Effects of positive airway pressure therapy on cardiovascular and metabolic markers in males with obstructive sleep apnea

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RevPortPneumol.2017;23(4):193---202

www.revportpneumol.org

ORIGINAL

ARTICLE

Effects

of

positive

airway

pressure

therapy

on

cardiovascular

and

metabolic

markers

in

males

with

obstructive

sleep

apnea

A. Feliciano

a_,b_,_∗

_,

_M.J.

_Oliveira

c

_,

_A.

_Cysneiros

a

_,

_C.

_Martinho

a

_,

_R.P.

_Reis

b_,d

_,

_D.

_Penque

e

_,

P. Pinto

f_,g_,h

_,

_C.

_Bárbara

a_,g_,h

a_Pneumology_in_Thorax_Department,_Centro_Hospitalar_Lisboa_Norte,_Lisboa,_Portugal b_Faculdade_de_Ciências_Médicas,_Universidade_Nova_de_Lisboa,_Lisboa,_Portugal

c_Servic_¸o_de_Pneumologia,_Centro_Hospitalar_de_Vila_Nova_de_Gaia_e_Espinho,_EPE,_Vila_Nova_de_Gaia,_Portugal d_Cardiology_Unit,_Hospital_Pulido_Valente,_Centro_Hospitalar_Lisboa_Norte,_Lisboa,_Portugal

e_Proteomics_Laboratory,_Departamento_de_Genética_Humana,_Instituto_Nacional_de_Saúde_Dr._Ricardo_Jorge,_Lisboa,_Portugal f_Sleep_and_Non_Invasive_Ventilation_Unit,_Thorax_Department,_Centro_Hospitalar_Lisboa_Norte,_Lisboa,_Portugal

g_Faculdade_de_Medicina,_Universidade_de_Lisboa,_Lisboa,_Portugal

h_Instituto_de_Saúde_Ambiental,_Faculdade_de_Medicina,_Universidade_de_Lisboa,_Lisboa,_Portugal

Received21October2016;accepted25February2017 Availableonline7June2017

KEYWORDS Obstructivesleep apnea; Lipidmetabolism; Glucosemetabolism; HOMA-IR; Homocysteine; PAP Abstract

Introduction:Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascu-lar/metaboliccomplications.Someanalyticalparameters(homocysteine,glycemicandlipidic proﬁles)arerecognizedmarkersoftheseconsequences.Limiteddataisavailableonthe asso-ciation of these markersand OSAS’s severity/response to positive airway pressure therapy (PAP).

Materialandmethods: In this prospective study we analyzed polysomnographic and ana-lytical data of male patients admitted to sleep laboratory. The aim was to evaluate metabolic/cardiovascular markersinsnorersandOSASpatients,torelatewithsleep param-eters andPAP response.One-hundredandthreepatientswere included,and73 (71%)were OSAS patients. OSAS patients were similar to snorers except for higher body mass index (BMI) and dyslipidemia.Severe OSAS patients showed higherglycemia, HbA1c, insulin, and insulin resistance, and lower HDL cholesterol in comparison to mild---moderate (p<0.05, p<0.05, p<0.001,p<0.001, p<0.05,respectively). Glycemic proﬁleandtriglycerideswere slightlycorrelatedwithOSAS severity.46OSASpatientswere submittedto6monthsofPAP,

∗_{Corresponding}_author.

E-mailaddress:amelia.feliciano@chln.min-saude.pt(A.Feliciano). http://dx.doi.org/10.1016/j.rppnen.2017.02.010

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194 A.Felicianoetal.

withastatisticaldecreaseinmeanvaluesofhomocysteine,glycemia,totalandLDLcholesterol (p<0.05,p<0.05,p<0.05,respectively),andinglycemiaandLDLcholesterolinseveregroup only(p<0.05,p<0.05,respectively).

Results:Thisstudydemonstratedanassociationbetweenglucosemetabolismparametersand triglycerideswithOSASseverityunderlyingthecomplexityoftheprocessleadingto cardiovas-cular/metaboliccomplicationsinthisdisorder.Moreover,homocysteine,glycemicandlipidic proﬁleschangedsigniﬁcantlyafter6monthsofPAPtherapyinOSAS,supportingits cardiovas-cularandmetabolicprotectiveeffect.

Conclusion:Our studyhasreinforced theimportanceofanalyticalcardiovascular/metabolic evaluationascomplementarytoolofdiagnosis/treatmentresponseinOSAS.

Introduction

Obstructive sleep apnea syndrome (OSAS) is a com-mon sleep and chronic respiratory disorder,1,2 _associated

with cardiovascular3---5 _and _metabolic _(such _as _obesity,6

dyslipidemia7 _and _type ₂ _diabetes)8 _{complications.} _It _has

beendifﬁcult todetermine iftheseareduetoOSASor to associatedrisk factors.Sleepfragmentation and intermit-tent hypoxia are some mechanisms contributing to OSAS complications,9,10_which_improve_with_positive_airway

pres-sure treatment (PAP). However, the impact of PAP on othermechanisms involved isstillnot wellcharacterized. Someoxidative stressbiomarkershave been associatedto OSAS morbidity.11 _Still _controversy _remains _regarding _the

bestdiagnostic/prognosticmarker.Anexampleis homocys-teine(Hcy), which is considered a‘‘promising’’ marker.12

Hcy is an intermediate product in the biosynthesis of methionineandcysteine,13_and_is_determinant_of_the

meth-ylation cycle.14 _Hcy _levels _in _adults _follow _a _circadian

variation,15 _being _lower _in _the _morning. _Studies _reported

Hcy asan independent risk factor for atherosclerosis,16,17

cerebral, and cardiovascular diseases (CVD),13,18---24 _being

related with their prognosis.18 _The _proposed _mechanisms

areitsadverseeffectsonvascularstructureandfunction,25

hypercoagulabilitystate,23 _and_depletion_of_nitric _oxide.26

Moreover,dyslipidemia,diabetes,cancer,renal,andthyroid dysfunction13,23_are_associated_with_elevated_Hcy._Also,_older

age, malegender, variousdrugs, tobacco/coffee/alcohol, andvitamins deﬁciency.13,23 _Hcy _has _been _proposed _as_an

OSASbiomarkerregardingitsrelationshipwithCVD.Studies showhigherlevelsofHcy inOSAS with27---30 _or _without31,32

pre-existingcardiacdisease.Moreoverthereare contradic-torystudiesreportingtheeffectofPAPonHcylevels.29,33---37

TheaimofthisstudywastoanalyzeHcylevelsinsnorers andOSASpatients,itscorrelation withOSASseverity,and responsetoPAP.Additionally,glycemicandlipidparameters werealsoevaluated.

Material

and

methods

This prospective study included one hundred three con-secutivemale subjectswith suspicionof OSAS, whowere evaluated at a Sleep Clinic. Demographic data included age,bodymassindex(BMI),Epworthsleepinessscale,and

medicalhistory.Exclusioncriteriawerefemalegender(to avoidhormonalinﬂuence),othersleepdisorders, neuromus-cular,renal,andthyroiddisease,heartfailure,cancer,acute disease,andpreviousPAP.

All patients underwent an overnight polysomnography (PSG)usingEmblaS7000System(Embla,USA)witha techni-cianmonitoring.Sleeprecordingandeventsweremanually analyzed according tostandard criteria.38 _The _respiratory

disturbanceindex (RDI),oxygen desaturation index(ODI), percentage of time with saturation under 90% (T90) and lowest oxygen saturation (SpO2) were calculated. Based

on RDI≥5 obstructive events/h of sleep, patients were diagnosed as OSAS (n=73) and grouped into mild (RDI 5---14.9), moderate (RDI 15---29.9), and severe (RDI≥30). Later,inpre/postOSAStreatmentanalysis,mildand moder-atepatientswerecombined(RDI<30),inordertoevaluate theextremeofdiseasespectrum.

To calculate the sample size we focused in the main objective,thatisHcyanalysisbefore/afterPAPtreatment. The sample size wascalculatedwithPS software,version 3.1.2. It was planned a study of a continuous response variablefrom matched pairsof study subjects. Prior data indicated that the differencein the responseof matched pairswasnormallydistributedwithstandarddeviation2.If thetruedifferenceinthemeanresponseofmatchedpairs is0.95,thesamplesizeneedtobeof37pairsofsubjectsto beabletorejectthenullhypothesisthatthisresponse dif-ferenceiszerowithprobability(power)0.8(i.e.beta0.20). ThetypeIerrorprobabilityassociatedwiththistestofthis nullhypothesisis0.05(i.e.alfa0.05).

According to criteria,39 _PAP _therapy _with _automatic

devices (S9, Resmed, Australia) was prescribed for 46 patients in severe disease or in disease of any severity when associated with excessivediurnal sleepiness and/or cardio/cerebrovascularcomplications.Thesepatientswere evaluated at six months for compliance registration. As described,41 _more _than ₄_h _use/night _for _at _least _70% _of

nightswasconsideredasacceptablecompliance.AfterPAP initiation,nomoreindications(excludinghealthylifestyle) weregiven,assumingareallifescenario.

Venous blood samples were collected after PSG and a 12-h fasting period, into EDTA-coated polypropylene tubes.At six monthsof PAP asecond morningblood sam-ple was collected. The collected blood was processed between 1 and 2h to determine Hcy (chemiluminescence

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Effectsofpositiveairwaypressuretherapyoncardiovascularandmetabolicmarkersinmales 195 (CLIA), ADVIA Centaur xp, Siemens). Additionally,

param-eters of glycemic proﬁle were determined, such as glucose(Enzyme UVHexoquinase --- ADVIA2400 Siemens), haemoglobin A1c (HbA1c) (HPLC --- Variant II BioRad), insulin (chemiluminescence (CLIA), ADVIA Centaur xp, Siemens) and insulin resistance (calculated by homeo-staticmodel assessment ofinsulin resistance--- HOMA-IR). Parametersoflipidproﬁlewere,also,determinedsuchas totalcholesterol(CHOD-PAP(enzymaticcolorimetric)ADVIA 2400, Siemens), low-density lipoprotein (LDL) cholesterol (bycalculation),high-densitylipoprotein(HDL)cholesterol (HDLPlus2ndgenerationelimination/catalaseADVIA2400, Siemens),andtriglycerides (Enzymaticcolorimetric(GPO) ADVIA 2400, Siemens). The HOMA-IR was determined by the product between fasting plasma glucose and insulin concentration, which has a reasonable linear correlation withthe gold standard of insulin resistance measurement (hyperinsulinemic---euglycemicclamp).40

All subjectsunderwentrestrictionof alcohol, tea, cof-fee,chocolate,beetroot,banana,avocado,tomato,plum, pineapple,kiwi,orange,nut,hazelnut,vanillacandies,and confectioneryduringthethreedayspriortoPSG.Patients underwent 24h urine collection (into a hydrochloric acid container andstoredat 4◦C)for catecholamines determi-nation(adrenaline,nor-adrenaline,anddopamine)(HPLC ---BioRad).

Thestudyprotocolwasapprovedbythelocalethics com-mitteesandallpatientsgavewritteninformedconsent.

Statistical analyses were performed using SPSS for windowssoftware(SPSS20Inc.,Chicago,IL,USA).All varia-bles were tested for normality of the distribution using Kolmogorov---Smirnovtest.Continuousvariableswithnormal distributionswereexpressedasmeans±standarddeviation (SD) and categorical variables in numbers (percentages). Pearson’sanalysiswasperformed forcorrelationsbetween parametricvariables.Independent-samplesT-testwasused forcomparisonsbetweenindependentgroupsforvaluesthat were normally distributed and paired-samples T-test was usedtocomparevariablesnormallydistributedbeforeand afterPAPtreatment.Categoricalvariableswerecompared usingX2 _test. _Results _were_considered _{statistically}

signiﬁ-cantwhenpvaluewas<0.05.

Results

Clinical and analytical evaluation of snorers and OSAS patientsareshown in Table1.There werenostatistically signiﬁcantdifferencesregardingdemographicandanalytical parameters.Instead,the existenceof knowndyslipidemia andBMIwerehigherinOSASpatients(p<0.001,p=0.001, respectively).HOMA-IR,totalcholesterol,andurinary nor-adrenalinewerehigherthannormalrangeinOSASpatients andHcywashigherthannormalrangeinbothgroups.

Concerning OSAS patients, there were no statistically differences betweenmild---moderate (46,63%) andsevere (27,37%)regardingdemographicparameters.Instead, dys-lipidemia and BMI were higher in severe OSAS patients (p<0.05,p<0.001,respectively).Glycemia,HbA1c,insulin, andHOMA-IRwerehigherandHDLcholesterolwaslowerin severegroup(p<0.05,p<0.05,p<0.001,p<0.001,p<0.05, respectively).Moreover,HbA1c,HOMA-IR,triglycerides,and

urinarycatecholamines werehigher than normalrange in severeOSASpatientsandtotalcholesterolandHcyinboth groups.

Somemetabolicparameterswereslightlycorrelatedwith OSASseverity.Glycemia,HbA1c,andtriglycerideswere pos-itivelycorrelatedwithRDI (p<0.05, Pearsoncorrelation). GlycemiaandHbA1cwerenegatively correlatedwith low-estSpO2(p<0.05,Pearsoncorrelation).Instead,insulinand

HOMA-IRwerepositivelycorrelatedwithRDI,T90,andODI (p<0.001, Pearson correlation) and negatively correlated withlowestSpO2(p<0.001)(Table2).

Clinical and analytical evaluation of OSAS treatment patients are shown in Tables 1 and 3. 46 OSAS patients underwent PAP (22 (48%) were mild---moderate and 24 (52%) were severe). Patients showed a mean compliance of4.37h/night.Additionally inPAP follow up,weightand smoking habits were always asked and there were no changes in both parameters. After six months of treat-ment,OSASpatientsshoweda statisticaldecreasein Hcy, glycemia, total and LDL cholesterol (p<0.05) (Table 3). Instead,insevere OSASonlyglycemiaandLDLcholesterol showedasigniﬁcantreduction(p<0.05).

Discussion

This study showed after six months of PAP, homocys-teine,glycemia,totalandLDLcholesteroldecreaseinOSAS patients pointing to cardiovascular/metabolic protective roleofthistreatment.

Inourstudy,HcywassimilarinsnorersandOSASpatients, andalsoindifferentOSASseverities,althoughbeinghigher thannormalrange.Hcyisanemergingindependentrisk fac-torfor CVD, but it is not clearits association withOSAS. BothsmokingandobesitymayaffectHcylevels,42---47_which

couldbeconfounders in theassociation with CVD.In this study,smokinghabitsandprevalence of CVDwere similar betweensnorersandOSASpatients,andbetweendifferent levelsofOSASseverity.Concerningobesity,snorersandOSAS patientswereobese,stillOSASpatientspresentedahigher BMI,whichcouldinﬂuencetheHcylevels.Thepresenceof obesityeveninsnorersisprobablyresponsibleforOSAS sus-picionandreferraltosleepclinic.48 _Also,_several_diseases

suchasdyslipidemia13,23_are_associated_with_elevated_levels

ofHcy,andthisdiseasewasmoreprevalentinOSASpatients. Ameta-analysis(432subjects)showedhigherHcylevels inOSASthanincontrols,49_especially_when_BMI_≥_30,_age_<₅₀

years, and severe OSAS. Other authors50,51 _also _reported

higherHcylevelsinsevereOSAS. Arecentstudy reported higherHcylevelsinpatientswithcoronaryarterydisease, withOSASandwithbothdiseases,30_and_the_highest_values

for Hcywere observedin the latter group.Further, there wasnocorrelation between Hcylevelsand oxygen desat-uration,asshowedinthepresent study.Contrarytothese results,somestudiesdidnotreportincreasedlevelsofHcy inOSASpatientswith34,35 _or_without_associated_CVD.28,29,36

Although, Hcy wasnot correlated withsleep parameters, in OSAS patients it decreased for normal values after 6 monthsof PAP therapy,which may suggest that its levels couldinpartberelatedwithOSAS.Theseresultsaresimilar toastudyof12OSASpatientswithCVD,whichreporteda reductioninHcylevelsafterPAPtherapy.33 _This_behaviour

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196

A.

Feliciano

et

al.

Table1 Initialevaluationofstudyparticipants:demographics,comorbidities,polysomnographydata,glycemicandlipidicproﬁles,homocysteine,andurinarycatecholamines

(BMI:bodymassindex;EPW:Epworthsleepinessscale;LDL:low-densitylipoprotein;HDL:high-densitylipoprotein;HOMA-IR:homeostasismodelassessment;OSAS:obstructive sleepapneasyndrome;RDI:respiratorydisturbanceindex;SD:standarddeviation;T90:desaturationtimeunder90%;U:urine).

Total Snorers OSAS Snorersvs. OSAS(p)

Mild-Mod OSAS

SevereOSAS Mild-Modvs. SevereOSAS (p) Mild-Mod OSASbefore PAP SevereOSAS beforePAP Mild-Modvs. severeOSAS beforePAP (p) N=103 N=30 N=73 N=46 N=27 N=22 N=24 Age(years) (media/SD) 46/8 45/10 46/8 0.354 46/8 47/7 0.737 47/9 47/7 0.931 Smokinghistory(n/%) 69/67.0 21/70.0 48/65.8 0.681 29/63.0 19/70.4 0.531 14/63.6 17/70.8 0.612 Alcoholconsumption (n/%) 66/64.1 15/50.0 51/69.9 0.057 30/65.2 21/77.8 0.265 15/68.2 18/75.0 0.617 BMI(kg/m2₎ (media/SD) 29.4/3.8 27.4/3.3 30.2/3.7 0.001 28.9/3.0 32.3/3.8 <0.001 29.4/2.4 32.0/3.7 0.006 Cardiacdisease(n/%) 55/53.4 13/43.3 42/57.5 0.193 23/50.0 19/70.4 0.092 12/54.5 17/70.8 0.263 Respiratorydisease (n/%) 15/14.6 2/6.7 13/17.8 0.188 7/15.2 6/22.2 0.571 3/13.6 6/25.0 0.382 Dyslipidemia(n/%) 49/47.6 4/13.3 45/61.6 <0.001 22/47.8 23/85.2 0.026 10/45.5 20/83.3 0.030 Diabetes(n/%) 7/6.8 1/3.3 6/8.2 0.374 2/4.3 4/14.8 0.115 0/0 3/12.5 0.099 EPWscale(media/SD) 9.5/4.8 9.3/5.1 9.5/4.7 0.843 9.7/4.7 9.2/4.8 0.694 11.7/4.1 9.5/5.0 0.103 RDI(events/h) (media/SD) 20.4/23.3 2.8/1.3 27.6/24.2 <0.001 11.9/6.1 54.3/19.5 <0.001 12.2/6.2 55.0/19.3 <0.001 T90(%)(media/SD) 5.6/13.2 1.6/8.1 7.2/14.5 0.047 1.0/2.3 17.9/19.6 <0.001 1.2/2.0 16.4/18.2 <0.001 Sleepefﬁciency(%) (media/SD) 79.2/14.4 77.3/14.4 79.1/14.5 0.407 80.4/14.7 79.1/14.0 0.703 75.2/18.6 77.2/13.8 0.675 LowestSpO2(%) (media/SD) 84.1/7.5 88.5/4.6 82.3/7.7 <0.001 85.3/5.4 77.1/8.3 <0.001 83.3/6.6 77.7/7.8 0.012 ODI (dessaturations/h) (media/SD) 16.8/22.5 2.2/2.9 22.8/24.2 <0.001 8.1/5.7 47.8/23.2 <0.001 8.9/6.0 48.1/23.8 <0.001 Glucose(mg/dL) (media/SD) 101.0/25.8 101.2/31.3 100.9/23.4 0.951 95.9/17.2 109.4/29.8 0.017 97.3/20.2 109.4/31.0 0.128 Glycosylated haemoglobin(%) (media/SD) 5.8/0.8 5.8/1.0 5.8/0.8 0.957 5.6/0.5 6.1/1.0 0.012 5.6/0.7 6.2/1.0 0.036 Insulin(mU/L) (media/SD) 14.7/8.6 12.7/6.8 15.5/9.1 0.124 12.4/6.8 20.9/10.1 <0.001 11.3/5.0 20.8/10.4 <0.001 HOMA-IR(media/SD) 3.8/2.8 3.3/2.8 4.0/2.8 0.241 3.1/2.2 5.7/2.9 <0.001 2.8/1.7 5.6/2.9 <0.001

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Effects of positive airway pressure therapy on cardiovascular and metabolic markers in males 197 Table1(Continued)

Total Snorers OSAS Snorersvs. OSAS(p)

Mild-Mod OSAS

SevereOSAS Mild-Modvs. SevereOSAS (p) Mild-Mod OSASbefore PAP SevereOSAS beforePAP Mild-Modvs. severeOSAS beforePAP (p) N=103 N=30 N=73 N=46 N=27 N=22 N=24 Totalcholesterol (mg/dL) (media/SD) 192.1/37.7 185.9/41.3 194.6/36.1 0.290 194.2/38.4 195.3/32.4 0.092 191.6/42.7 193.7/30.0 0.852 LDLcholesterol (mg/dL) (media/SD) 121.0/31.6 117.2/33.4 122.6/30.9 0.435 122.1/30.6 123.5/32.0 0.854 123.8/32.6 122.0/28.2 0.850 HDLcholesterol (mg/dL) (media/SD) 44.7/10.1 44.7/10.4 44.7/10.0 1.000 46.8/11.3 41.2/6.0 0.019 44.6/12.3 41.0/5.5 0.190 Triglycerides(mg/dL) (media/SD) 134.6/79.3 121.0/68.0 140.2/83.3 0.265 128.8/79.4 159.7/87.6 0.126 120.0/57.1 160.7/88.7 0.074 Homocysteine (␮mol/L) 15.2/3.4 14.7/3.3 15.3/3.5 0.399 15.3/3.8 15.3/2.9 0.997 14.9/3.1 15.6/2.6 0.436 Adrenaline(␮g/24h U)(media/SD) 19.9/15.5 17.7/16.3 20.8/54.2 0.765 13.8/12.3 32.7/87.4 0.152 14.2/13.1 34.7/92.6 0.308 Noradrenaline (_␮g/24hU) (media/SD) 85.7/180.4 64.6/28.1 94.3/213.4 0.45 63.1/35.5 147.5/345.4 0.103 62.0/35.4 149.7/365.9 0.269 Dopamine(_␮g/24hU) (media/SD) 434.6/771.5 373.9/197.0 459.5/908.5 0.611 340.9/202.1 661.5/1465.5 0.147 334.7/220.4 657.2/1550.0 0.339

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198 A.Felicianoetal. Table2 Correlationbetweenvariablesofpolysomnographyandglycemicandlipidicproﬁles,homocysteine,andurinary cate-cholamines(LDL:low-densitylipoprotein;HDL:high-densitylipoprotein;HOMA-IR:homeostasismodelassessment;ODI:oxygen desaturationindex;RDI:respiratorydisturbanceindex;T90:desaturationtimeunder90%;U:urine).

Glucose(mg/dL) Glycosylatedhaemoglobin(%) Insulin(mU/L) HOMA-IR

r p r p r p r p RDI(events/h) 0.217 0.027 0.217 0.028 0.423 <0.001 0.382 <0.001 T90(%) 0.179 0.071 0.121 0.224 0.342 <0.001 0.331 0.001 Sleepefﬁciency(%) 0.01 0.923 0.018 0.857 0.009 0.925 0.061 0.539 LowestSpO2(%) 0.264 0.007 0.242 0.014 0.321 0.001 0.372 <0.001 ODI(dessaturations/h) 0.181 0.068 0.172 0.083 0.428 <0.001 0.384 <0.001 Totalcholesterol(mg/dL) LDLcholesterol(mg/dL) HDLcholesterol(mg/dL) Triglycerides(mg/dL)

r p r p r p r p RDI(events/h) 0.087 0.385 0.056 0.577 0.123 0.215 0.205 0.038 T90(%) 0.133 0.180 0.111 0.267 0.021 0.833 0.154 0.122 Sleepefﬁciency(%) 0.115 0.246 0.126 0.206 0.012 0.908 0.002 0.986 LowestSpO2(%) 0.110 0.269 0.079 0.432 0.008 0.937 0.141 0.155 ODI(dessaturations/h) 0.094 0.343 0.081 0.421 0.119 0.229 0.175 0.076

Homocysteine(␮mol/L) Adrenaline(␮g/24hU) Noradrenaline(␮g/24hU) Dopamine(␮g/24hU)

r p r p r p r p RDI(events/h) 0.028 0.782 0.083 0.407 0.107 0.284 0.08 0.42 T90(%) 0.083 0.405 0.045 0.651 0.028 0.78 0.001 0.99 Sleepefﬁciency(%) 0.135 0.176 0.095 0.342 0.052 0.61 0.033 0.744 LowestSpO2(%) 0.001 0.992 0.029 0.773 0.044 0.659 0.013 0.899 ODI(dessaturations/h) 0.056 0.577 0.024 0.81 0.053 0.592 0.029 0.77

underPAP wasconﬁrmed in a recent meta-analysis.52 _On

thecontrary,otherstudies29,35---37_reported_that_PAP_therapy

ormandibularadvancementdevice37_did_not_inﬂuence_Hcy

levelsinOSASpatients.

Previous studies suggest that OSAS is associated with dyslipidemia7_and_type₂_diabetes.8_In_fact,_in_this_study

dys-lipidemiawasmoreprevalentinOSASpatientscomparingto snorers,althoughbothgroupsshowedsimilarglycemicand lipidproﬁles.

Indeed,someauthorsfoundthatOSASisindependently associatedwithdisordersoflipidmetabolism,53_mainly_due

tointermittent hypoxia54 _and _sleep _{fragmentation.}55

Fur-thermore,asinthisstudy,triglycerideswereassociatedwith OSASseverity.53_This_is_an_important_issue_once_dyslipidemia

isamajorcauseofatheroscleroticCVD.56

Moreover, severe OSAS showed a change in glycemic proﬁle,eveninabsenceofknowndiabetes, probably sug-gestingapre-diabeticstate,anditwascorrelatedwithsleep parameters(RDI and nocturnal desaturation). A condition characterizedbyinsulinresistanceandglucoseintolerance isknownasprediabetes.57 _Individuals_presenting_this_state

areatriskofCVDandthemajoritywilldevelopdiabetes,58,59

puttingourseverepatientsinanincreasedriskforboth dis-orders.Theseresultsareinagreementwithameta-analysis whichconﬁrmedthatmoderate/severeOSASincreasesthe risk of development of type 2 diabetes,60 _even _following

adjustmentofobesity,age,co-morbidities,andmedication use.61 _Sleep _{fragmentation} _and _intermittent _hypoxia62

seem to be involved in carbohydrate dysregulation in OSAS, with impaired lipid metabolism, inﬂammation,

oxidative stress and sympathetic nervous system activation.63

Concerning the evaluation of both proﬁles after PAP therapy, OSAS patients presented a statistical change in glycemicandlipidproﬁles,withadecreaseinglucose,total andLDLcholesterol.SometrialsprovideevidencethatPAP therapy may improve glucose metabolism64 _especially _in

sleepypatients.65_However,_other_studies_do_not_support_this

improvement,66 _but_the_duration_of_treatment_could_be_an

explanation.Arecentstudyhasshownimprovementin glu-cose metabolism with PAP therapy evenin OSAS patients (overweightorobese)withprediabetes.67_{Additionally,}_even

in non-diabeticadultswithOSAS,twometa-analyseshave reportedthatPAPtherapymodestlydecreasesHOMA-IR.68,69

AnotherstudyindiabeticOSASpatientshasshownthatone month of PAPtherapy ledtoreductionof fastingglucose, HbA1c,andHOMA-IR,withoutchangeinBMI.70

A meta-analysis reported that PAP therapy decreases total cholesterol level, especially in OSAS patients who are younger, more obese, and who use PAP for a longer period (≥12 weeks).71 _However,_in _this _{meta-analysis}_PAP

had no effect on fasting glucose or HOMA-IR. Also in a meta-regression analysis, PAP improved total and LDL cholesterol, withan increasein HDLcholesterol.7 _A _more

recentmeta-analysis72 _reported_that_PAP _{signiﬁcantly}

low-eredtotalcholesterol,triglyceride,andHDL,butnotLDL, particularlyinmoderate-severepatients,goodcompliance anddaytimesomnolence. Howeverthe magnitudeoflipid reductionwasmodestandonlysigniﬁcantinstudieswhere autonomichyperactivitywasalsoloweredbyPAP.Infact,in

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Effectsofpositiveairwaypressuretherapyoncardiovascularandmetabolicmarkersinmales 199 T able 3 OSAS, Mild-Moderate and severe OSAS patients: comparative analysis in terms of glycemic and lipidic proﬁles, homocysteine, and urinary catecholamines, before and after PA P therapy (LDL: low-density lipoprotein; HDL: high-density lipoprotein; HOMA-IR: homeostasis model assessment; OSAS: obstructive sleep apnea syndrome; PAP: positive airway pressure; U: urine). OSAS Mild-Moderate OSAS Severe OSAS n Pr e PA P P ost PA P p n Pr e PA P P ost PA P p n Pr e PA P P ost PA P p Glucose (mg/dL) 46 103.6/26.8 99.24/22.2 0.030 22 97.3/20.2 96.6/21.7 0.695 24 109.4/31.0 101.6/22.9 0.027 Glycosylated haemoglobin (%) 46 5.9/0.9 5.9/1.0 0.914 22 5.6/0.7 5.7/0.8 0.125 24 6.2/1.0 6.1/1.1 0.584 Insulin (mU/L) 46 16.3/9.5 20.9/23.1 0.169 22 11.3/5.0 12.1/5.9 0.316 24 20.8/10.4 28.9/29.6 0.206 HOMA-IR 43 4.4/2.8 5.4/6.2 0.294 20 2.9/1.8 3.0/2.0 0.762 23 5.6/2.9 7.4/7.8 0.311 Total cholesterol (mg/dL) 46 192.7/36.2 184.2/29.5 0.043 22 191.6/42.7 184.0/28.4 0.254 24 193.7/29.9 184.3/31.0 0.087 LDL cholesterol (mg/dL) 45 122.9/30.1 108.6/32.6 0.003 22 123.8/32.6 114.6/25.3 0.066 23 122.0/28.2 102.9/37.9 0.017 HDL cholesterol (mg/dL) 46 42.7/9.4 43.3/8.6 0.657 22 44.6/12.3 45.9/10.0 0.598 24 41.0/5.5 40.9/6.4 0.937 T riglycerides (mg/dL) 46 141.2/77.2 137.4/76.0 0.736 22 120.0/57.1 118.3/47.1 0.861 24 160.7/88.7 154.9/92.8 0.775 Homocysteine (␮ mol/L) 46 15.3/2.8 13.2/2.6 0.005 22 14.9/3.1 16.0/2.5 0.039 24 15.6/2.6 16.5/2.7 0.065 Adrenaline (␮ g/24 h U) 46 24.9/67.6 18.4/11.5 0.53 22 14.2/13.1 16.9/6.8 0.386 24 34.7/92.6 19.8/14.5 0.451 Noradrenaline (␮ g/24 h U) 46 107.8/266.4 54.3/22.0 0.182 22 62.0/35.4 51.3/17.4 0.212 24 149.7/365.9 56.9/25.6 0.229 Dopamine (␮ g/24 h U) 46 503.0/1130.1 311.8/132.0 0.26 22 334.7/220.4 298.8/122.0 0.453 24 657.2/1550.0 323.8/142.2 0.307

thepresentstudyOSASpatientspresentedahigher preva-lenceofdyslipidemiaandafterPAPtherewasadecreasein totalandLDLcholesterol,withoutchanginglifestylehabits. Moreover,urinarycathecolaminesdecreasetonormallevels, howeverwithoutstatistical signiﬁcance,whichcouldhave conditionedlipidloweringeffectofPAP.

Treatment withPAP in OSAS mayimprove dyslipidemia throughameliorating hypoxia, inﬂammation,73 _and _insulin

resistance.74 _However,_dyslipidemia_in_OSAS_patients_is_far

frombeingasimpleprocessbecause,besidesOSASseverity, severalfactorscancontributeforitsuchasobesity,diet,and exercise.34,53,75,76 _This _fact_and_probably_sample _size_could

explainthat theremainder of lipidic proﬁle (triglyceride, totalandHDLcholesterol)wasnotaffected byPAPinthis study.

This study showed a similar pattern of urinary cate-cholaminesbetweensnorersandOSASpatientsandbetween OSASpatientsofdifferentseverities.Additionally,insevere OSAS patients urinary catecholamines were higher than normal range. Although urinary cathecolamines were not correlatedwithsleepparameters,aftersixmonthsofPAP, theydecreased tonormal levels,nonetheless without sta-tistical signiﬁcance. These results may be due to sample sizebecauseprevious studiesreportedthat inOSAS there is an increase in sympathetic activity, independently of obesity.77 _In _fact,_Pinto_et_al.78 _reported_24-h _urinary

nor-epinephrinelevelssigniﬁcantlyhigherinsevereOSASthan in mild---moderate, with a signiﬁcant reduction after one month of PAP. Another study79 _reported _that _PAP

with-drawal resulted in rise in urinary noradrenaline and that waspositivelyassociatedwithhypoxaemiaseverity. Reduc-tionofsympatheticactivitycanbeapotentialmediatorof metabolicbeneﬁtfromPAP (withimprovement ofglucose levels)asshowninastudybyPamidietal.67

Thereare somelimitations of thisstudy,such assmall samplesize,femaleexclusion,andBMIdifferencesbetween groups.Furthermore,drugsanddiseasesthatinterferewith vitaminBmetabolism arepotential causes for higherHcy concentrations,80 _and_these_vitamins_were_not_determined

inthisstudy.

Conclusion

Thepresentstudydemonstratedanassociationbetween glu-cose metabolism parameters and triglycerides with OSAS severity, contributing to the complexity of the process leading to cardiovascular/metabolic complications in this disorder.Moreover,Hcy,glycemic,andlipidproﬁleschanged signiﬁcantlyafter6monthsofPAPtherapyinOSASpatients, supporting its cardiovascular and metabolic protective effect.

Inconclusion, ourstudy hasreinforcedthe importance ofanalytical cardiovascular/metabolicevaluation as com-plementary toolof diagnosis/treatment response in OSAS patients.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

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Conﬁdentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

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