Background: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). Objectives: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). Methods: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). Results: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. Conclusions: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

1.
Heart disease and stroke statistics: Update. 2005. American Heart Association.
2.
Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269–1276.
3.
Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W: The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. I. Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation 2006;114:2850–2870.
4.
Zaninotto P, Mindell J, Hirani V: Prevalence of cardiovascular risk factors among ethnic groups: results from the Health Surveys for England. Atherosclerosis 2007;195:e48–e57.
5.
Smith SC Jr: Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med 2007;120(suppl 1):S3–S11.
6.
Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino R, Newman AB, Lebowitz MD, Pickering TG: Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;283:1829–1836.
7.
Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J: Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea. Am J Respir Crit Care Med 2005;166:159–165.
8.
Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto J, O´Connor GT, Boland LL, Schwartz JE, Samet JM: Sleep-disordered breathing and cardiovascular disease. Am J Respir Crit Care Med 2001;163:19–25.
9.
Peppard P, Young T, Palta M, Skatrud J: Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384.
10.
Marin JM, Carrizo SJ, Vicente E, Agusti AGN: Long-term cardiovascular outcomes in men with obstructive sleep apnea. Effects of treatment with CPAP. Lancet 2005;365:1046–1053.
11.
Dincer HE, O’Neill W: Deleterious effects of sleep-disordered breathing on the heart and vascular system. Respiration 2006;73:124–130.
12.
McNicholas WT, Bonsignore MR: Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156–178.
13.
Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi-Filho G: Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:613–618.
14.
de la Peña M, Barcelo A, Barbe F, Pierola J, Pons J, Rimbau E, Ayllon O, Agusti AG: Endothelial function and circulating endothelial progenitor cells in patients with sleep apnea syndrome. Respiration 2008;76:28–32.
15.
Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VK: Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607–2610.
16.
Ip MSM, Tse HF, Lam B, Tsang KWT, Lam WK: Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348–353.
17.
Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR, Sinoway LI, Leuenberger UA: Impaired vasodilator responses in obstructive sleep apnea improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med 2002;165:950–953.
18.
Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012.
19.
Cohen RA: The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 1995;38:105–128.
20.
Boger RH, Vallance P, Cooke JP: Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atheroscler Suppl 2003;4:1–3.
21.
Vallance P, Leiper J: Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004;24:1023–1030.
22.
Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP: Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998;98:1842–1847.
23.
Boger RH, Maas R, Schulze F, Schwedhelm E: Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality. Clin Chem Lab Med 2005;43:1124–1129.
24.
Schulze F, Lenzen H, Hanefeld C, Bartling A, Osterziel KJ, Goudeva L, Schmidt-Lucke C, Kusus M, Maas R, Schwedhelm E, Strodter D, Simon BC, Mugge A, Daniel WG, Tillmanns H, Maisch B, Streichert T, Boger RH: Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination Investigating the Influence of ADMA Concentration (CARDIAC) study. Am Heart J 2006;152:493–498.
25.
Ip MSM, Lam B, Chan LY, Zheng L, Tsang KWT, Fung PCW, Lam WK: 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.
26.
Ohike Y, Kozaki K, Iijima K, Eto M, Kojima T, Ohga E, Santa T, Imai K, Hashimoto M, Yoshizumi M, Ouchi Y: 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;69:221–226.
27.
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415.
28.
Touyz RM, Schiffrin EL: Role of endothelin in human hypertension. Can J Physiol Pharmacol 2003;81:533–541.
29.
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.
30.
Jordan W, Reinbacher A, Cohrs S, Grunewald RW, Mayer G, Ruther 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;26:1654–1660.
31.
Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S: New markers of inflammation and endothelial cell activation. Part I. Circulation 2003;108:1917–1923.
32.
Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR: Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002;106:896–899.
33.
Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, Simoons ML: Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348:1104–1111.
34.
Kobayashi K, Nishimura Y, Shimada T, Yoshimura S, Funada Y, Satouchi M, Yokoyama M: Effect of continuous positive airway pressure on soluble CD40 ligand in patients with obstructive sleep apnea syndrome. Chest 2006;129:632–637.
35.
Cooke JP, Dzau VJ: Derangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular diseases. Circulation 1997;96:379–382.
36.
Cooke JP, Dzau VJ: Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997;48:489–509.
37.
Busse R, Fleming I: Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 1995;27:331–340.
38.
Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T: Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999;99:1141–1146.
39.
Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ: Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995;346:467–471.
40.
Celermajer DS: Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 1997;30:325–333.
41.
Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini F, Bosello O, Lechi A: Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity. Int J Obes Relat Metab Disord 1999;23:936–942.
42.
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;17:61–66.
43.
Saarelainen S, Hasan J: Circulating endothelin-1 and obstructive sleep apnoea. Eur Respir J 2000;16:794–795.
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