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Vol. 45. Issue 12.
Pages 577-584 (December 2009)
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Vol. 45. Issue 12.
Pages 577-584 (December 2009)
Original article
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Long Term Effect of Autoadjusting Positive Airway Pressure on C-Reactive Protein and Interleukin-6 in Men With Obstructive Sleep Apnoea Syndrome
Efecto a largo plazo de la presión positiva automática en la vía aérea sobre la proteína C reactiva y la interleucina-6 en varones con síndrome de apnea obstructiva del sueño
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Marta Drummonda,
Corresponding author
marta.drummond@gmail.com

Corresponding author.
, João Wincka, João Guimarãesb, Ana C. Santosc, João Almeidaa, João Marquesa
a Departamento de Neumología, Hospital de João de Sao, Facultad de Medicina de Porto, Oporto, Portugal
b Departamento de Bioquímica y Patología Clínica, Hospital de João de Sao, Facultad de Medicina de Porto, Oporto, Portugal
c Departamento de Epidemiología e Higiene, Hospital de João de Sao, Facultad de Medicina de Porto, Oporto, Portugal
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Abstract
Background and objectives

Obstructive sleep apnoea (OSA) has been increasingly linked to cardiovascular disease. Inflammatory processes associated with OSA may contribute to this morbidity. Some studies have reported serum levels of high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) to be increased in these patients. Primary objective: investigate the impact of short and long-term autoadjusting positive airway pressure (APAP) therapy on IL-6 and hs-CRP serum levels in patients with moderate to severe obstructive sleep apnoea. Secundary Objective: evaluate the basal hs-CRP and IL-6 levels in OSA patients and its possible relation to OSA severity, independently of confounders and compare the hs-CRP levels in OSA patients with those in community controls.

Patients and methods

This is a prospective study including 98 male patients with moderate to severe OSA confirmed by domiciliary sleep study. Malignancy and chronic inflammatory diseases were exclusion criteria. hs-CRP and IL-6 serum levels were evaluated before APAP, 9 days and 6 months after therapy. Community controls (n=103) were selected using random digit dialling, and matched by age and body mass index (BMI) for comparison of hs-CRP levels at baseline.

Results

The studied population had a mean age of 55.3±10.7 years, mean BMI 33.2±5.0kg/m2, mean apnoeahypopnoea index 51.7±21.3/h and mean desaturation index 86.3±5.3/h. The APAP compliance was good: 91.27&%×000B1;20.45 days usage and 5.76±1.59h/night of usage.

Mean basal hs-CRP and IL-6 serum values were 0.52±0.53 μg/l and 17.7±22.5 μg/l, respectively. CRP levels at baseline correlated significantly with apnoea-hypopnoea index, desaturation index and minimum nocturnal oxygen saturation. IL-6 levels at baseline correlated significantly and negatively with minimum nocturnal oxygen saturation. When adjusting for confounding factors found in this study, all these relations lost significance.

CRP is significantly increased in patients when compared to controls (P=.002) and when considering hs-CRP cardiovascular risk stratified categories, cases had significantly more patients at high risk of cardiovascular events than controls (P=.002).

After adjustment for BMI and arterial hypertension, cases had an almost twofold moderate risk of cardiovascular events and more than a twofold severe risk of cardiovascular events when compared to controls.

We found no significant difference between hs-CRP and IL-6 concentrations pre-treatment and in two moments post-treatment (9 days and 6 months) (CRP: P=.720 and P=.387, respectively; IL-6: P=.266 and P=.238, respectively).

Conclusions

OSA is associated with a low-grade inflammatory process; hs-CRP serum levels are elevated in OSA patients when comparing to community controls, independently of age and BMI and the former have a significantly higher risk of cardiovascular events when compared to the latter. There was no significant decrease of both inflamatory mediators (hs-CRP, IL-6) after short and long-term APAP therapy.

Keywords:
Obstructive sleep apnoea
High sensitivity C- reactive protein
Interleukin-6
Resumen
Introducción

La apnea obstructiva del sueño (AOS) se ha vinculado de forma creciente con las enfermedades cardiovasculares. Los procesos inflamatorios asociados a la AOS pueden contribuir a esta morbilidad. Algunos estudios han señalado que las concentraciones séricas de proteína C reactiva de alta sensibilidad (PCR-as) y de interleucina-6 (IL-6) están aumentadas en estos pacientes. El objetivo principal del estudio has sido investigar la repercusión a corto y largo plazo del tratamiento de presión positiva automática en la vía aérea (APAP) sobre las concentraciones séricas de PCR-as e IL-6 en pacientes con AOS clasificada entre moderada y grave. Como objetivo secundario, nos propusimos evaluar las concentraciones basales de PCRas e IL-6 en los pacientes con AOS y su posible relación con la gravedad de dicho síndrome, independientemente de los factores de confusión, y comparar las concentraciones de PCR-as en los afectados de AOS con los de una población de control procedente de la comunidad.

Pacientes y métodos

Se trata de un estudio prospectivo que ha incluido a 98 pacientes varones con AOS de moderada a grave, confirmada mediante un estudio domiciliario del sueño. Las neoplasias malignas y las enfermedades inflamatorias crónicas fueron criterios de exclusión. Se evaluaron las concentraciones séricas de PCR-as y de IL-6 antes de la APAP, a los 9 días y a los 6 meses del tratamiento. Los controles de la comunidad (n=103), que se seleccionaron mediante llamadas telefónicas aleatorias, se emparejaron por edad e índice de masa corporal (IMC) con el grupo de pacientes con objeto de comparar las concentraciones de PCR-as al inicio del estudio.

Resultados

La población estudiada presentaba una media (± desviación estándar) de edad de 55,3±10,7 años, un IMC medio de 33,2±5,0kg/m2, un índice medio de apneas-hipopneas de 51,7±21,3/h y un índice de desaturación de 86,3±5,3/h. El cumplimiento del tratamiento con APAP fue bueno, con un uso de un 91,27±20,45% de los días y de 5,76±1,59h/noche.

Al inicio del estudio, los valores séricos medios de PCR-as e IL-6 fueron de 0,52±0,53 y 17,7±22,5 μg/l, respectivamente. Los de PCR-as se correlacionaban de forma significativa con el índice de apneas-hipopneas, el índice de desaturación y la saturación de oxígeno mínima durante la noche, y los de IL-6 estaban correlacionados de forma significativa y negativa con la saturación de oxígeno mínima durante la noche. Al ajustar por los factores de confusión encontrados en el estudio, todas estas relaciones perdieron significación. La PCR-as se encontraba significativamente elevada en los pacientes respecto a los controles (P=.002). Al considerar las categorías de estratificación del riesgo cardiovascular mediante la PCR-as, en el grupo de pacientes era significativamente mayor el número de personas con riesgo elevado de episodios cardiovasculares en comparación con el grupo control (P=.002).

Tras el ajuste por IMC e hipertensión arterial, el grupo de pacientes presentaba un riesgo moderado casi 2 veces superior y un riesgo importante más de 2 veces superior de desarrollar episodios cardiovasculares en comparación con el grupo de control.

No encontramos diferencias significativas entre las concentraciones de PCR-as e IL-6 antes del tratamiento y en los 2 períodos posteriores, es decir, a los 9 días y a los 6 meses (PCR: P=.720 y P=.387; IL-6: P=.266 y P=.238, respectivamente).

Conclusiones

La AOS está asociada con un proceso inflamatorio de bajo grado. Las concentraciones séricas de PCR-as se encuentran elevadas en los pacientes con AOS al compararlas con las de un grupo de control procedente de la comunidad, independientemente de la edad y del IMC. Además, el grupo de pacientes presentaba un riesgo significativamente mayor de desarrollar episodios cardiovasculares que el de control. No se observó una disminución significativa de las concentraciones de los mediadores inflamatorios (PCRas e IL-6) tras el tratamiento de APAP a corto ni a largo plazo.

Palabras clave:
Proteína C reactiva de alta sensibilidad
Interleucina-6
Apnea obstructiva del sueño
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References
[1.]
T. Young, M. Palta, J. Dempsey, J. Skatrud, S. Weber, S. Badr.
The occurrence of sleepdisordered breathing among middle-aged adults.
N Engl J Med, 328 (1993), pp. 1230-1235
[2.]
E. Shahar, C.W. Whitney, S. Redline, E.T. Lee, A.B. Newman, F.J. Nieto, et al.
Sleepdisordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health.
Am J Respir Crit Care Med, 163 (2001), pp. 19-25
[3.]
R.S. Leung, T.D. Bradley.
Sleep Apnea and cardiovascular disease.
Am J Respir Crit Care Med, 164 (2001), pp. 2147-2165
[4.]
A.B. Newman, F.J. Nieto, U. Guidry, B.K. Lind, S. Redline, T.J. Pickering, et al.
Relation of sleep-disordered breathing to cardiovascular disease risk factors: The Sleep Heart Health Study.
Am J Epidemiol, 154 (2001), pp. 50-59
[5.]
V.K. Somers, M.E. Dyken, M.P. Clary, F.M. Abboud.
Sympathetic neural mechanisms in obstructive sleep apnea.
J Clin Invest, 96 (1995), pp. 1897-1904
[6.]
A.N. Vgontzas, D.A. Papanicolaou, E.O. Bixler, A. Kales, K. Tyson, G.P. Chrousos.
Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.
J Clin Endocrinol Metab, 82 (1997), pp. 1313-1316
[7.]
H. Liu, J. Liu, S. Xiong, G. Shen, Z. Zhang, Y. Xu.
The change of interleukin-6 and tumor necrosis factor in patients with obstructive sleep apnea syndrome.
J Tongji Med Univ, 20 (2000), pp. 200-202
[8.]
A.N. Vgontzas, D.A. Papanicolaou, E.O. Bixler, K. Hopper, A. Lotsikas, H. Lin, et al.
Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.
J Clin Endocrinol Metab, 85 (2000), pp. 1151-1158
[9.]
T. Yokoe, K. Minoguchi, H. Matsuo, N. Oda, H. Minoguchi, G. Yoshino, et al.
Elevated levels of C-Reactive Protein and Interleukin-6 in patients with Obstructive Sleep Apnea Syndrome are decreased by Nasal Continuous Positive Airway Pressure.
Circulation, 107 (2003), pp. 1129-1134
[10.]
A.S.M. Shamsuzzaman, M. Winnicki, P. Lanfranchi, R. Wolk, T. Kara, V. Accurso, V.K. Somers.
Elevated C-Reactive Protein in patients with Obstructive Sleep Apnea.
Circulation, 105 (2002), pp. 2462-2464
[11.]
O. Kokturk, T.U. Ciftci, E. Mollarecep, B. Ciftci.
Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome.
Int Heart J, 46 (2005), pp. 801-809
[12.]
A. Barceló, F. Barbé, E. Llompart, L.R. Mayoralas, A. Ladaria, M. Bosch, et al.
Effects of obesity on C-reactive protein level and metabolic disturbances in male patients with obstructive sleep apnea.
Am J Respir Crit Care Med, 117 (2004), pp. 118-121
[13.]
C. Guilleminault, C. Kirisoglu, M.M. Ohayon.
C-reactive protein and sleep-disordered breathing.
Sleep, 27 (2004), pp. 1507-1511
[14.]
J.S. Yudkin, M. kumari, S.E. Humphries, V. Mohamed-Ali.
Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?.
Atherosclerosis, 148 (2000), pp. 209-214
[15.]
T.B. Harris, L. Ferruci, R.P. Tracy, M.C. Corti, S. Wacholder, W.H. Ettinger Jr, et al.
Association of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.
Am J Med, 106 (1999), pp. 506-512
[16.]
P. Pasulka, B.R. Bristian, G.L. Blackburn.
Obesity and erythrocyte sedimentation rates.
Ann Intern Med, 103 (1985), pp. 304
[17.]
L. Roytblat, M. Rachinsky, A. Fisher, L. Greemberg, Y. Shapira, A. Douvdevani, et al.
Raised interleukin-6 levels in obese patients.
Obes Res, 8 (2000), pp. 673-675
[18.]
H.K. Meier-Ewert, P.M. Ridker, N. Rifai, N. Price, D.F. Dinges, J.M. Mullington.
Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects.
Clin Chem, 47 (2001), pp. 426-430
[19.]
B. Lindhal, H. Toss, A. Siegbahn, P. Venge, L. Wallentin.
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary heart disease. FRISC Study Group.
N Engl J Med, 343 (2000), pp. 1139-1147
[20.]
P.M. Ridker, N. Rifai, M.A. Pfeffer, F. Sacks, E. Braunwald.
Long term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators.
Circulation, 100 (1999), pp. 230-235
[21.]
P.M. Ridker.
Clinical Application of C-Reactive Protein for Cardiovascular Disease Detection and Prevention.
Circulation, 107 (2003), pp. 363-369
[22.]
J. Danesh, P. Whincup, M. Walker, L. Lennon, A. Thomson, P. Appleby, et al.
Low grade inflammation and coronary heart disease: prospective study and updated metaanalysis.
BMJ, 321 (2000), pp. 199-204
[23.]
I. Jialal, S. Devaraj, S.K. Venugopal.
C-reactive protein: risk marker or mediator in atherothrombosis?.
[24.]
P. Calabro, J.T. Willerson, E.T. Yeh.
Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells.
Circulation, 108 (2003), pp. 1930-1932
[25.]
S. Devaraj, D.Y. Xu, I. Jialal.
C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis.
Circulation, 107 (2003), pp. 398-404
[26.]
K.H. Han, K.H. Hong, J.H. Park, J. Ko, D.H. Kang, K.J. Choi, et al.
C-reactive protein promotes monocyte chemoattractant protein-I-mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes.
Circulation, 109 (2004), pp. 2566-2571
[27.]
S. Fichlscherer, S. Breuer, V. Schachinger, S. Dimmeler, A.M. Zeiher.
C-reactive protein levels determine systemic nitric oxide bioavailability in patients with coronary artery disease.
Eur Heart J, 25 (2004), pp. 1412-1418
[28.]
G. Hartmann, M. Tschop, R. Fischer, C. Bidlingmaier, R. Riepl, K. Tschöp, et al.
High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-Reactive Protein.
Cytokine, 12 (2000), pp. 246-252
[29.]
R. Tauman, A. Ivanenko, L.M. O’Brien, D. Gozal.
Plasma C-Reactive Protein levels among children with sleep-disordered breathing.
Pediatrics, 113 (2004), pp. e.564-e.569
[30.]
C.E. Sullivan, F.G. Issa, M. Berthon-Jones, L. Eves.
Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares.
Lancet, 1 (1981), pp. 862-865
[31.]
T. Giles, T. Lasserson, B.J. Smith, J. White, J. Wright, C.J. Cates.
Continuous positive airways pressure for obstructive leep apnoea in adults.
Cochrane Database Syst Rev, 1 (2006),
[32.]
Y. Peker, J. Hedner, J. Norum, H. Kraiczi, J. Carlson.
Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7 year follow-up.
Am J Respir Crit Care Med, 166 (2002), pp. 159-165
[33.]
O. Milleron, R. Pilliere, A. Foucher, F. de Roquefeuil, P. Aegerter, G. Jondeau, et al.
Benefits of obstructive sleep apnoea treatment in coronary artery disease: a longterm follow-up study.
Eur Heart, 25 (2004), pp. 728-734
[34.]
M.A. Arias, F. García-Río, A. Alonso-Fernández, A. Hernanz, R. Hidalgo, V. Martínez- Mateo, et al.
CPAP decreases plasma levels of soluble tumour necrosis factor-· receptor 1 in obstructive sleep apnoea.
Eur Respir J, 32 (2008), pp. 1009-1015
[35.]
Y. Nussbaumer, K.E. Block, T. Genser, R. Thurneer.
Equivalence of autoadjusted and constant continuous positive airway pressure in home treatment of sleep apnea.
Chest, 129 (2006), pp. 638-643
[36.]
C.A. Massie, N. McArdle, R.W. Hart, W.W. Schmidt-Nowara, A. Lankford, D.W. Hudgel, et al.
Comparison between automatic and fixed positive airway pressure therapy in the home.
Am J Respir Crit Care Med, 167 (2003), pp. 20-23
[37.]
J.R. Stradling.
Reducing the cost of treating obstructive sleep apnoea: good news for the patients.
Am J Respir Crit Care Med, 170 (2004), pp. 1143-1144
[38.]
V. Patruno, S. Aiolfi, G. Costantino, R. Murgia, C. Selmi, A. Malliani, et al.
Fixed and autoadjusting continuous positive airway pressure treatments are not similar in reducing cardiovascular risk factors in patients with obstructive sleep apnea.
Chest, 131 (2007), pp. 1393-1399
[39.]
E. Ramos, C. Lopes, H. Barros.
Investigating the effect of nonparticipation using a population-based case-control study on myocardial infarction.
Ann Epidemiol, 14 (2004), pp. 437-441
[40.]
M. Folstein, S. Folstein, P. Mchush.
“Mini mental state”. A pratical method for grading the cognitive state of patients for the clinician.
J Psych Res, 12 (1975), pp. 189-198
[41.]
E. García-Díaz, E. Quintana-Gallego, A. Ruiz, C. Carmona-Bernal, A. Sanchéz-Armengol, G. Botebol-Benhamou, et al.
Respiratory Poligraphy with actigraphy in the diagnosis of Sleep Apnea-Hypopnea Syndrome.
Chest, 131 (2007), pp. 725-732
[42.]
The report of an American Academy of Sleep Medicine Task Force.
Sleep- related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. 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, 22 (1999), pp. 667-689
[43.]
G.A. Bray.
Pathophysiology of obesity.
Am J Clin Nutr, 55 (1992), pp. 4883-4943
[44.]
G. Mancia, G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, et al.
New European Guidelines on Treatment of Hypertension.
J Hypertens, 25 (2007), pp. 1751-1762
[45.]
American Diabetes Association.
Diagnosis and Classification of Diabetes mellitus.
Diabetes Care, 31 (2008), pp. S55-60
[46.]
S.M. Grundy, H.B. Brewer Jr, J.I. Cleeman, S.C. Smith Jr, C. Lenfant, American Heart Association; National Heart, Lung, and Blood Institute.
Definition of Metabolic Syndrome: Report of the National Heart, Lung and Blood Institute/ American Heart Association Conference on Scientific Issues Related to Definition.
Circulation, 109 (2004), pp. 433-438
[47.]
P.M. Ridker.
High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease.
Circulation, 103 (2001), pp. 1813-1818
[48.]
M.A. Albert, E. Danielson, N. Rifai, P.M. Ridker, PRINCE Investigators.
Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study.
JAMA, 286 (2001), pp. 64-70
[49.]
V. Pasceri, J.S. Cheng, J.T. Willerson, E.T. Yeh.
Modulation of C-reactive proteinmediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs.
Circulation, 103 (2001), pp. 2531-2534
[50.]
T. Nakajima, S. Schulte, K.J. Warrington, S.L. Kopecky, R.L. Frye, J.J. Goronzy, et al.
T-cell mediated lysis of endothelial cells in acute coronary syndromes.
Circulation, 105 (2002), pp. 570-575
[51.]
T. Ahashiba, T. Akahoshi, S. Kawahara, T. Majima, T. Horie.
Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome.
Intern Med, 44 (2005), pp. 899-900
[52.]
S. Ryan, G. Nolan, E. Hannigan, S. Cunningham, C. Taylor, W.T. McNicholas.
Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity.
Thorax, 62 (2007), pp. 509-514
[53.]
W.L. Biffl, E.E. Moore, F.A. Moore, V.M. Peterson.
Interleukin-6 in the injured patient.
Ann Surg, 224 (1996), pp. 647-664
[54.]
N.A. Vgontzas, E. Zoumakis, M. Lin H-, E.O. Bixler, G. Trakada, G.P. Chrousos.
Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-· antagonist.
J Clin endocrinol Metab, 89 (2004), pp. 4409-4413
[55.]
A.N. Vgontzas, E. Zoumakis, E.O. Bixler, H.M. Lin, B. Collins, M. Basta, et al.
Selective effects of CPAP on sleep apnoea-associated manifestations.
Eur J Clin Invest, (2008),
[56.]
J.K. Plenge, T.L. Hernandez, K.M. Weil, P. Poirier, G.K. Grunwald, S.M. Marcovina, et al.
Sinvastatin lowers C-reactive protein within 14 days. An effect independent of low-density lipoprotein cholesterol reduction.
Circulation, 106 (2002), pp. 1447-1452
[57.]
S.K. Sharma, H.K. Mishra, H. Sharma, A. Goel, V. Sreenivas, V. Glati, et al.
Obesity, and not obstructive sleep apnea, is responsible for increased serum hs-CRP levels in patients with sleep disordered breathing in Delhi.
Sleep Med, 9 (2008), pp. 149-156
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