am J Respir Crit Care Med. 2000;  162 2166-2171
• 36 Saarelainen S, Seppala E, Laasonen K, Hasan J. Circulating endothelin-1 in obstructive sleep apnea.  Endothelium. 1997;  5 115-118
• 37 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;  15 320-325
• 38 Krieger J, Benzoni D, Sforza E, Saasard J. Urinary excretion of prostanoids during sleep in obstructive sleep apnoea patients.  Clin Exp Pharmacol Physiol. 1991;  18 551-555
• 39 Kimura H, Niijima M, Abe Y, Edo H, Sakabe H, Kojima A, Hasako K, Masuyama S, Tatsumi K, Kuriyama T. Compensatory excretion of prostacyclin and thromboxane metabolites in obstructive sleep apnea syndrome.  Intern Med. 1998;  37 127-133
• 40 Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger F. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy.  Am J Respir Crit Care Med. 2000;  162 566-570
• 41 Fletcher E C. Hypertension in patients with sleep apnoea, a combined effect?.  Thorax. 2000;  55 726-728
• 42 Wali S O, Bahammam A S, Massaeli H, Pierce G N, Iliskovic N, Singal P K, Kryger M H. Susceptibility of LDL to oxidative stress in obstructive sleep apnea.  Sleep. 1998;  21 290-296
• 43 Barcelo A, Miralles C, Barbe F, Vila M, Pons S, Agusti A GN. Abnormal lipid peroxidation in patients with sleep apnoea.  Eur Respir J. 2000;  16 644-647
• 44 Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, Ouchi Y. Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome.  J Appl Physiol. 1999;  87 10-14
• 45 Chin K, Nakamura T, Shimizu K, Mishima M, Nakamura T, Miyasaka M, Ohi M. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome.  Am J Med. 2000;  109 562-567
• 46 Entzian P, Linnemann K, Schlaak M, Zabel P. Obstructive sleep apnea syndrome and circadian rhythms of hormones and cytokines.  Am J Respir Crit Care Med. 1996;  153 1080-1086
• 47 Vgontzas A N, Papanicolaou D A, Bixler E O, Kales A, Tyson K, Chrousos G P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.  J Clin Endocrinol Metab. 1997;  82 1313-1316
• 48 Vgontzas A N, Papanicolaou D A, Bixler E O, Hopper K, Lotsikas A, Lin H M, Kales A, Chrousos G P. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance and hypercytokinemia.  J Clin Endocrinol Metab. 2000;  85 1151-1158
• 49 Krieger J, Sforza E, Barthelmebs M, Imbs J L, Kurtz D. Overnight decrease in hematocrit after nasal CPAP treatment in patients with OSA.  Chest. 1990;  97 729-730
• 50 Krieger J, Sforza E, Delanoe C, Petiau C. Decrease in hematocrit with continuous positive airway pressure treatment in obstructive sleep apnea patients.  Eur Respir J. 1992;  5 228-233
• 51 Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure.  Chest. 1995;  108 625-630
• 52 Eisensehr I, Ehrenberg B L, Noachtar S, Korbett K, Byrne A, McAuley A, Palabrica T. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome.  Neurology. 1998;  51 188-195
• 53 Sanner B M, Konermann M, Tepel M, Groetz J,  Mummenhoff, Zidek W. Platelet function in patients with obstructive sleep apnoea syndrome.  Eur Respir J. 2000;  16 648-652
• 54 Chin K, Ohi M, Kita H, Noguchi T, Otsuka N, Tsuboi T, Mishima M, Kuno K. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome.  Am J Respir Crit Care Med. 1996;  153 1972-1976
• 55 Wessendorf T E, Thilmann A F, Wang Y M, Schreiber A, Konietzko N, Teschler H. Fibrinogen levels and obstructive sleep apnea in ischemic stroke.  Am J Respir Crit Care Med. 2000;  162 2039-2042
• 56 Rangemark C, Hedner J A, Carlson J T, Gleerup G, Winther K. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients.  Sleep. 1995;  18 188-194
• 57 Chin K, Kita H, Noguchi T, Otsuka N, Tsuboi T, Nakamura T, Shimizu K, Mishima M, Ohi M. Improvement of factor VII clotting activity following long-term NCPAP treatment in obstructive sleep apnoea syndrome.  QJM. 1998;  91 627-633
• 58 Grote L, Kraiczi H, Hedner J. Reduced alpha- and β₂-adrenergic vascular response in patients with obstructive sleep apnea.  Am J Respir Crit Care Med. 2000;  162 1480-1487
• 59 Follenius M, Krieger J, Krauth M O, Sforza F, Brandenberger G. Obstructive sleep apnea treatment: peripheral and central effects on plasma renin activity and aldosterone.  Sleep. 1991;  14 211-217
• 60 Saarelainen S, Hasan J, Siitonen S, Seppala E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea.  J Sleep Res. 1996;  5 181-185
• 61 Rodenstein D O, D'Odemont J P, Pieters T, Aubert-Tulkens G. Diurnal and nocturnal diuresis and natriuresis in obstructive sleep apnea. Effects of nasal continuous positive airway pressure therapy.  Am Rev Respir Dis. 1992;  145 1367-1371
• 62 Ichioka M, Hirata Y, Inase N, Tojo N, Yoshizawa M, Chida M, Miyazato I, Taniai S, Marumo F. Changes of circulating atrial natriuretic peptide and antidiuretic hormone in obstructive sleep apnea syndrome.  Respiration. 1992;  59 164-168
• 63 Baruzzi A, Riva R, Cirignotta F, Zucconi M, Cappelli M, Lugaresi E. Atrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome.  Sleep. 1991;  14 83-86
• 64 Krieger J, Laks L, Wilcox I, Grunstein R R, Costas L J, McDougall J G, Sullivan C E. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure.  Clin Sci. 1989;  77 407-411
• 65 Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor (VEGF) are elevated in patients with obstructive sleep apnea and severe night-time hypoxia. Submitted
• 66 Dean R T, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnea.  Sleep. 1993;  16 S15-22
• 67 Kourembanas S, Morita T, Christou H, Liu Y, Koike H, Brodsky D, Arthur V, Mitsial S A. Hypoxic responses of vascular cells.  Chest. 1998;  114 25S-28S
• 68 Kourembanas S, Morita T, Liu Y, Christou H. Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature.  Kidney Int. 1997;  51 438-443
• 69 Faller D V. Endothelial cell responses to hypoxic stress.  Clin Exp Pharmacol Physiol. 1999;  26 74-84
• 70 Ballermann B J, Dardik A, Eng E, Liu A. Shear stress and the endothelium.  Kidney Int. 1998;  67 S100-S108
• 71 Resnick N, Gimbrone Jr M A. Hemodynamic forces are complex regulators of endothelial gene expression.  FASEB J. 1995;  9 874-882
• 72 Chien S, Li S, Shyy Y J. Effects of mechanical forces on signal transduction and gene expression in endothelial cells.  Hypertension. 1998;  31 162-169
• 73 Resnick N, Yahav H, Khachigian L M, Collins T, Anderson K R, Dewey F C, Gimbrone Jr M A. Endothelial gene regulation by laminar shear stress.  Adv Exp Med Biol. 1997;  430 155-164
• 74 Semenza G L, Agani F, Iyer N, Jiang B H, Leung S, Wiener C, Yu A. Hypoxia-inducible factor 1. From molecular biology to cardiopulmonary physiology.  Chest. 1998;  114 40S-45S
• 75 Semenza G L, Agani F, Feldser D, Iyer N, Kotch L, Laughner E, Yu A. Hypoxia, HIF-1 and the pathophysiology of common human diseases.  Adv Exp Med Biol. 2000;  475 123-130
• 76 He J, Kryger M H, Zorick F J, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients.  Chest. 1988;  94 9-14
• 77 Partinen M, Jamieson A, Guilleminault C. Long term outcome for obstructive sleep apnea syndrome patients; mortality.  Chest. 1988;  94 1200-1204
• 78 Peker Y, Hedner J, Johansson A, Bende M. Reduced hospitalization with cardiovascular and pulmonary disease in obstructive sleep apnea patients on nasal CPAP treatment.  Sleep. 1997;  20 645-653

1