obstructive sleep apnea and inflammation

Obstructive Sleep Apnea and Inflammation

Walter T. McNicholas

The pathogenesis of cardiovascular complicationsin obstructive sleep apnea syndrome (OSAS) is notfully understood but is likely multifactorial in origin.Inflammatory processes play an important role inthe pathogenesis of atherosclerosis, and circulatinglevels of several markers of inflammation have beenassociated with future cardiovascular risk. Theseinclude cell adhesion molecules such as intercel-lular adhesion molecule-1 and selectins, cytokinessuch as tumour necrosis factor α and interleukin 6,chemokines such as interleukin 8, and C-reactiveprotein. There is also increasing evidence thatinflammatory processes play an important role inthe cardiovascular pathophysiology of OSAS andmany of the inflammatory markers associated withcardiovascular risk have been reported as elevatedin patients with OSAS. Furthermore, animal and cellculture studies have demonstrated preferentialactivation of inflammatory pathways by intermittenthypoxia, which is an integral feature of OSAS. Theprecise role of inflammation in the development ofcardiovascular disease in OSAS requires furtherstudy, particularly the relationship with oxidativestress, metabolic dysfunction, and obesity.© 2009 Elsevier Inc. All rights reserved.

O bstructive sleep apnea syndrome (OSAS) is ahighly prevalent disorder affecting at least

4% of adult males and 2% of adult females andcharacterized by repetitive episodes of upperairway obstruction during sleep with associated

From the Sleep Research Laboratory, St. Vincent'sUniversity Hospital, Dublin, Ireland, and School oMedicine and Medical Science, The Conway InstituteUniversity College Dublin, Dublin, Ireland.

Address reprint requests to Walter T. McNicholas, MDFRCPI, FRCPC, FCCP, Department of RespiratoryMedicine, St. Vincent's University Hospital, Elm ParkDublin 4, Ireland. E-mail: [email protected]

0033-0620/$ - see front matter© 2009 Elsevier Inc. All rights reserved.doi:10.1016/j.pcad.2008.10.005

Progress in Cardiov392

f,

,

,

ascula

intermittent hypoxemia.1 Recent clinical evidencehas demonstrated OSAS to be a major indepen-dent risk factor for cardiovascular disease,2 butthe mechanisms underlying this association areunclear. Furthermore, confounding variables suchas obesity, hypertension, smoking, alcohol intake,age, and level of exercise make this independentrelationship difficult to prove.3 However, recentlarge-scale cross-sectional studies have yieldedconvincing evidence of a modest, but definiteassociation between OSAS and cardiovasculardisease, independent of possible confoundingfactors such as age, sex, and obesity. Both theSleep Heart Health Study, which included morethan 6000 participants, and the Wisconsin SleepCohort study of 1069 employed subjects identi-fied an independent association between OSASand systemic arterial hypertension.4,5 Moreover, aprospective follow-up of the latter populationdemonstrated that subjects with an apnoea/hypopnoea index of 0 to 4.9, 5 to 14.9, andmore than 15 events per hour of sleep had oddsratios of developing systemic hypertension overthe next 4-year period of 1.42, 2.03, and 2.89respectively, compared with matched controlsubjects without OSAS.6 The prevalence of OSASis particularly high in patients with drug-resistanthypertension and one study found occult OSAS inup to 83% of patients who had uncontrolledhypertension despite taking 3 or more antihyper-tensive agents at optimum dosage.7 Obstructivesleep apnea syndrome is cited as the firstdifferential in treatable causes of hypertension inthe Seventh Report of the Joint National Commit-tee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure.8

Data linking OSAS to other cardiovasculardiseases are not as clear-cut but nonethelesspersuasive. Indeed, in the Sleep Heart HealthStudy cohort, OSAS emerged as an independentrisk factor for coronary artery disease (CAD),congestive cardiac failure, and cerebrovascular

r Diseases, Vol. 51, No. 5 (March/April), 2009: pp 392-399

mailto:[email protected]

http://dx.doi.org/10.1016/j.pcad.2008.10.005

393INFLAMMATION IN OSAS

disease,9 and a recent report concerning thiscohort has also demonstrated an independentassociation with cardiac arrhythmias includingatrial fibrillation and complex ventriculararrhythmias.10 Furthermore, long-term outcomestudies of patients with CAD have demonstratedhigher death rates from cardiovascular disease inpatients with coexisting OSAS compared to thosewithout, even after controlling for importantconfounding risk factors such as age, weight,and smoking.11

Continuous positive airway pressure (CPAP)therapy, which is the most effective treatment forOSAS, decreases cardiovascular morbidity andmortality. Peker et al12 reported an increasedincidence of cardiovascular disease among incom-pletely treated patients with OSAS compared tothose effectively treated over a 7-year follow-upperiod. Furthermore, data from our laboratoryhave demonstrated a reduction in deaths fromcardiovascular causes in patients with OSAScomparing CPAP-treated to untreated patientsover an average follow-up of 7.5 years.13 Similarly,in a large cardiovascular outcome study with a10-year period of follow-up, severe untreatedOSAS significantly increased the risk of fatal andnonfatal cardiovascular events.14

ig 1. Proposed pathways leading to cardiovascularisease in obstructive sleep apnea.

Pathogenesis of CardiovascularDisease in OSAS

The mechanisms underlying cardiovascular dis-ease in patients with OSAS are still poorlyunderstood. The pathogenesis is likely to be amultifactorial process involving a diverse range ofmechanisms including sympathetic nervous sys-tem overactivity, selective activation of inflamma-tory pathways, oxidative stress, vascularendothelial dysfunction, and metabolic dysregula-tion, the latter particularly involving insulinresistance and disordered lipid metabolism.Although OSAS is associated with a diverserange of pathophysiological features rangingfrom sleep fragmentation and daytime sleepinessto recurring episodes of apnea-associated oxygendesaturation, there is growing evidence thatintermittent hypoxia is a key feature in thecardiovascular pathophysiology of the disorderbecause of the associated intermittent reoxygena-tion. This latter feature has been compared toreperfusion injury.15 A summary of proposed

mechanisms of cardiovascular disease in OSAS isgiven in Fig 1.

An adaptive response to sustained hypoxia ismediated principally by the transcription factorhypoxia-inducible factor-1 (HIF-1).16 Hypoxia-inducible factor-1 is activated in hypoxia througha well-defined mechanism, resulting in increasedexpression of a number of genes encodingproteins such as erythropoietin, vascularendothelial growth factor, and inducible nitricoxide synthase which increase tissue oxygena-tion. Such factors allow an adaptation to hypoxiathat is directed toward increasing tissue perfusionand oxygenation and hence overcoming theinitial hypoxic insult.17 Sustained hypoxia alsoleads to the activation of another critical tran-scription factor nuclear factor κ B (NF-κB). NF-κB plays a central role in the inflammatoryresponse with an increased production of pro-inflammatory cytokines that have been linked tothe pathogenesis of atherosclerosis and hyperten-sion including tumour necrosis factor α (TNF-α),interleukin 6 (IL-6), and interleukin 8 (IL-8).18

These molecular responses to hypoxia are sum-marized in Table 1.

Inflammatory processes have emerged as cri-tical in the pathogenesis of atherosclerosis ingeneral and mediate many stages of atheromaformation.19 Circulating levels of several inflam-matory markers have been associated with future

Fd

Table 1. Molecular Responses to Hypoxia

Adaptive responseHIF-1• Increased blood flow/oxygenation of hypoxic tissue• Increased glycolytic capacity

Inflammatory responseNF-κB• Central transcriptional mediator of the inflammatoryresponse○ Increased levels of TNF-α, IL-8, ICAM-1

• May contribute to chronic inflammation andatherosclerosis

• Tissue remodeling

394 WALTER T. MCNICHOLAS

cardiovascular risk.20,21 These markers includecell adhesion molecules (CAMs) such as inter-cellular adhesion molecule-1 (ICAM-1) and selec-tins, cytokines such as TNF-α and IL-6,chemokines such as IL-8, and C-reactive protein(CRP). There is increasing evidence that inflam-matory processes also play a central role in thecardiovascular pathophysiology of OSAS, whichinclude cell culture and animal studies identifyinga preferential activation of inflammatory pathwaysby intermittent hypoxia and reoxygenation inaddition to studies of circulating inflammatorymarkers in patients with OSAS demonstratingelevated markers in untreated patients that arereduced by CPAP therapy.22

Inflammation in the Pathogenesis ofCardiovascular Diseases in OSAS

Obstructive sleep apnea syndrome is associatedwith a variety of features that have been shown tocause pathophysiological responses such as inter-mittent hypoxia, sleep deprivation and fragmenta-tion, frequent arousals, and frequently associatedcomorbidities, particularly obesity. This complex-ity of the disease makes a multifactorial pathogen-esis likely. The progress in the understanding ofcardiovascular diseases in OSAS is closely linkedto the understanding of the development ofatherosclerosis in general. Accumulating evidencesupports a central role for inflammation in allphases of atherosclerosis, from initiation of thefatty streak to the culmination in plaque rupturepresenting as acute coronary syndrome.19,23

Systemic inflammation occurs in the vasculatureas a response to injury, lipid peroxidation, andperhaps infection.24-26 Inflammatory cells, parti-cularly monocytes, adhere to the endothelium and

release a number of inflammatory mediatorsincluding cytokines such as tumour necrosisfactor α (TNF-α) or interleukin (IL)-1, chemo-kines such as IL-8 or monocyte chemoattractantprotein-1 (MCP-1), or adhesion molecules such asICAM-1 or selectins. Expression of adhesionmolecules and chemokines facilitates the recruit-ment of macrophages, differentiated from mono-cytes, laden with oxidized lipid (foam cells). Theaccumulation of foam cells leads to the formationof a lipid pool, and collagen produced by smoothcells contributes to the strength of the fibrous cap.Particularly smooth cells also release IL-6 which isthe main hepatic stimulus for the acute phasereactant, CRP, which causes expression of adhe-sion molecules and mediates MCP-1 induction.25

A number of investigations in animal modelsand humans demonstrate inflammatory processesin OSAS. In a rat model, recurrent obstructiveapnoeas led to a significant increase in variousleukocyte-endothelial cell interactions such asleukocyte rolling and firm adhesion of leukocytesin comparison to a sham group.27 Furthermore, aseries of elegant studies documented activation ofvarious leukocyte subpopulations in OSAS incomparison to controls leading to higher expres-sion of adhesion molecules promoting firm adhe-sion to endothelial cells and stronger cytotoxicityagainst endothelial cells.28-31 Moreover, a numberof inflammatory cardiovascular risk markers havebeen found to be upregulated in OSAS.

The unique form of hypoxia with repetitiveshort cycles of desaturation followed by rapidreoxygenation, termed intermittent hypoxia,which occurs in OSAS, is likely to play asignificant role in the initiation of the inflamma-tory process. In particular, the intermittentreoxygenation that distinguishes intermittentfrom sustained hypoxia resembles reperfusioninjury and may result in the development ofatherosclerosis. We have developed a novel invitro model of intermittent hypoxia and generateddata supporting a paradigm by which intermittenthypoxia leads to a selective dose-dependentactivation of pro-inflammatory events mediatedby NF-κB without significant activation of theprotective HIF-1–dependent pathway.32 Thesefindings demonstrate selective activation ofproatherogenic molecular pathways by intermit-tent hypoxia, and in this way the cellular responseto intermittent hypoxia differs greatly from the


response to sustained hypoxia. These findingshave been subsequently replicated by others,demonstrating activation of NF-κB and increasedactivity of downstream products of NF-κB activa-tion in an animal model of intermittent hypoxia.18

Recent data from our laboratory suggest a crucialrole of p38 mitogen–activated protein kinase inthe intermittent hypoxia-induced NF-κB activa-tion and pharmacological as well as targetedsiRNA inhibition of p38 which leads to asignificant reduction in the NF-κB activity.33

We have also translated the findings of our cellculture model into the clinical setting of OSAS bydemonstrating in a large prospective study ofpatients with OSAS and healthy controls matchedfor age, sex, and body mass index (BMI) asignificant relationship of the NF-κB–dependentgenes TNF-α and IL-8 with sleep-related oxygendesaturation in the disorder.34 Importantly, con-trolling for BMI in this manner minimized thepossibility of obesity acting as a confounder in thestudy. Furthermore, we have demonstrated thatCPAP therapy is an effective treatment to lowerTNF-α and IL-8.

Inflammatory Biomarkers in OSAS

Inflammatory biomarkers are increasingly recog-nized as independent risk indicators for cardio-vascular diseases and have also attracted attentionin the cardiovascular risk assessment of patientswith OSAS. Various reports have assessed circulat-ing levels of inflammatory markers in OSAS withCRP, TNF-α, IL-6, IL-8, and CAMs, alone or incombination, being the most extensively studied.

C-Reactive Protein

C-reactive protein is a prototypic marker ofinflammation, which is mainly produced in theliver in response to IL-6. Recent data support anactive role for CRP in atherogenesis by promotingexpression of adhesion molecules and by mediat-ing the induction of MCP-1.35 In the high-normalrange, and when measured with a high-sensitivityassay, CRP levels are proposed as independentpredictors of future cardiovascular events amongapparently healthy subjects36,37 as well as insubjects with known cardiovascular disease.38

However, recent large population studies suggestthat the elevated levels may be attributable to the

presence of abnormal conventional cardiovascularrisk factors, in particular obesity.39,40

The association of CRP with OSAS has been asubject of debate in recent years with differingconclusions in various studies that have exploredthe relationship. The strong relationship betweenCRP levels and obesity41 may have influencedsome studies investigating CRP levels in adultpatients with OSAS where the populations inves-tigated were not optimally matched for BMI. Afterthe index report in 2002 on a pilot trial suggestingthat CRP level might be related to OSAS severity,42

a number of further case-control studies have alsostudied the role of CRP in OSAS with differentconclusions.43-50 Yokoe et al43 observed in a cohortincluding 30 patients with OSAS and 14 controlselevated CRP levels in the patient group; however,patients with OSAS had significantly higher BMIand the populations also included subjects withhypertension, CAD, stroke, and diabetes mellitus.Further studies suggested an association of CRPwith OSAS but with similar methodologicallimitations.44-46 However, recent studies havesuggested that obesity rather than OSAS per se isthe better predictor of CRP.47-49 Furthermore, theWisconsin Sleep Cohort Study analyzing 907adults failed to detect an independent associationbetween CRP and OSAS after adjustment forBMI.50 In a recent prospective controlled studyfrom our laboratory, CRP levels were similar inBMI-matched patients with OSAS and controls butsignificantly higher in patients with OSAS whowere more obese.49 Furthermore, flow-mediateddilatation asmarker of endothelial dysfunctionwasassociated with OSAS-related intermittenthypoxia, whereas CRP levels in the same cohortwere associated with BMI but not OSAS vari-ables.51 The impact of CPAP therapy on CRP levelsis unclear. Although Yokoe et al43 found animprovement in levels after 1 month of CPAPtherapy, subsequent studies have failed to confirmthese results,49,52 including the recent report fromour group.52 In contrast, Steiropoulos et al53

followed 53 patients with OSAS on CPAP therapyfor 6months and in the groupof compliant patients(n = 20), CRP values improved significantly.

Tumour Necrosis Factor α

The pro-inflammatory cytokine TNF-α promotesthe development of atherosclerosis by inducing the


expression of cellular adhesion molecules thatmediate adhesion of leucocytes to the vascularendothelium.54 Circulating levels of TNF-α havebeen reported to correlate with signs of earlyatherosclerosis amongst healthy middle-agedmen55 and are predictive of coronary heart diseaseand congestive cardiac failure.56 Moreover, persis-tent increased levels of TNF-α after myocardialinfarction are predictive of future coronary events.57

Several case-controlled studies have demon-strated elevated circulating TNF-α in patients withOSAS in comparison to controls, independent ofobesity, and a significant fall with effective CPAPtherapy.34,58,59 Furthermore, a gene polymorphismassociated with increased TNF-α production hasrecently been reported to be more common inOSAS.60 Both T cells and monocytes have beensuggested as potential sources of TNF-α. Tumornecrosis factor α has also been reported to relate tosleepiness in disorders of excessive daytime sleepi-ness, and Vgontzas et al61,62 have reported asignificant decrease in sleepiness with the TNF-αreceptor antagonist etanercept in a small pilot study.Recently, a large prospective study from ourlaboratory identified the oxygen desaturation indexas the strongest predictor of TNF-α levels in OSAS,which supports the key role of intermittent hypoxiaas mediator of the inflammatory response.34

Interleukin 8

Interleukin 8 is, like TNF-α, predominantly underthe control of NF-κB. IL-8 belongs to the family ofchemokines, which play a major pathogenic rolein atherogenesis and plaque destabilization. Infact, IL-8 mediates adhesion of neutrophils andmonocytes to the vascular endothelium, promotesneovascularization within the atheroscleroticlesion, and enhances oxidative stress.20,63 Ele-vated plasma IL-8 levels have been associated withan increased risk of cardiovascular disease inapparently healthy individuals.64,65 Increased IL-8levels in patients with OSAS in comparison tocontrols have been demonstrated in severalstudies34,66,67 with one study from our groupdemonstrating a significant fall with effectiveCPAP therapy.34

Cell Adhesion Molecules

Adherence of leukocytes to the vascular endothe-lium is an important step in the initiation of

atheroma formation. Potential adhesion mole-cules mediating leukocyte attachment to theendothelium include ICAM-1, vascular adhesionmolecule 1, and the family of selectins. Celladhesion molecules are predictive of futurecardiovascular risk in generally healthy popula-tions68,69 and are associated with adverse eventsin patients with documented cardiovasculardisease.70,71

Several case-controlled studies have demon-strated an association between CAD and OSAS,and the oxygen desaturation index was signifi-cantly related to the levels of ICAM-1, vascularadhesion molecule 1, and L-selectin.72-75 Further-more, effective CPAP therapy was associated witha significant decrease in CAM levels after 1 monthof treatment.76 Although these studies support anassociation of CAM with OSAS, several involvedsmall patient numbers and single peripheral bloodsamples may not accurately reflect their biologicalimportance at the level of the vascular endothe-lium.77 Thus, large-scale studies with repeatedmeasurements of CAMs at various time points areneeded to clearly establish an independentrelationship with OSAS.

Interleukin 6

Interleukin 6 levels appear to be predictive offuture cardiovascular disease78 and are elevated inpatients with unstable angina when compared tothose with stable angina.79 Raised IL-6 levels areoften found to correlate with CRP levels, con-sistent with IL-6 being the main stimulant for thehepatic production of CRP. A wide variety of cellsin the body can release IL-6 and it has been shownthat adipose tissue is responsible for a significantproportion of circulating IL-6.80

Early studies suggested increased IL-6 levels inpatients with OSAS,43,58,61 but some of thesereports may have been limited by small numbers;lack of adequately matched normal controlpopulations, particularly in terms of BMI; andthe inclusion of patients with established cardio-vascular and/or metabolic diseases. A recentreport from our group did not find any differencein IL-6 levels between a group of patients withOSAS who were free of any comorbidity and agroup of carefully matched control subjects.62

Furthermore, effective CPAP therapy had nosignificant effect.62 These findings are supported


by a large cross-sectional analysis of the ClevelandFamily Study, which did not detect an associationbetween IL-6 and OSAS after adjustment for BMI.However, interestingly, there was an independentassociation between OSAS severity parametersand soluble IL-6 receptor, which appears to beassociated with the processes of inflammation andmyocardial injury during the acute phase of acutemyocardial infarction.81

Conclusion

There is growing evidence that inflammatory cellandmolecularmechanisms play an important role inthe pathophysiology of cardiovascular disease inpatients with OSAS. However, the potential con-founding effect of variables such as BMI limits theability to draw reliable conclusions from someprevious studies of this association. Thus, thereremains a need for large-scale prospective studies ofpatient populations with OSAS that are wellcontrolled for important confounding variablessuch as BMI, smoking history, and comorbid disease.

References1. Deegan PC, McNicholas WT: Pathophysiology of

obstructive sleep apnea. Eur Respir J 8:1161-1178,1995

2. McNicholas WT, Bonsignore MR: Sleep apnoea as anindependent risk factor for cardiovascular disease:current evidence, basic mechanisms and researchpriorities. Eur Respir J 29:156-178, 2007

3. Kiely JL, McNicholas WT: Cardiovascular risk factorsin patients with obstructive sleep apnoea syndrome.Eur Respir J 16:128-133, 2000

4. Nieto FJ, Young TB, Lind BK, et al: Association ofsleep-disordered breathing, sleep apnea, and hyper-tension in a large community-based study. SleepHeart Health Study. JAMA 283:1829-1836, 2000

5. Young T, Peppard P, Palta M, et al: Population-basedstudy of sleep-disordered breathing as a risk factor forhypertension. Arch Intern Med 157:1746-1752, 1997

6. Peppard PE, Young T, Palta M, et al: Prospectivestudy of the association between sleep-disorderedbreathing and hypertension. N Engl J Med 342:1378-1384, 2000

7. Logan AG, Perlikowski SM, Mente A, et al: Highprevalence of unrecognized sleep apnea in drug-resistant hypertension. J Hypertens 19:2271-2277,2001

8. Chobanian AV, Bakris GL, Black HR, et al: TheSeventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment ofHigh Blood Pressure (The JNC 7 Report). JAMA 289:2560-2571, 2003

9. Shahar E, Whitney CW, Redline S, et al: Sleep-disordered breathing and cardiovascular disease:cross-sectional results of the Sleep Heart HealthStudy. Am J Respir Crit Care Med 163:19-25, 2001

10. Mehra R, Benjamin EJ, Shahar E, et al: Association ofnocturnal arrhythmias with sleep-disordered breath-ing: the Sleep Heart Health Study. Am J Respir CritCare Med 173:910-916, 2006

11. Peker Y, Hedner J, Kraiczi H, et al: Respiratorydisturbance index: an independent predictor of mor-tality in coronary artery disease. Am J Respir Crit CareMed 162:81-86, 2000

12. Peker Y, Hedner J, Norum J, et al: Increased incidenceof cardiovascular disease in middle-aged men withobstructive sleep apnea: a 7-year follow-up. Am JRespir Crit Care Med 166:159-165, 2002

13. Doherty LS, Kiely JL, Swan V, et al: Long-term effectsof nasal continuous positive airway pressure therapyon cardiovascular outcomes in sleep apnea syn-drome. Chest 127:2076-2084, 2005

14. Marin JM, Carrizo SJ, Vicente E, et al: Long-termcardiovascular outcomes in men with obstructivesleep apnoea-hypopnoea with or without treatmentwith continuous positive airway pressure: an observa-tional study. Lancet 365:1046-1053, 2005

15. Lavie L: Obstructive sleep apnoea syndrome: anoxidative stress disorder. Sleep Med Rev 7:35-51,2003

16. Cummins EP, Taylor CT: Hypoxia-responsive tran-scription factors. Pflugers Arch 450:363-371, 2005

17. Semenza GL: O2-Regulated gene expression: tran-scriptional control of cardiorespiratory physiology byHIF-1. J Appl Physiol 96:1173-1177, 2004

18. Greenberg H, Ye X, Wilson D, et al: Chronicintermittent hypoxia activates nuclear factor-kappaBin cardiovascular tissues in vivo. Biochem BiophysRes Commun 343:591-596, 2006

19. Libby P. Inflammation in atherosclerosis. Nature420:868-874.

20. Aukrust P, Yndestad A, Smith C, et al: Chemokines incardiovascular risk prediction. Thromb Haemost 97:748-754, 2007

21. Blake GJ, Ridker PM: C-Reactive protein and otherinflammatory risk markers in acute coronary syn-dromes. J Am Coll Cardiol 41:37S-42S, 2003(4 Suppl S)

22. Williams A, Scharf SM: Obstructive sleep apnea,cardiovascular disease, and inflammation—is NFκBthe key? Sleep Breath 11:69-76, 2007

23. Ross R: Atherosclerosis—an inflammatory disease.N Engl J Med 340:115-126, 1999

24. Glass CK, Witztum JL: Atherosclerosis. The roadahead. Cell 104:503-516, 2001

25. Lusis AJ: Atherosclerosis. Nature 407:233-241, 200026. Willerson JT, Ridker PM: Inflammation as a cardio-

vascular risk factor. Circulation 109:II2-II10, 2004 (21Suppl 1)

27. Nacher M, Serrano-Mollar A, Farre R, et al: Recurrentobstructive apneas trigger early systemic inflamma-tion in a rat model of sleep apnea. Respir PhysiolNeurobiol 155:93-96, 2007


28. Dyugovskaya L, Lavie P, Lavie L: Lymphocyte activa-tion as a possible measure of atherosclerotic risk inpatients with sleep apnea. Ann N Y Acad Sci 1051:340-350, 2005

29. Dyugovskaya L, Lavie P, Hirsh M, et al: Activated CD8+ T-lymphocytes in obstructive sleep apnoea. EurRespir J 25:820-828, 2005

30. Dyugovskaya L, Lavie P, Lavie L: Phenotypic andfunctional characterization of blood gammadeltaT cells in sleep apnea. Am J Respir Crit Care Med168:242-249, 2003

31. Dyugovskaya L, Lavie P, Lavie L: Increased adhesionmolecules expression and production of reactiveoxygen species in leukocytes of sleep apneapatients. Am J Respir Crit Care Med 165:934-939,2002

32. Ryan S, Taylor CT, McNicholas WT: Selective activa-tion of inflammatory pathways by intermittent hypoxiain obstructive sleep apnea syndrome. Circulation 112:2660-2667, 2005

33. Ryan S, McNicholas WT, Taylor CT: A critical role forp38 map kinase in NF-kappaB signaling duringintermittent hypoxia/reoxygenation. Biochem BiophysRes Commun 355:728-733, 2007

34. Ryan S, Taylor CT, McNicholas WT: Predictors ofelevated nuclear factor kappa B– dependent genes inobstructive sleep apnea syndrome. Am J Respir CritCare Med 174:824-830, 2006

35. Pasceri V, Cheng JS, Willerson JT, et al: Modulationof C-reactive protein-mediated monocyte chemoat-tractant protein-1 induction in human endothelialcells by anti-atherosclerosis drugs. Circulation 103:2531-2534, 2001

36. Ridker P, Buring MJ, Shih J, et al: Prospective study ofC-reactive protein and the risk of future cardiovascularevents among apparently healthy women. Circulation98:731-733, 1998

37. Koenig W, Sund M, Frohlich M, et al: C-Reactiveprotein, a sensitive marker of inflammation, predictsfuture risk of coronary heart disease in initially healthymiddle-aged men: results from the MONICA (Mon-itoring Trends and Determinants in CardiovascularDisease) Augsburg Cohort Study, 1984 to 1992.Circulation 99:237-242, 1999

38. Haverkate F, Thompson SG, Pyke SD, et al: Produc-tion of C-reactive protein and risk of coronary events instable and unstable angina. European ConcertedAction on Thrombosis and Disabilities Angina PectorisStudy Group. Lancet 349:462-466, 1997

39. Khera A, de Lemos JA, Peshock RM, et al: Relation-ship between C-reactive protein and subclinicalatherosclerosis: the Dallas Heart Study. Circulation113:38-43, 2006

40. Cao JJ, Arnold AM, Manolio TA, et al: Association ofcarotid artery intima-media thickness, plaques, andC-reactive protein with future cardiovascular diseaseand all-cause mortality: the Cardiovascular HealthStudy. Circulation 116:32-38, 2007

41. Visser M, Bouter LM, McQuillan GM, et al: ElevatedC-reactive protein levels in overweight and obeseadults. JAMA 282:2131-2135, 1999

42. Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al:Elevated C-reactive protein in patients with obstruc-tive sleep apnea. Circulation 105:2462-2464, 2002

43. Yokoe T, Minoguchi K, Matsuo H, et al: Elevated levelsof C-reactive protein and interleukin-6 in patients withobstructive sleep apnea syndrome are decreased bynasal continuous positive airway pressure. Circulation107:1129-1134, 2003

44. Hayashi M, Fujimoto K, Urushibata K, et al: Hypoxia-sensitive molecules may modulate the development ofatherosclerosis in sleep apnoea syndrome. Respirol-ogy 11:24-31, 2006

45. Can M, Acikgoz S, Mungan G, et al: Serum cardio-vascular risk factors in obstructive sleep apnea. Chest129:233-237, 2006

46. Kokturk O, Ciftci TU, Mollarecep E, et al: ElevatedC-reactive protein levels and increased cardiovascularrisk in patients with obstructive sleep apnea syn-drome. Int Heart J 46:801-809, 2005

47. Barcelo A, Barbe F, Llompart E, et al: Effects of obesityon C-reactive protein level and metabolic distur-bances in male patients with obstructive sleepapnea. Am J Med 117:118-121, 2004

48. Guilleminault C, Kirisoglu C, Ohayon MM: C-Reactiveprotein and sleep-disordered breathing. Sleep 27:1507-1511, 2004

49. Ryan S, Nolan GM, Hannigan E, et al: Cardiovascularrisk markers in obstructive sleep apnoea syndromeand correlation with obesity. Thorax 62:509-514, 2004

50. Taheri S, Austin D, Lin L, et al: Correlates of serumC-reactive protein (CRP)—no association with sleepduration or sleep disordered breathing. Sleep 30:991-996, 2007

51. Chung S, Yoon IY, Shin YK, et al: Endothelialdysfunction and C-reactive protein in relation withthe severity of obstructive sleep apnea syndrome.Sleep 30:997-1001, 2007

52. Akashiba T, Akahoshi T, Kawahara S, et al: Effects oflong-term nasal continuous positive airway pressureon C-reactive protein in patients with obstructive sleepapnea syndrome. Intern Med 44:899-900, 2005

53. Steiropoulos P, Tsara V, Nena E, et al: Effect ofcontinuous positive airway pressure treatment onserum cardiovascular risk factors in patients withobstructive sleep apnea-hypopnea syndrome. Chest132:843-851, 2007

54. Kritchevsky SB, Cesari M, Pahor M: Inflammatorymarkers and cardiovascular health in older adults.Cardiovasc Res 66:265-275, 2005

55. Skoog T, Dichtl W, Boquist S, et al: Plasma tumournecrosis factor-alpha and early carotid atherosclerosisin healthy middle-aged men. Eur Heart J 23:376-383,2002

56. Cesari M, Penninx BW, Newman AB, et al: Inflamma-tory markers and onset of cardiovascular events:results from the Health ABC study. Circulation 108:2317-2322, 2003

57. Ridker PM, Rifai N, Pfeffer M, et al: Elevation of tumornecrosis factor-alpha and increased risk of recurrentcoronary events after myocardial infarction. Circula-tion 101:2149-2153, 2000


58. Ciftci TU, Kokturk O, Bukan N, et al: The relationshipbetween serum cytokine levels with obesity andobstructive sleep apnea syndrome. Cytokine 28:87-91, 2004

59. Minoguchi K, Tazaki T, Yokoe T, et al: Elevatedproduction of tumor necrosis factor-alpha by mono-cytes in patients with obstructive sleep apnea syn-drome. Chest 126:1473-1479, 2004

60. Riha RL, Brander P, Vennelle M, et al: Tumour necrosisfactor-alpha (-308) gene polymorphism in obstructivesleep apnoea-hypopnoea syndrome. Eur Respir J 26:673-678, 2005

61. Vgontzas AN, Papanicolaou DA, Bixler EO, et al:Elevation of plasma cytokines in disorders of exces-sive daytime sleepiness: role of sleep disturbance andobesity. J Clin Endocrinol Metab 82:1313-1316, 1997

62. Vgontzas AN, Zoumakis E, Lin HM, et al: Markeddecrease in sleepiness in patients with sleep apnea byetanercept, a tumor necrosis factor-alpha antagonist.J Clin Endocrinol Metab 89:4409-4413, 2004

63. Gerszten RE, Garcia-Zepeda EA, Lim YC, et al: MCP-1and IL-8 trigger firm adhesion of monocytes tovascular endothelium under flow conditions. Nature398:718-723, 1999

64. Boekholdt SM, Peters RJ, Hack CE, et al: IL-8 Plasmaconcentrations and the risk of future coronary arterydisease in apparently healthy men and women: theEPIC-Norfolk prospective population study. Arterios-cler Thromb Vasc Biol 24:1503-1508, 2004

65. Romuk E, Skrzep-Poloczek B, Wojciechowska C, et al:Selectin-P and interleukin-8 plasma levels in coronaryheartdiseasepatients.Eur JClin Invest32:657-661,2002

66. Alzoghaibi MA, Bahammam AS: Lipid peroxides,superoxide dismutase and circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: apilot study. Sleep Breath 9:119-126, 2005

67. Ohga E, Tomita T, Wada H, et al: Effects of obstructivesleep apnea on circulating ICAM-1, IL-8, and MCP-1.J Appl Physiol 94:179-184, 2003

68. Hwang SJ, Ballantyne CM, Sharrett AR, et al:Circulating adhesion molecules VCAM-1, ICAM-1,and E-selectin in carotid atherosclerosis and incidentcoronary heart disease cases: the AtherosclerosisRisk In Communities (ARIC) study. Circulation 96:4219-4225, 1997

69. Ridker PM, Buring JE, Rifai N: Soluble P-selectin andthe risk of future cardiovascular events. Circulation103:491-495, 2001

70. Haim M, Tanne D, Boyko V, et al: Soluble intercellularadhesion molecule-1 and long-term risk of acutecoronary events in patients with chronic coronaryheart disease. Data from the Bezafibrate InfarctionPrevention (BIP) Study. J Am Coll Cardiol 39:1133-1138, 2002

71. Blankenberg S, Rupprecht HJ, Bickel C, et al:Circulating cell adhesion molecules and death inpatients with coronary artery disease. Circulation104:1336-1342, 2001

72. Ohga E, Nagase T, Tomita T, et al: Increased levels ofcirculating ICAM-1, VCAM-1, and L-selectin inobstructive sleep apnea syndrome. J Appl Physiol87:10-14, 1999

73. El-Solh AA, Mador MJ, Sikka P, et al: Adhesionmolecules in patients with coronary artery disease andmoderate-to-severe obstructive sleep apnea. Chest121:1541-1547, 2002

74. Ursavas A, Karadag M, Rodoplu E, et al: CirculatingICAM-1 and VCAM-1 levels in patients with obstruc-tive sleep apnea syndrome. Respiration 74:525-532,2007

75. Zamarron-Sanz C, Ricoy-Galbaldon J, Gude-Sampe-dro F, et al: Plasma levels of vascular endothelialmarkers in obstructive sleep apnea. Arch Med Res 37:552-555, 2006

76. Chin K, Nakamura T, Shimizu K, et al: Effects of nasalcontinuous positive airway pressure on soluble celladhesion molecules in patients with obstructive sleepapnea syndrome. Am J Med 109:562-567, 2000

77. Ridker PM: Role of inflammatory biomarkers inprediction of coronary heart disease. Lancet 358:946-948, 2001

78. Luc G, Bard JM, Juhan-Vague I, et al: C-Reactiveprotein, interleukin-6, and fibrinogen as predictors ofcoronary heart disease: the PRIME Study. ArteriosclerThromb Vasc Biol 23:1255-1261, 2003

79. Biasucci LM, Vitelli A, Liuzzo G, et al: Elevated levels ofinterleukin-6 in unstable angina. Circulation 94:874-877, 1996

80. Mohamed-Ali V, Goodrick S, Rawesh A, et al:Subcutaneous adipose tissue releases interleukin-6,but not tumor necrosis factor-alpha, in vivo. J ClinEndocrinol Metab 82:4196-4200, 1997

81. Ueda K, Takahashi M, Ozawa K, et al: Decreasedsoluble interleukin-6 receptor in patients with acutemyocardial infarction. Am Heart J 138:908-915, 1999(5 Pt 1)

obstructive sleep apnea and inflammation

Documents