review article obstructive sleep apnea, oxidative stress...

Review ArticleObstructive Sleep Apnea Oxidative Stress and CardiovascularDisease Evidence from Human Studies

Hans-Joachim Eisele Philipp Markart and Richard Schulz

Department of Pneumology University Hospital of Marburg Campus Fulda Pacelliallee 4 36043 Fulda Germany

Correspondence should be addressed to Richard Schulz richardschulzklinikum-fuldade

Received 17 December 2014 Revised 6 May 2015 Accepted 28 May 2015

Academic Editor Jacek Zielonka

Copyright copy 2015 Hans-Joachim Eisele et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Obstructive sleep apnea (OSA) is a frequent disease mainly affecting obese people and caused by repetitive collapse of the upperairways during sleepThe increased morbidity andmortality of OSA are mainly thought to be the consequence of its adverse effectson cardiovascular (CV) health In this context oxidative stress induced by nocturnal intermittent hypoxia has been identified toplay a major role This is suggested by biomarker studies in OSA patients showing excessively generated reactive oxygen speciesfrom leukocytes reduced plasma levels of nitrite and nitrate increased lipid peroxidation and reduced antioxidant capacityBiopsy studies complement these findings by demonstrating reduced endothelial nitric oxide synthase expression and increasednitrotyrosine immunofluorescence in the vasculature of these patients Furthermore oxidative stress in OSA correlates withsurrogate markers of CV disease such as endothelial function intima-media thickness and high blood pressure Continuouspositive airway pressure therapy reverses oxidative stress in OSA The same may be true for antioxidants however more studiesare needed to clarify this issue

1 Introduction

Obstructive sleep apnea (OSA) is the most common formof sleep-disordered breathing (SDB) and represents a majorpublic health problem It is caused by repetitive collapseof a narrow upper airway during sleep [1] The main riskfactors of the disease are obesity male gender and advancedage [2] but it may also occur in lean subjects women andchildren Earlier studies have reported that OSA affects 2and 4 of middle-aged women and men respectively [3]However owing to the global obesity epidemic these featuresmight even underestimate the actual prevalence of OSA assuggested by more recent data from epidemiological studies[4]

The episodes of OSA are terminated by arousals Theseevents disturb normal sleep architecture and can lead toexcessive daytime sleepiness in many patients Furthermorethe risk of traffic accidents is increased Finally OSA islinked to enhanced cardiovascular (CV) morbidity andmortality [5] The gold standard in the diagnosis of OSAis polysomnography and the mainstay of its treatment is

continuous positive airway pressure (CPAP) therapy Bycreating a pneumatic splint CPAP rapidly eliminates upperairway collapse and thereby also most sequelae of the disease[6]

The aim of the current review article is to summarizethe evidence for oxidative stress being present in humanswith OSA and its relation to CV disease Of note this hasbeen paralleled by the results of animal studies evaluatingthe effects of intermittent hypoxia (IH) on the CV system ofrodents For further details the interested reader is referredto an earlier article we have published in this journal [7]

2 Clinical Spectrum of OSA-AssociatedCardiovascular Diseases

During the night blood pressure (BP) surges can be observedin both the systemic and pulmonary circulation [8] Simi-larly cyclical variations of the heart rate emerge (ie sinustachycardiabradycardia [9]) Furthermore cardiac rhythmdisturbances may occur [10] These include sinus arrests

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 608438 9 pageshttpdxdoiorg1011552015608438

2 Oxidative Medicine and Cellular Longevity

atrioventricular conduction blocks atrial fibrillation andventricular arrhythmias It is hypothesized that through thesearrhythmias OSA can cause sudden cardiac death howeverthe evidence for this is still somewhat circumstantial [11]

The deleterious effects of OSA on the CV system arecarried over into daytime hours Thus up to one half ofthese patients suffer from arterial hypertension The OSA-associated arterial hypertension is characterized by a nondip-ping 24-hour BP pattern and a high percentage of refractoryandmasked hypertension [12ndash14] Mainly through its pressoreffects OSA increases the risks for stroke heart failureand myocardial infarction [5] In addition this may lead tomore rapid expansion of aortic aneurysms [15] OSA canalso cause pulmonary hypertension however this occursin a lower proportion of patients and usually is not verypronounced [16] Furthermore it may be a risk factor forthromboembolic disorders such as deep vein thrombosis andpulmonary embolism [17] Finally otherwise healthy OSApatients can already display more subtle CV changes such asendothelial dysfunction and vascular remodeling [18 19]

CV risk in OSA depends on the severity of SDB that isthose patients with an apnea-hypopnea-index exceeding 30per hour of sleep are mainly affected [5] Most studies eval-uating CV morbidity and mortality in OSA have primarilyenrolled typical sleep laboratory cohorts that is middle-agedobese men

However more recent data show that CV risk is alsoincreased in other subsets of OSA patients such as womenand the elderly [20 21] Of note this is independent fromestablished CV risk factors such as advanced age obesitysmoking and metabolic disorders

It is well known that sleep characteristics such as sleepduration and the ability to fall asleep or maintain normalsleep can impact on CV health [22 23] Consequently thoseOSA patients who suffer from insomnia or excessive daytimesleepiness have a higher CV risk than those who do not [24]

3 Pathophysiology of OSA-AssociatedCardiovascular Diseases

Over the last two decades the intermediary pathways linkingOSA to CV disease have been further elucidated The maintrigger of these metabolic and cellular changes is IH that isthe nocturnal hypoxia-reoxygenation events accompanyingOSA Other OSA-associated stimuli such as hypercapniaarousals and intrathoracic pressure swings may also playsignificant roles however this has been less extensivelystudied

One major pathogenic mechanism of CV disease inOSA is sympathetic activation [25] It is mediated byenhanced chemoreflex activity in the carotid body Fur-thermore inflammatory changes within the vasculature andthe adipose tissue which are due to NF120581B activation havebeen described [26 27] Additional pathways include theupregulation of hypoxia-sensitive endothelial-derived pep-tides such as endothelin and vascular endothelial growthfactor enhanced coagulation and decreased fibrinolysis aswell as disturbed vascular repairmechanisms [28ndash31] Finally

0

10

20

30

40

50

1995 2000 2005 2010 2015

Num

ber o

f art

icle

s

Year of publication

Figure 1 Publications found in Pubmed with the search terms ofldquosleep apneardquo ldquocardiovascularrdquo and ldquooxidative stressrdquo

OSA is linked to insulin resistance and dyslipidemia whichmay also contribute to the emergence of CV disease [32 33]

Another potential mechanism of CV disease in OSA isan increased oxidative stress Under physiologic conditionsthere is a balance between aggressive and protective factorsinfluencing redox control The term ldquooxidative stressrdquo refersto an imbalance between reactive oxygen species (ROS)and reactive nitrogen species production and the systemof antioxidant defense resulting in a serious disorder ofredox homeostasis [34] Oxidative stress has been reportedto underlie the process of aging and plays a role in thepathogenesis of such different diseases as cancer chronicinflammatory and neurodegenerative disorders [35] Fur-thermore there is a strong correlation between oxidativestress and CV diseases such as atherosclerosis hypertensionand endothelial dysfunction [36]

4 Evidence for Oxidative Stress inHumans with OSA

In the following paragraphs the various aspects of oxidativestress in patients with OSA will be discussed in moredetail For this purpose a Pubmed search was performedwith the search terms ldquosleep apneardquo ldquocardiovascularrdquo andldquooxidative stressrdquo As can be seen from Figure 1 this searchyielded a growing number of publications dating back tothe late 1990s Overall a total of 292 entries were retrievedOnly full-length original publications dealing with humansubjects with OSA were taken into consideration With a fewexceptions replication studies as well as those not evaluatingthe effects of CPAP therapy on oxidative stress parameterswere excluded Following this strategy 36 publications wereselected for this review article

41 Methodological Aspects of Studies The studies exploringoxidative stress in OSA have employed different method-ological approaches Most commonly biomarkers of oxida-tive stress were determined in peripheral venous bloodsamples obtained after sleep Other studies aimed to inte-grate CV surrogate markers such as vasoreactivity and

Oxidative Medicine and Cellular Longevity 3

intima-media thickness (IMT) Finally some investigatorshave applied more invasive procedures that is vascularbiopsies

Most studies enrolled patients with OSA and controlswithout SDB and measured the aforementioned parametersbefore and after CPAP therapy The majority of these studieshad low patient numbers Furthermore most of them werenot randomized and uncontrolled that is they did nothave a treatment arm with for example sham CPAP (iewith subtherapeutical pressure) Finally many earlier studiesrecruited patients with comorbidities which might causeoxidative stress by itself Therefore it is recommended torestrict study participation to otherwise healthy nonobeseand nonsmoking OSA patients when performing investiga-tions in this field

It should be acknowledged that the studies evaluatingoxidative stress in OSA have not yielded unequivocal resultsThis may be due to varying severities of IH in the patientsstudied (ie frequency and extent of nocturnal oxygendesaturations [37ndash39]) Patient characteristics as age genderand bodyweightmay also have an influence however this hasnot yet been substantiated Furthermore as mentioned abovediscrepancies in comorbidities may introduce some bias intoanalyses of oxidative stress parameters in these patientsFinally differences in study design may play important rolesin this context (ie full-night polysomnography versus split-night protocols [40])

42 Enhanced Release of Superoxide from Leukocytes Thefirst studies demonstrating the presence of oxidative stressin humans with OSA were performed in our laboratory atthe University of Giessen Lung Center Germany and atthe University of Haifa Israel by the group of Lena andPeretz Lavie [41 42] It was observed that circulating neu-trophils and monocytes of OSA patients exhibited markedlyenhanced in vitro release of superoxide radical anions Thiswas the case in response to different stimuli such as formyl-methionylleucylphenylalanine and phorbol myristate acetatebut also in the unstimulated state The increased oxidativeburst of leukocytes in OSA is due to an activation of NADPHoxidase (NOX) The expression of this major superoxide-generating enzyme is upregulated in leukocytes from OSApatients This was shown by measuring p22phox mRNA inperipheral blood mononuclear cells [43] Furthermore theserum levels of soluble NOX2-derived peptide a marker ofNOX activation by blood cells decrease after CPAP therapyin patients with OSA [44]

43 Reduced Bioavailability of Nitric Oxide Nitric oxide(NO) is synthesized from the amino acid L-arginine by theaction of NO synthases (NOS) They occur in three differentisoforms endothelial inducible and neuronal Endothe-lial NOS (eNOS) is the enzyme responsible for vascularNO production [45] Importantly some naturally occurringcompounds can interfere with NO formation For exampleasymmetric dimethylarginine (ADMA) inhibits eNOS andarginasemetabolizes L-arginine to L-ornithine and urea [46]

NO is the main endothelial-derived vasodilator Thiseffect is mediated by its second messenger guanosine 3101584051015840-cyclicmonophosphate [47]NOalso possesses other vasopro-tective properties such as inhibition of platelet aggregationand adhesion molecule expression The consequences ofNO deficiency are for example elevated BP and enhancedatherosclerosis [48]

Through various pathways oxidative stress can reduceNO bioavailability First superoxide directly interacts withNO resulting in the formation of peroxynitrite [49] Secondthe degradation of the eNOS cofactor tetrahydrobiopterin isaccelerated [50] Third the activity of the enzyme dimethy-larginine dimethylaminohydrolase is decreased leading tohigher levels of ADMA [51]

Due to its very short half-life of only a few secondsit is challenging to measure NO itself More feasible is thedetermination of its oxidation products nitrite and nitrate Inpatients with OSA it was shown that serum levels of nitriteandnitrate are reducedwhen comparedwith controlswithoutSDB [52ndash54]The decreased nitrite and nitrate pool in OSA isprobably due to decreased NO biosynthesisThis is suggestedby the findings of increased plasma concentrations of ADMAand arginase in these patients [55ndash57]

44 Increased Oxidation of Lipids Proteins and DNA Exces-sively generated ROS may lead to increased oxidation ofbiological compounds such as lipids proteins and DNAThus OSA patients show evidence for increased lipid per-oxidation as mirrored by elevated plasma concentrations ofthiobarbituric acid reactive substances [58 59] In addition toinflammatory changes in response to IH this may be respon-sible for accelerated atherosclerosis in affected patients

Moreover increased concentrations of 8-isoprostane canbe found in exhaled breath condensate of OSA patients[60] The isoprostanes are prostaglandin-like compoundsformed in vivo from the free radical-catalyzed peroxidationof essential fatty acids (primarily arachidonic acid [61])Theyenhance vasoconstrictor tone and may thus contribute to thedevelopment of arterial hypertension in OSA

Some authors have reported on higher plasma advancedoxidation protein products in OSA versus non-OSA patients[62 63] DNA oxidation also takes place in OSA as sug-gested by the finding of increased urinary excretion of 8-hydroxy-21015840-deoxyguanosine in patients with severe versusmild-to-moderate OSA [64] In addition the levels of DNAdamage in peripheral blood lymphocytes as assessed by thecytokinesis-blockedmicronucleus assay are increased inOSA[65] Finally a significant decrease in mitochondrial DNAcopy number was observed in genomic DNA isolated fromwhole blood of OSA patients [66] The pathophysiologicalsignificance of these changes in the context ofOSA-associatedCV disease awaits to be determined

45 Reduced Antioxidant Capacity The effects of ROS maybe counterbalanced by antioxidant substances such as glu-tathione and vitamins A C and E Some studies suggestthat this defense line against oxidative stress is impairedin untreated patients with OSA Antioxidant capacity as


measured by the trolox equivalent antioxidant capacity assaywas found to be reduced in OSA [67] Furthermore plasmatotal antioxidant status and levels of vitamins A and E werelower in OSA patients versus controls [68] Finally theantioxidant properties of serum albumin were shown to beimpaired in OSA [69]

Oxidative stress in OSA may also stem from reducedactivity of antioxidant enzymes Thus lower plasma levelsof superoxide dismutase (SOD) have been described inOSA versus non-OSA patients [43 70] Similarly a studyevaluating microarray measures of gene transcript levelsnoted changes in genes encoding for antioxidant enzymesthat is SOD and catalase [71] Finally OSA patients exhibit adecrease in paraoxonase-1 that is an enzyme which protectslipoproteins from oxidation and thereby exerts antiathero-genic effects [59]

46 Vascular Biopsy Studies Up to now only a few studieshave directly evaluated oxidative stress in the vasculatureof OSA patients This may be due to the reluctance ofpatients to have biopsies performed and also to the limitedavailability of these techniques Jelic et al harvested endothe-lial cells by introducing vascular guidewires into forearmveins When compared to controls without SDB the cellsobtained from OSA patients showed reduced expression ofeNOS and increased nitrotyrosine immunofluorescence [72]Quite similar findings were later reported by Patt et al whoinvestigated arterioles isolated from forearm subcutaneousbiopsies [73] In a most recent study endothelial tissue wasobtained from gluteal biopsies of OSA and control subjectsand eNOS uncoupling was identified as a novel pathway ofOSA-associated endothelial dysfunction [74]

47 Correlation of Oxidative Stress in OSA with SurrogateMarkers of CVDisease OSApatientsmay exhibit endothelialdysfunction that is a reduction of endothelial-dependentvasorelaxation This has been shown by various techniquesinvestigating vasoreactivity as for example venous occlu-sion plethysmography and measurements of flow-mediatedvasodilation (FMD) of the brachial artery [18 75] Endothe-lial dysfunction is a precursor lesion for both atherosclerosisand arterial hypertension and can already be detected inOSApatients without clinically overt CV disease

Since endothelial-dependent vasodilation is mainly theresult of NO release it is not surprising that OSA patientswith lower circulating levels of nitrite and nitrate have moreseverely impaired FMD [76] Furthermore the expression ofeNOS correlates with FMD in these patients [72] Finallyinverse relationships between FMD and circulating levelsof ADMA soluble NOX2-derived peptide and isoprostaneshave been found [76 77] Taken together these data clearlyshow that oxidative stress mechanisms underlie endothelialdysfunction in OSA

Ultrasonographic studies have shown that OSA patientshave greater IMT of their common carotid arteries whencompared with non-OSA control subjects and that this isrelated to the degree of nocturnal hypoxia [19] IMT reflects

the early stages of atherosclerosis and predicts the risks offuture stroke and myocardial infarction Up to now thereis only one study which has investigated the correlationbetween oxidative stress and IMT in OSA Monneret et alfound that the IMT of these patients was greater with higherurinary levels of isoprostanes [78]

Likewise there is a paucity of data on the relationshipbetween oxidative stress and BP in patients with OSA Ip etal have reported that the serum levels of nitrite and nitrateare inversely correlated with BP values in OSA [53] Insofarthe NO deficiency characteristic of OSA may constitute onepathophysiological pathway for the development of arterialhypertension in these patients however it is felt that moreinvestigations are required to support this hypothesis

48 Effects of Therapeutical Interventions As already statedmany of the studies evaluating the effects of CPAP therapyon oxidative stress in OSA had methodological drawbackssuch as low patient numbers inclusion of patients withcomorbidities and observational design Nevertheless thereis no doubt that CPAP therapy ameliorates or even eliminatesoxidative stress in OSA Thus most changes in biomarkerstudies were rapidly reversible after only some nights ofCPAP (Table 1) For instance it was reported that CPAPtherapy decreases the release of superoxide from leukocytesand increases circulating levels of nitrite and nitrate [4142 52ndash54] In addition the immunohistochemical changesin endothelial cells consistent with oxidative stress werereversible after 1ndash3 months of CPAP therapy [72 73] Thesefindings argue for more structural effects of CPAP therapyon the vasculature which may translate into a long-lastingsuppression of oxidative stress in affected individuals

On the other hand it must be realized that a significantproportion of OSA patients is not able or willing to use CPAPtherapy Pilot studies suggest that antioxidants may be usedto prevent or treat CV disease in such patients We haveshown that intravenous administration of the antioxidantvitamin C can acutely improve vasoreactivity in OSA [79]This observation was later confirmed by another group [80]Furthermore it was found that the xanthine oxidase inhibitorallopurinol when given orally over two weeks increases FMDin OSA [81]

49 Prospects for Future Research Despite the advancementshighlighted in this review we believe that more research isneeded to ascertain a causal role of oxidative stress in OSA-associated CV disease Appropriate studies should eitherinvestigate highly selected OSA patients (ie lean subjectswithout any comorbidities) or large cohorts allowing forstatistical control of confounders Furthermore randomizedcontrolled designs as for example with sham-CPAP treat-ment should be applied if possible

One important area of future research certainly is thecorrelation of oxidative stress biomarkers in OSA with CVread-out parameters such as FMD IMT and BP Long-termstudies could possibly also evaluate the association withmorerobust CV endpoints such as the occurrence of myocardial


Table 1 Overview of selected biomarker studies of oxidative stress in OSA

Biomarkerinvestigated

Authoryear [referencenumber]

OSA119899 =comorbidities yesno

Controls119899 =comorbidities yesno

Change ofbiomarker

Effects ofCPAP

PMN oxidative burst Schulz et al2000 [41] 18yes 10yes and 10no uarr darr

PMN oxidative burst Dyugovskaya et al2002[42] 18yes 31yes uarr darr

PMN p22phoxmRNA Liu et al2009 [43] 107yes 69yes uarr na

Serum NOX2 Del Ben et al2012 [44] 91yes 47yes harr darr

Nitrite and nitrate Schulz et al2000 [52] 21yes 18yes and 13no darr uarr

Nitrite and nitrate Ip et al2000 [53] 30yes 40no darr uarr

Nitrite and nitrate Alonso-Fernandez etal2009 [54] 31no 15no darr uarr

ADMA Barcelo et al2009 [56] 23yes and 18no 13no uarr naArginase Yuksel et al2014 [57] 41yes and 10no 15no uarr naTBARS Barcelo et al2000 [58] 14yes 13no uarr darr

TBARS Lavie et al2004 [59] 59yes and 55no 30yes uarr darr

Exhaled 8-isoprostane Carpagnano et al2003[60] 18no 12no uarr darr

Urinary 8-OHdG Yamauchi et al2005 [64] 128yes na uarrlowast na

Vitamins A and E Barcelo et al2006 [68] 47yes 37no darr harr

SOD Wysocka et al2008 [70] 41no 39no darr naParaoxonase-1 Lavie et al2004 [59] 59yes and 55no 30yes darr nauarr increase darr decrease andharr no changelowastPatients with severe versus mild-to-moderate OSAADMA asymmetric dimethylargininena = not availableNOX NADPH oxidase8-OHdG 8-hydroxy-21015840-deoxyguanosinePMN polymorphonuclear neutrophilsSOD superoxide dismutaseTBARS thiobarbituric acid reactive substances

infarction or strokeThis could for instance be accomplishedby enrolling those patients who are noncompliant with CPAPtherapy

The same patient population may also help to establishthe role of antioxidants in the treatment of OSA-associatedCV diseases In this context it is an open question whichantioxidants should be given and at what dose and routeof administration Regardless of these considerations suchstudies would need larger patient numbers and long-termfollow-up periods to delineate a therapeutic effect of antioxi-dants in OSA

In addition to these more clinically oriented questionsresearch efforts should be undertaken to elucidate the basicmechanisms of oxidative stress in OSA One possibility toaccomplish this task is to go back from bench to bedside thatis to see if the results of animal studies can be extrapolated tohumans with the disease In this context numerous studiesin mice and rats have shown that an upregulation of NOXunderlies many of the CV sequelae of IH [7 82] Apartfrom NOX and its different isoforms one could also lookat other ROS-generating enzymes within the human body

as for example xanthine oxidase uncoupled eNOS andmitochondrial respiratory chain enzymes Finally one shouldtry to decipher the interaction of oxidative stress with otherputative pathophysiological pathways of CV disease in OSAIn this context animal studies suggest that ROS can mediateor aggravate sympathetic activation in response to IH [83]Up to now it is not known if this is also the case in patientswith OSA

5 Conclusions

In summary there is accumulating evidence from humanstudies that untreated OSA causes oxidative stress andthat effective CPAP therapy can reverse these abnormali-ties (Figure 2) Given the well-known role of ROS in thepathogenesis of CV disease the oxidative stress inducedby OSA may account for its associated CV morbidityand mortality however more studies are clearly neededin this area of research In particular the cardioprotectiverole of antioxidants in those patients not tolerating CPAP


OSAintermittent hypoxia

Endothelial cells

eNOS

NO

ADMA

Leukocytes

NOX

ROS

Lipid peroxidationisoprostanes

Antioxidantcapacity

Vitamins A E(i)SOD(ii)

(iii) Paraoxonase-1

Endothelial dysfunctionatherosclerosisCV disease

Figure 2 Oxidative stress as an intermediary pathway of OSA-associated CV disease The intermittent hypoxia characteristic ofOSA leads to increased oxidative burst of leukocytes via activationof NOX Excessively produced ROS enhance lipid peroxidation andisoprostane formation NO bioavailability is reduced by diminishedexpression of eNOS and its inhibition by ADMA Finally antioxi-dant capacity is impaired in affected patients ADMA asymmetricdimethylarginine eNOS endothelial nitric oxide synthase NOnitric oxide NOX NADPH oxidase ROS reactive oxygen speciesSOD superoxide dismutase

therapy and the basic mechanisms leading to oxidativestress in patients with OSA should be explored in moredetail

Abbreviations

ADMA Asymmetric dimethylarginineBP Blood pressureCPAP Continuous positive airway pressureCV CardiovasculareNOS Endothelial nitric oxide synthaseFMD Flow-mediated vasodilationIH Intermittent hypoxiaIMT Intima-media thicknessNO Nitric oxideNOS Nitric oxide synthaseNOX NADPH oxidaseOSA Obstructive sleep apneaROS Reactive oxygen speciesSDB Sleep-disordered breathingSOD Superoxide dismutase

Conflict of Interests

The authors declare that they have no conflict of interests

References

[1] M Younes ldquoRole of respiratory control mechanisms in thepathogenesis of obstructive sleep disordersrdquo Journal of AppliedPhysiology vol 105 no 5 pp 1389ndash1405 2008

[2] T Young P E Peppard and D J Gottlieb ldquoEpidemiologyof obstructive sleep apnea a population health perspectiverdquo

American Journal of Respiratory and Critical Care Medicine vol165 no 9 pp 1217ndash1239 2002

[3] T YoungM Palta J Dempsey J Skatrud SWeber and S BadrldquoThe occurrence of sleep-disordered breathing among middle-aged adultsrdquoThe New England Journal of Medicine vol 328 no17 pp 1230ndash1235 1993

[4] C E Woods K Usher and G P Maguire ldquoObstructivesleep apnoea in adult indigenous populations in high-incomecountries an integrative reviewrdquo Sleep and Breathing vol 19 no1 pp 45ndash53 2015

[5] JMMarin S J Carrizo E Vicente andAGN Agusti ldquoLong-term cardiovascular outcomes in men with obstructive sleepapnoea-hypopnoea with or without treatment with continuouspositive airway pressure an observational studyrdquo The Lancetvol 365 no 9464 pp 1046ndash1053 2005

[6] C E Sullivan F G Issa M Berthon-Jones and L EvesldquoReversal of obstructive sleep apnoea by continuous positiveairway pressure applied through the naresrdquo The Lancet vol 1no 8225 pp 862ndash865 1981

[7] R Dumitrascu J Heitmann W Seeger N Weissmann andR Schulz ldquoObstructive sleep apnea oxidative stress and car-diovascular disease lessons from animal studiesrdquo OxidativeMedicine and Cellular Longevity vol 2013 Article ID 2346317 pages 2013

[8] O Marrone and M R Bonsignore ldquoPulmonary haemodynam-ics in obstructive sleep apnoeardquo Sleep Medicine Reviews vol 6no 3 pp 175ndash193 2002

[9] C Guilleminault S Connolly and R Winkle ldquoCyclical varia-tion of the heart rate in sleep apnoea syndrome Mechanismsand usefulness of 24 h electrocardiography as a screeningtechniquerdquoThe Lancet vol 1 no 8369 pp 126ndash131 1984

[10] V A Rossi J R Stradling andMKohler ldquoEffects of obstructivesleep apnoea on heart rhythmrdquo European Respiratory Journalvol 41 no 6 pp 1439ndash1451 2013

[11] A S Gami E J Olson W K Shen et al ldquoObstructive sleepapnea and the risk of sudden cardiac death a longitudinal studyof 10701 adultsrdquo Journal of the American College of Cardiologyvol 62 no 7 pp 610ndash616 2013

[12] J Wolf D Hering and K Narkiewicz ldquoNon-dipping pattern ofhypertension and obstructive sleep apnea syndromerdquoHyperten-sion Research vol 33 no 9 pp 867ndash871 2010

[13] AG Logan SM Perlikowski AMente et al ldquoHigh prevalenceof unrecognized sleep apnoea in drug-resistant hypertensionrdquoJournal of Hypertension vol 19 no 12 pp 2271ndash2277 2001

[14] J-P Baguet P Levy G Barone-Rochette et al ldquoMaskedhypertension in obstructive sleep apnea syndromerdquo Journal ofHypertension vol 26 no 5 pp 885ndash892 2008

[15] RHMasonG Ruegg J Perkins et al ldquoObstructive sleep apneain patients with abdominal aortic aneurysms highly prevalentand associated with aneurysm expansionrdquo American Journal ofRespiratory and Critical Care Medicine vol 183 no 5 pp 668ndash674 2011

[16] D Sajkov T Wang N A Saunders A J Bune A M Neill andR D McEvoy ldquoDaytime pulmonary hemodynamics in patientswith obstructive sleep apnea without lung diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 159 no 5I pp 1518ndash1526 1999

[17] MArzt R Luigart C Schumet al ldquoSleep-disordered breathingin deep vein thrombosis and acute pulmonary embolismrdquoEuropean Respiratory Journal vol 40 no 4 pp 919ndash924 2012


[18] J T Carlson C Rangemark and J A Hedner ldquoAttenuatedendothelium-dependent vascular relaxation in patients withsleep apnoeardquo Journal of Hypertension vol 14 no 5 pp 577ndash584 1996

[19] R Schulz W Seeger C Fegbeutel et al ldquoChanges in extracra-nial arteries in obstructive sleep apnoeardquo European RespiratoryJournal vol 25 no 1 pp 69ndash74 2005

[20] F Campos-Rodriguez M A Martinez-Garcia I de la Cruz-Moron C Almeida-Gonzalez P Catalan-Serra and J MMontserrat ldquoCardiovascular mortality in women with obstruc-tive sleep apnea with or without continuous positive airwaypressure treatment a cohort studyrdquoAnnals of InternalMedicinevol 156 no 2 pp 115ndash122 2012

[21] M-AMartınez-Garcıa F Campos-Rodrıguez P Catalan-Serraet al ldquoCardiovascular mortality in obstructive sleep apnea inthe elderly role of long-term continuous positive airway pres-sure treatment a prospective observational studyrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 186 no9 pp 909ndash916 2012

[22] F P Cappuccio D Cooper L DrsquoElia P Strazzullo and MA Miller ldquoSleep duration predicts cardiovascular outcomesa systematic review and meta-analysis of prospective studiesrdquoEuropean Heart Journal vol 32 no 12 pp 1484ndash1492 2011

[23] F Sofi F Cesari A Casini C Macchi R Abbate and G FGensini ldquoInsomnia and risk of cardiovascular disease a meta-analysisrdquo European Journal of Preventive Cardiology vol 21 no1 pp 57ndash64 2014

[24] M A Gupta and K Knapp ldquoCardiovascular and psychiatricmorbidity in Obstructive Sleep Apnea (OSA) with Insomnia(sleep apnea plus) versus obstructive sleep apnea withoutinsomnia a case-control study from a nationally representativeUS samplerdquo PLoS ONE vol 9 no 3 Article ID e90021 2014

[25] V K Somers M E Dyken M P Clary and F M AbboudldquoSympathetic neural mechanisms in obstructive sleep apneardquoThe Journal of Clinical Investigation vol 96 no 4 pp 1897ndash19041995

[26] A K Htoo H Greenberg S Tongia et al ldquoActivation of nuclearfactor kappaB in obstructive sleep apnea a pathway leading tosystemic inflammationrdquo Sleep and Breathing vol 10 no 1 pp43ndash50 2006

[27] S A Gharib A L Hayes M J Rosen and S R Patel ldquoApathway-based analysis on the effects of obstructive sleep apneain modulating visceral fat transcriptomerdquo Sleep vol 36 no 1pp 23ndash30 2013

[28] B G Phillips K Narkiewicz C A Pesek W G Haynes M EDyken and V K Somers ldquoEffects of obstructive sleep apnea onendothelin-1 and blood pressurerdquo Journal of Hypertension vol17 no 1 pp 61ndash66 1999

[29] R Schulz C Hummel S Heinemann W Seeger and FGrimminger ldquoSerum levels of vascular endothelial growthfactor are elevated in patients with obstructive sleep apnea andsevere nighttime hypoxiardquo American Journal of Respiratory andCritical Care Medicine vol 165 no 1 pp 67ndash70 2002

[30] G Bokinsky M Miller K Ault P Husband and J MitchellldquoSpontaneous platelet activation and aggregation duringobstructive sleep apnea and its response to therapy withnasal continuous positive airway pressure A preliminaryinvestigationrdquo Chest vol 108 no 3 pp 625ndash630 1995

[31] M de la Pena A Barcelo F Barbe et al ldquoEndothelial functionand circulating endothelial progenitor cells in patients withsleep apnea syndromerdquo Respiration vol 76 no 1 pp 28ndash322008

[32] M SM Ip B LamMM T NgW K Lam KW T Tsang andK S L Lam ldquoObstructive sleep apnea is independently asso-ciated with insulin resistancerdquo American Journal of Respiratoryand Critical Care Medicine vol 165 no 5 pp 670ndash676 2002

[33] AMAdedayoOOlafiranye D Smith et al ldquoObstructive sleepapnea and dyslipidemia evidence and underlying mechanismrdquoSleep and Breathing vol 18 no 1 pp 13ndash18 2014

[34] H Sies ldquoOxidative stress a concept in redox biology andmedicinerdquo Redox Biology vol 4 pp 180ndash183 2015

[35] B Halliwell ldquoFree radicals antioxidants and human diseasecuriosity cause or consequencerdquoTheLancet vol 344 no 8924pp 721ndash724 1994

[36] B Halliwell ldquoThe role of oxygen radicals in human disease withparticular reference to the vascular systemrdquo Haemostasis vol23 no 1 pp 118ndash126 1993

[37] S Cofta E Wysocka T Piorunek M Rzymkowska H Batura-Gabryel and L Torlinski ldquoOxidative stress markers in theblood of persons with different stages of obstructive sleep apneasyndromerdquo Journal of Physiology and Pharmacology vol 59 no6 pp 183ndash190 2008

[38] K Katsoulis T Kontakiotis D Spanogiannis et al ldquoTotalantioxidant status in patients with obstructive sleep apneawithout comorbidities the role of the severity of the diseaserdquoSleep and Breathing vol 15 no 4 pp 861ndash866 2011

[39] C Papandreou ldquoLevels of TBARS are inversely associated withlowest oxygen saturation in obese patients with OSASrdquo Sleepand Breathing vol 17 no 4 pp 1319ndash1322 2013

[40] A Svatikova R Wolk L O Lerman et al ldquoOxidative stress inobstructive sleep apnoeardquo European Heart Journal vol 26 no22 pp 2435ndash2439 2005

[41] R Schulz S Mahmoudi K Hattar et al ldquoEnhanced release ofsuperoxide frompolymorphonuclear neutrophils in obstructivesleep apnea impact of continuous positive airway pressuretherapyrdquo American Journal of Respiratory and Critical CareMedicine vol 162 no 2 part 1 pp 566ndash570 2000

[42] L Dyugovskaya P Lavie and L Lavie ldquoIncreased adhesionmolecules expression and production of reactive oxygen speciesin leukocytes of sleep apnea patientsrdquo American Journal ofRespiratory and Critical Care Medicine vol 165 no 7 pp 934ndash939 2002

[43] H-G Liu K Liu Y-N Zhou and Y-J Xu ldquoRelationshipbetween reduced nicotinamide adenine dinucleotide phosphateoxidase subunit p22phox gene polymorphism and obstructivesleep apnea-hypopnea syndrome in the Chinese Han popula-tionrdquo Chinese Medical Journal vol 122 no 12 pp 1369ndash13742009

[44] M Del Ben M Fabiani L Loffredo et al ldquoOxidative stressmediated arterial dysfunction in patients with obstructive sleepapnoea and the effect of continuous positive airway pressuretreatmentrdquo BMC Pulmonary Medicine vol 12 article 36 2012

[45] P J Andrew and B Mayer ldquoEnzymatic function of nitric oxidesynthasesrdquo Cardiovascular Research vol 43 no 3 pp 521ndash5311999

[46] J L Boucher CMoali and J P Tenu ldquoNitric oxide biosynthesisnitric oxide synthase inhibitors and arginase competition for L-arginine utilizationrdquo Cellular and Molecular Life Sciences vol55 no 8-9 pp 1015ndash1028 1999

[47] S Imai ldquoCyclic GMP as a second messenger in the cardiovas-cular systemrdquo Japanese Heart Journal vol 36 no 2 pp 127ndash1771995


[48] R A Cohen ldquoThe role of nitric oxide and other endothelium-derived vasoactive substances in vascular diseaserdquo Progress inCardiovascular Diseases vol 38 no 2 pp 105ndash128 1995

[49] W H Koppenol J J Moreno W A Pryor H Ischiropoulosand J S Beckman ldquoPeroxynitrite a cloaked oxidant formed bynitric oxide and superoxiderdquo Chemical Research in Toxicologyvol 5 no 6 pp 834ndash842 1992

[50] Z S Katusic ldquoVascular endothelial dysfunction does tetrahy-drobiopterin play a rolerdquo American Journal of PhysiologymdashHeart and Circulatory Physiology vol 281 no 3 pp H981ndashH986 2001

[51] F Arrigoni B Ahmetaj and J Leiper ldquoThe biology andtherapeutic potential of the DDAHADMA pathwayrdquo CurrentPharmaceutical Design vol 16 no 37 pp 4089ndash4102 2010

[52] R Schulz D Schmidt A Blum et al ldquoDecreased plasma levelsof nitric oxide derivatives in obstructive sleep apnoea responseto CPAP therapyrdquoThorax vol 55 no 12 pp 1046ndash1051 2000

[53] M S M Ip B Lam L-Y Chan et al ldquoCirculating nitric oxideis suppressed in obstructive sleep apnea and is reversed bynasal continuous positive airway pressurerdquoAmerican Journal ofRespiratory and Critical Care Medicine vol 162 no 6 pp 2166ndash2171 2000

[54] A Alonso-Fernandez F Garcıa-Rıo M A Arias et al ldquoEffectsof CPAP on oxidative stress and nitrate efficiency in sleepapnoea a randomised trialrdquoThorax vol 64 no 7 pp 581ndash5862009

[55] YOzkanH Firat B SimsekMTorun and S Yardim-AkaydinldquoCirculating nitric oxide (NO) asymmetric dimethylarginine(ADMA) homocysteine and oxidative status in obstructivesleep apnea-hypopnea syndrome (OSAHS)rdquo Sleep and Breath-ing vol 12 no 2 pp 149ndash154 2008

[56] A Barcelo M de la Pena O Ayllon et al ldquoIncreased plasmalevels of asymmetric dimethylarginine and soluble CD40 ligandin patients with sleep apneardquo Respiration vol 77 no 1 pp 85ndash90 2009

[57] M Yuksel H K Okur Z Pelin A V Ogunc and L OzturkldquoArginase activity and nitric oxide levels in patients withobstructive sleep apnea syndromerdquo Clinics vol 69 no 4 pp247ndash252 2014

[58] A Barcelo C Miralles F Barbe M Vila S Pons and A GN Agustı ldquoAbnormal lipid peroxidation in patients with sleepapnoeardquo European Respiratory Journal vol 16 no 4 pp 644ndash647 2000

[59] L Lavie A Vishnevsky and P Lavie ldquoEvidence for lipidperoxidation in obstructive sleep apneardquo Sleep vol 27 no 1 pp123ndash128 2004

[60] G E Carpagnano S A Kharitonov O Resta M P Foschino-Barbaro E Gramiccioni and P J Barnes ldquo8-Isoprostanea marker of oxidative stress is increased in exhaled breathcondensate of patients with obstructive sleep apnea after nightand is reduced by continuous positive airway pressure therapyrdquoChest vol 124 no 4 pp 1386ndash1392 2003

[61] G L Milne Q Dai and L J Roberts II ldquoThe isoprostanesmdash25years laterrdquo Biochimica et Biophysica Acta vol 1851 no 4 pp433ndash445 2015

[62] S Ozben N Huseyinoglu F Hanikoglu et al ldquoAdvancedoxidation protein products and ischaemia-modified albumin inobstructive sleep apneardquo European Journal of Clinical Investiga-tion vol 44 no 11 pp 1045ndash1052 2014

[63] E Hopps B Canino V Calandrino M Montana R Lo Prestiand G Caimi ldquoLipid peroxidation and protein oxidation are

related to the severity of OSASrdquo European Review for Medicaland Pharmacological Sciences vol 18 no 24 pp 3773ndash37782014

[64] M Yamauchi H Nakano J Maekawa et al ldquoOxidative stressin obstructive sleep apneardquo Chest vol 127 no 5 pp 1674ndash16792005

[65] J Xie J Jiang K Shi et al ldquoDNA damage in peripheral bloodlymphocytes from patients with OSAHSrdquo Sleep and Breathingvol 18 no 4 pp 775ndash780 2014

[66] Y S Kim J W Kwak K E Lee et al ldquoCan mitochondrialdysfunction be a predictive factor for oxidative stress in patientswith obstructive sleep apneardquo Antioxidants amp Redox Signalingvol 21 no 9 pp 1285ndash1288 2014

[67] K Christou A N Moulas C Pastaka and K I GourgoulianisldquoAntioxidant capacity in obstructive sleep apnea patientsrdquo SleepMedicine vol 4 no 3 pp 225ndash228 2003

[68] A Barcelo F Barbe M de la Pena et al ldquoAntioxidant status inpatients with sleep apnoea and impact of continuous positiveairway pressure treatmentrdquo European Respiratory Journal vol27 no 4 pp 756ndash760 2006

[69] P Faure R Tamisier J-P Baguet et al ldquoImpairment of serumalbumin antioxidant properties in obstructive sleep apnoeasyndromerdquo European Respiratory Journal vol 31 no 5 pp1046ndash1053 2008

[70] E Wysocka S Cofta M Cymerys J Gozdzik L Torlinski andH Batura-Gabryel ldquoThe impact of the sleep apnea syndromeon oxidant-antioxidant balance in the blood of overweight andobese patientsrdquo Journal of Physiology and Pharmacology vol 59supplement 6 pp 761ndash769 2008

[71] M S Hoffmann P Singh R Wolk A Romero-Corral SRaghavakaimal and V K Somers ldquoMicroarray studies ofgenomic oxidative stress and cell cycle responses in obstructivesleep apneardquo Antioxidants and Redox Signaling vol 9 no 6 pp661ndash669 2007

[72] S JelicM Padeletti SMKawut et al ldquoInflammation oxidativestress and repair capacity of the vascular endothelium inobstructive sleep apneardquo Circulation vol 117 no 17 pp 2270ndash2278 2008

[73] B T Patt D Jarjoura D N Haddad et al ldquoEndothelialdysfunction in themicrocirculation of patients with obstructivesleep apneardquo The American Journal of Respiratory and CriticalCare Medicine vol 182 no 12 pp 1540ndash1545 2010

[74] S Varadharaj K Porter A Pleister et al ldquoEndothelial nitricoxide synthase uncoupling a novel pathway in OSA inducedvascular endothelial dysfunctionrdquo Respiratory Physiology ampNeurobiology vol 207 pp 40ndash47 2015

[75] M S M Ip H-F Tse B Lam K W T Tsang and W-K LamldquoEndothelial function in obstructive sleep apnea and responseto treatmentrdquoAmerican Journal of Respiratory and Critical CareMedicine vol 169 no 3 pp 348ndash353 2004

[76] Y Ohike K Kozaki K Iijima et al ldquoAmelioration of vascularendothelial dysfunction in obstructive sleep apnea syndrome bynasal continuous positive airway pressure possible involvementof nitric oxide and asymmetric NG NG-dimethylargininerdquoCirculation Journal vol 69 no 2 pp 221ndash226 2005

[77] L Loffredo A M Zicari F Occasi et al ldquoEndothelial dys-function and oxidative stress in children with sleep disorderedbreathing role of NADPHoxidaserdquoAtherosclerosis vol 240 no1 pp 222ndash227 2015

[78] D Monneret J-L Pepin D Godin-Ribuot et al ldquoAssociationof urinary 15-F2t-isoprostane level with oxygen desaturation


and carotid intima-media thickness in nonobese sleep apneapatientsrdquo Free Radical Biology and Medicine vol 48 no 4 pp619ndash625 2010

[79] MGrebeH J EiseleNWeissmann et al ldquoAntioxidant vitaminC improves endothelial function in obstructive sleep apneardquoAmerican Journal of Respiratory and Critical Care Medicine vol173 no 8 pp 897ndash901 2006

[80] N J Buchner I Quack M Woznowski C Stahle U Wenzeland L C Rump ldquoMicrovascular endothelial dysfunction inobstructive sleep apnea is caused by oxidative stress andimproved by continuous positive airway pressure therapyrdquoRespiration vol 82 no 5 pp 409ndash417 2011

[81] A A El Solh R Saliba T Bosinski B J B Grant E Berbaryand N Miller ldquoAllopurinol improves endothelial functionin sleep apnoea a randomised controlled studyrdquo EuropeanRespiratory Journal vol 27 no 5 pp 997ndash1002 2006

[82] R Schulz G Murzabekova B Egemnazarov et al ldquoArterialhypertension in amurinemodel of sleep apnea role of NADPHoxidase 2rdquo Journal of Hypertension vol 32 no 2 pp 300ndash3052014

[83] N R Prabhakar G K Kumar and Y-J Peng ldquoSympatho-adrenal activation by chronic intermittent hypoxiardquo Journal ofApplied Physiology vol 113 no 8 pp 1304ndash1310 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


atrioventricular conduction blocks atrial fibrillation andventricular arrhythmias It is hypothesized that through thesearrhythmias OSA can cause sudden cardiac death howeverthe evidence for this is still somewhat circumstantial [11]

The deleterious effects of OSA on the CV system arecarried over into daytime hours Thus up to one half ofthese patients suffer from arterial hypertension The OSA-associated arterial hypertension is characterized by a nondip-ping 24-hour BP pattern and a high percentage of refractoryandmasked hypertension [12ndash14] Mainly through its pressoreffects OSA increases the risks for stroke heart failureand myocardial infarction [5] In addition this may lead tomore rapid expansion of aortic aneurysms [15] OSA canalso cause pulmonary hypertension however this occursin a lower proportion of patients and usually is not verypronounced [16] Furthermore it may be a risk factor forthromboembolic disorders such as deep vein thrombosis andpulmonary embolism [17] Finally otherwise healthy OSApatients can already display more subtle CV changes such asendothelial dysfunction and vascular remodeling [18 19]

CV risk in OSA depends on the severity of SDB that isthose patients with an apnea-hypopnea-index exceeding 30per hour of sleep are mainly affected [5] Most studies eval-uating CV morbidity and mortality in OSA have primarilyenrolled typical sleep laboratory cohorts that is middle-agedobese men

However more recent data show that CV risk is alsoincreased in other subsets of OSA patients such as womenand the elderly [20 21] Of note this is independent fromestablished CV risk factors such as advanced age obesitysmoking and metabolic disorders

It is well known that sleep characteristics such as sleepduration and the ability to fall asleep or maintain normalsleep can impact on CV health [22 23] Consequently thoseOSA patients who suffer from insomnia or excessive daytimesleepiness have a higher CV risk than those who do not [24]

3 Pathophysiology of OSA-AssociatedCardiovascular Diseases

Over the last two decades the intermediary pathways linkingOSA to CV disease have been further elucidated The maintrigger of these metabolic and cellular changes is IH that isthe nocturnal hypoxia-reoxygenation events accompanyingOSA Other OSA-associated stimuli such as hypercapniaarousals and intrathoracic pressure swings may also playsignificant roles however this has been less extensivelystudied

One major pathogenic mechanism of CV disease inOSA is sympathetic activation [25] It is mediated byenhanced chemoreflex activity in the carotid body Fur-thermore inflammatory changes within the vasculature andthe adipose tissue which are due to NF120581B activation havebeen described [26 27] Additional pathways include theupregulation of hypoxia-sensitive endothelial-derived pep-tides such as endothelin and vascular endothelial growthfactor enhanced coagulation and decreased fibrinolysis aswell as disturbed vascular repairmechanisms [28ndash31] Finally

0

10

20

30

40

50

1995 2000 2005 2010 2015

Num

ber o

f art

icle

s

Year of publication

Figure 1 Publications found in Pubmed with the search terms ofldquosleep apneardquo ldquocardiovascularrdquo and ldquooxidative stressrdquo

OSA is linked to insulin resistance and dyslipidemia whichmay also contribute to the emergence of CV disease [32 33]

Another potential mechanism of CV disease in OSA isan increased oxidative stress Under physiologic conditionsthere is a balance between aggressive and protective factorsinfluencing redox control The term ldquooxidative stressrdquo refersto an imbalance between reactive oxygen species (ROS)and reactive nitrogen species production and the systemof antioxidant defense resulting in a serious disorder ofredox homeostasis [34] Oxidative stress has been reportedto underlie the process of aging and plays a role in thepathogenesis of such different diseases as cancer chronicinflammatory and neurodegenerative disorders [35] Fur-thermore there is a strong correlation between oxidativestress and CV diseases such as atherosclerosis hypertensionand endothelial dysfunction [36]

4 Evidence for Oxidative Stress inHumans with OSA

In the following paragraphs the various aspects of oxidativestress in patients with OSA will be discussed in moredetail For this purpose a Pubmed search was performedwith the search terms ldquosleep apneardquo ldquocardiovascularrdquo andldquooxidative stressrdquo As can be seen from Figure 1 this searchyielded a growing number of publications dating back tothe late 1990s Overall a total of 292 entries were retrievedOnly full-length original publications dealing with humansubjects with OSA were taken into consideration With a fewexceptions replication studies as well as those not evaluatingthe effects of CPAP therapy on oxidative stress parameterswere excluded Following this strategy 36 publications wereselected for this review article

41 Methodological Aspects of Studies The studies exploringoxidative stress in OSA have employed different method-ological approaches Most commonly biomarkers of oxida-tive stress were determined in peripheral venous bloodsamples obtained after sleep Other studies aimed to inte-grate CV surrogate markers such as vasoreactivity and

































Change ofbiomarker

Effects ofCPAP


















5 Conclusions




Endothelial cells

eNOS

NO

ADMA

Leukocytes

NOX

ROS


Antioxidantcapacity


(iii) Paraoxonase-1




Abbreviations




References































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































Change ofbiomarker

Effects ofCPAP


















5 Conclusions




Endothelial cells

eNOS

NO

ADMA

Leukocytes

NOX

ROS


Antioxidantcapacity


(iii) Paraoxonase-1




Abbreviations




References































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Endothelial cells

eNOS

NO

ADMA

Leukocytes

NOX

ROS


Antioxidantcapacity


(iii) Paraoxonase-1




Abbreviations




References































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article obstructive sleep apnea, oxidative stress...

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