Serum visfatin and omentin levels in slow coronary flow

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Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

www.revportcardiol.org

ORIGINAL

ARTICLE

Serum

visfatin

and

omentin

levels

in

slow

coronary

ﬂow

Taner

Ucgun

a

_,

_Cengiz

_Bas

_¸ar

b,∗

_,

_Ramazan

_Memis

_¸o˘

_gulları

a

_,

_Hilmi

_Demirin

a

_,

Yasin

Türker

c

,

Yusuf

Aslantas

¸

c

a_Department_of_{Biochemistry,}_Düzce_University_Faculty_of_Medicine_Hospital,_Düzce,_Turkey

b_Department_of_Cardiology,_Düzce_Atatürk_State_Hospital,_Düzce,_Turkey_Düzce_State_Hospital,_Düzce,_Turkey c_Department_of_Cardiology,_Duzce_University_Faculty_of_Medicine_Hospital,_Istanbul,_Turkey

Received12March2014;accepted22April2014 Availableonline4December2014

KEYWORDS Slowcoronaryﬂow; Visfatin;

Omentin

Abstract

Objective: Theadipocytokinesvisfatinandomentinhaveadirecteffectoninflammationand endothelialinjury.Theexpressionofvisfatiniscloselyassociatedwiththeexpressionof proin-flammatorycytokines.Omentinhasananti-inflammatoryeffectandisinverselyassociatedwith coronaryarterydisease(CAD).Theslowcoronaryflowphenomenonisanangiographicfinding characterized by delayeddistal vessel opacification intheabsence ofsignificant epicardial coronarydisease.ThepathophysiologyofSCFhasnotbeenclearlyidentified,although multi-pleabnormalitiesincludingendothelialdysfunction,atherothrombosisandinflammationhave beenreported.However,therelationshipbetweenvisfatin,omentinandSCFisstillunknown. Inthisstudy,weaimedtoinvestigatetherelationshipoftheseadipocytokineswithSCF. Methods:The study included slow coronary flow (n=45) and normal coronary flow (n=55) subjects, according tothe corrected TIMI frame count,who underwent angiographyinthe catheterizationlaboratoryofDuzceUniversity.StatisticalanalyseswereperformedwithSPSS version12.

Results:VisfatinlevelsweresignificantlyhigherinpatientswithSCFthanincontrols(p<0.001). PlasmaomentinlevelswerelowerintheSCFgroupthanincontrols,althoughwithoutstatistical significance.Visfatin,genderandplateletcount weresignificantpredictorsofSCFin multi-variatelogisticregressionanalysis(OR0.748,95%CI0.632---0.886,p=0.01;OR30.016,95%CI 4.355---206.8,p=0.01;OR1.028,95%CI1.006---1.050,p=0.011,respectively).

Conclusion: Adipocytokinessuchasvisfatinandomentinmayplayaroleinthepathogenesisof coronaryslowﬂow.

∗_{Corresponding}_author.

E-mailaddress:basarcengiz84@gmail.com(C.Bas¸ar).

http://dx.doi.org/10.1016/j.repc.2014.04.007

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PALAVRAS-CHAVE Fluxocoronáriolento; Visfatina;

Omentin

Níveisséricosdevisfatinaeomentinnoﬂuxocoronáriolento

Resumo

Objetivo:Avisfatinaeoomentinsãoadipocitocinasetêmumefeitodiretosobreainflamaçãoe alesãoendotelial.Aexpressãodavisfatinaestáintimamenteassociadacomaexpressãode cito-quinaspró-inflamatórias.Oomentintemefeitoanti-inflamatórioeestáinversamenteassociado comadoençacoronária(DC).Ofenómenodofluxocoronáriolento(FCL)éumachado angiográ-ficocaracterizadaporatrasodeopacificaçãodistalnaausênciadedoençacoronáriaepicárdica significativa.AfisiopatologiadoFCLnãoestáclaramenteidentificada,apesardeteremsido relatadasvárias alterações,incluindodisfunção endotelial,aterotromboseeinflamação.No entanto,arelação entrevisfatina,oomentin eaFCLaindaédesconhecida. Nesteestudo, procurou-seinvestigaressasrelaçõesdasadipocitocinascomoFCL.

Métodos: Noestudoforamincluídosindivíduoscomfluxocoronáriolento(n=45)efluxo coro-nárionormal(n=55)deacordocomacontagemcorrigidadequadrosTIMI,quenecessitavam deangiografianolaboratóriodecateterismodaUniversidadedeDuzce.Asanálisesestatísticas foramrealizadascomoprogramaestatísticoSPSS12.

Resultados: OsníveisdevisfatinaforamsignificativamentemaisaltosempacientescomFCL doquenosdogrupocontrole(p<0,001).Osníveisplasmáticosdeomentinforammenores no grupo FCL do que nos controles, embora sem significado estatístico. Numa análise de regressãologísticamultivariadaavisfatina,ogéneroeacontagemdeplaquetasforamdefinidos comopreditoressignificativosdaFCL(respetivamente,OR0,748,IC95%0,632-0,886,p=0,01; OR30,016,95%CI4,355-206,8,p=0,01eOR1.028,IC95%1,006-1,050,p=0,011).

Conclusão:Asadipocitocinas,porexemploavisfatinaeoomentin,podem desempenharum papelnapatogénesedoﬂuxocoronáriolento.

Introduction

Theslowcoronaryﬂow(SCF)phenomenonwasidentiﬁedas adiscreteclinicalentityin19721_in_which_distal

opaciﬁca-tionofthecoronaryarteryisdelayedonangiographyinthe

absenceofsigniﬁcantcoronaryarterydisease.Another

fea-ture of SCFis its frequent occurrence inassociation with

morewidespreadvascularabnormalities.SCFisafrequent

ﬁndinginpatientspresentingwithacutecoronarysyndrome,

usuallyunstableangina.

Althoughsomeunderlyingetiologiessuchasabnormally

high microvascular resistance and widespread

atheroscle-rosis of the coronary arteries have been proposed, the

exact pathophysiological mechanism of this phenomenon

remains unclear. In some patients, diffuse atherosclerosis

or diffuse calciﬁcations have been identiﬁed on

intravas-cularultrasound.2---4 _Other _factors_that_may_cause _SCF_are

abnormalitiesinthecoronarymicrocirculation,

microvascu-larendothelialdysfunctionandinﬂammation.5

Inﬂammation is controlled by various hormones and

cytokines. Adipose tissue secretes a variety of

adipocy-tokines,includingleptin,adiponectin,visfatin,TNF-␣,IL-6

andomentin,anditisconsideredanendocrineorgandueto

itseffectsonmetabolisminseveralorgansandsystems.6

The inﬂammatory cytokine visfatin playsa key role in

delayedneutrophilapoptosisinsepsis.Itishighlyenriched

in the visceral fat of both humans and mice, and its

plasmalevelsincreaseduringthedevelopmentofobesity,7

aswellasbeingelevatedinpatientswithtype2diabetes,

suggesting that measurement of plasma visfatin can be a

usefultoolforunderstandingmetabolicdiseases.8,9

Omentinisarecentlyidentiﬁedadipokinethatis

selec-tively expressed in visceral adipose tissue.10,11 _Recent

studieshaveshownthatomentinlevelsarenegatively

cor-related with acute coronary syndrome and stable angina

pectoris.12_Plasma_omentin_levels_correlate_negatively_with

systolicblood pressure,hemoglobinA1C, bodymassindex

(BMI)andtotalcholesterollevels,andpositivelywithHDL

cholesterol.13

Therelationshipbetweenplasmalevelsofthese

adipocy-tokines and SCF has not been investigated. We aimed to

investigatetherelationsofvisfatinandomentinplasma

lev-elswithSCF.

Methods

Forty-ﬁve consecutive patients who had undergone

coro-nary angiography in Duzce University School of Medicine

CardiologyClinicbetweenJune2012andJanuary2013and

werefoundtohaveslowcoronaryﬂowwereincludedinthe

study.Fifty-ﬁveconsecutivepatientswithcompletely

nor-malcoronaryarterieswererecruitedasthecontrolgroup.

Theindicationsforcoronaryangiographywerestableangina

andpositivetreadmilltest.Patientswithahistoryof

conges-tiveheartfailure,CADincludingspasm,plaque,orectasia,

valvular heart disease, hyperthyroidism, chronic

obstruc-tive pulmonary disease and patients with acute coronary

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Table1 Demographicandclinicalcharacteristicsofthestudygroups. Controls(n=55) SCFgroup(n=45) p Male,n(%) 30(54) 33(70) <0.001 Age(mean±SD) 57.8±9.3 59.4±9.2 0.82 Diabetes,n(%) 12(21) 10(22) 0.832 Hypertension,n(%) 22(40) 20(44) 0.814 Smoking,n(%) 11(20) 22(48) <0.001 Obesity,n(%) 17(30) 27(60) 0.007 Hyperlipidemia,n 6 5 0.88 FamilyhistoryofCHD,n 9 7 0.17 Statinuse,n 5 5 0.756 BMI(kg/m2₎_(mean_±_SD) _27.5_±1.8 _28.6_±1.8 _0.010

BMI:bodymassindex;CHD:coronaryheartdisease;SCF:slowcoronaryﬂow.

of 30 or higher were considered obese. Coronary angiog-raphywasperformedusingthestandardJudkinstechnique andtheresultswereanalyzedbyatleasttwocardiologists. Slowcoronaryﬂowwasdeﬁnedasacorrected TIMIframe count>27withacorrectionfactorof1.7fortheleft ante-riordescending coronaryartery (LAD) based upon images acquiredat30frames/s.The studyprotocolwasapproved bytheEthicsCommitteeofDuzceUniversityandallsubjects providedwrittenconsent.

CalculationofTIMIframecount

We usedthe TIMIframe countmethod developedby Gib-sonetal.forobjectiveevaluationofcoronarybloodﬂow.14

Brieﬂy, theframe countwascalculated asthe numberof

angiographic frames elapsed until the contrast material

arrivedat thepre-speciﬁed distalmarkeroftheindividual

coronaryartery.Becauseofitsgreaterlength,thecorrected

TIMIframecountfortheLADwascalculatedbydividingthe

countedvalueby1.7.Theﬁrstframewasconsideredtobe

thatatwhich>70%lumenopaciﬁcationwithantegrade

ﬁll-ingwasnoted.Theframeinwhichdyeopaciﬁcationreached

acertaindistallandmarkineachvesselwasacceptedasthe

ﬁnalframe.NormalTIMIframecountvaluesare36.2±2.6,

22.2±4.1,20.4±3forLAD,leftcircumﬂexandrightcoronary

artery,respectively.14

Serumvisfatinandomentinmeasurements

Plasmavisfatinconcentrationsweremeasuredinduplicate

withahumanvisfatin(COOH-terminal)enzyme

immunomet-ricassay(PhoenixPharmaceuticals,Belmont,CA)performed

onan Alisei QualitySystem (SEACRadim Group, Pomezia,

Italy). Assay sensitivity was 2 ng/ml, and interassay and

intra-assay coefﬁcients of variation were <10% and <5%,

respectively. Plasma omentin-1 levels were determined

usinganenzyme-linkedimmunosorbentassay(ELISA)(USCN

LifeScienceInc.,Cologne,Germany).Intra-andinterassay

coefﬁcientsofvariationfortheomentinELISA were<6.7%

and<9.1%,respectively.

Statisticalanalysis

Statistical Packagefor the Social Sciences software(SPSS

12,Chicago,IL,USA)wasusedfortheanalysis.Descriptive

parameterswere expressed as mean±standard deviation

oraspercentages.The Kolmogorov-Smirnovtest wasused

totestfornormalityofdistribution.Abnormallydistributed

variableswere compared using the Mann-Whitney U test.

Independentsample t testsandPearson’schi-squaretests

wereusedtoanalyzethedifferencesinmeansand

propor-tions between groups. Comparisons between groups were

testedwithANOVA.Logisticregressionanalysiswasusedto

assesspredictorsofslowcoronaryﬂow.Variableswithp<0.1

by univariate analysis were included in the multivariate

logisticregressionanalysismodelandrespectiveoddsratios

(OR) and 95% conﬁdence intervals (CI) were calculated.

Continuous variables were expressed asmeans±standard

deviation.Apvalue<0.05wasconsideredsigniﬁcant.

Results

Forty-ﬁve patients (33 men and 12 women, mean age

59.4±11.5years)werediagnosedashavingSCF.Thecontrol

groupwasmadeupof55individuals(30menand25women,

meanage57.8±9.9years)withnormalcoronaryvessels.The

demographicandclinicalcharacteristicsofthestudygroups

areshowninTable1.

RatesofobesityandsmokingandBMIvalueswere

signi-ﬁcantlyhigherinthe SCFgroupthan inthe controlgroup

(p<0.05) (Table 1). As shown in Table 2, there were no

differences in laboratory variables, including white blood

cellcount,lipidparameters,andcreatinine, betweenthe

twogroups.However,hemoglobin,plateletcountandmean

plateletvolumewerehigherinSCFpatientsthanincontrols

(p<0.05).

Visfatin andomentinlevelsaresummarized inTable3.

Visfatin levels were signiﬁcantly higher in the SCF group

(p<0.001),while omentinlevelsweresimilarbetweenthe

twogroups(p=0.75).

In univariate analysis, visfatin, gender, smoking,

obe-sity,hemoglobin,plateletcountandmeanplateletvolume

were signiﬁcantly correlated with SCF (Table 4). Among

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Table2 Comparisonoflaboratoryﬁndingsinthestudygroups. Controls(n=55) SCFgroup(n=45) p WBCcount,103_/_␮l _5.8_±_1.9 _6.2_±_1.2 _0.51 Hemoglobin,g/dl 11.4±1.5 12.1±1.2 0.04 Hematocrit,% 34.9±4.5 36.3±4.5 0.11 Plateletcount,103_/_␮l _238.4_±_33.6 _266.2_±_54.2 _0.01 MPV,ﬂ 7.14±1.03 7.75±0.95 0.009 ALT,U/ml 18.5_±7.48 18.7_±4.8 0.909 AST,U/ml 17.5±6.2 18.9±3.3 0.497 TC,mg/dl 174.6_±39.7 177.6_±42.6 0.743 LDL-C,mg/dl 88.4±32.8 95.4±34.2 0.361 HDL-C,mg/dl 41.5_±25.2 38.7_±12.9 0.562 Triglycerides,mg/dl 157.7±61 159.2±93.3 0.931 BUN,mgr/dl 18.6±11.1 15.91±4.4 0.18 Creatinine,mg/dl 0.96±0.19 0.99±0.4 0.71

ALT:alanineaminotransferase;AST:aspartateaminotransferase;BUN:bloodureanitrogen;HDL-C:high-densitylipoproteincholesterol; LDL-C:low-densitylipoproteincholesterol;MPV:meanplateletvolume;SCF:slowcoronaryﬂow;TC:totalcholesterol;WBC:whiteblood cell.

Table3 Visfatinandomentinlevelsinthestudygroups.

Controls(n=55) SCFgroup(n=45) p

Visfatin,ng/ml 9.175±4.63 17.038±8.86 <0.001

Omentin,ng/ml 6.356_±2.89 6.11_±3.83 0.754

SCF:slowcoronaryﬂow.

Table 4 Predictors of slow coronary ﬂow in univariate analysis. OR 95%CI p Visfatin 0.829 0.751---0.915 <0.001 Omentin 1.020 0.897---1.160 0.759 Male 0.145 0.054---0.39 <0.001 Age 0.986 0.946---1.028 0.518 Diabetes 0.875 0.295---2.593 0.810 Hypertension 0.833 0.340---2.07 0.610 Smoking 0.135 0.04---0.445 <0.001 Obesity 0.394 0.159---0.977 0.045 Hemoglobin 0.693 0.491---0.978 0.037 Plateletcount 1.018 1.003---1.034 0.018 MPV 0.998 0.987---1.009 0.009 TC 1.000 0.994---1.005 0.934 LDL-C 1.000 0.975---1.030 0.339 HDL 0.994 0.980---1.007 0.359 Triglycerides 1.000 0.984---1.032 0.357

HDL-C:high-densitylipoproteincholesterol;LDL-C:low-density lipoproteincholesterol;MPV:meanplatelet volume;TC: total cholesterol.

signiﬁcantpredictorsofSCFinmultivariatelogistic regres-sionanalysis(Table5).

Discussion

Adipocytokinessuchasleptin,resistin,visfatinandomentin

arecurrently being investigatedaspotential drug targets

Table5 Independentpredictorsofslowcoronaryﬂowin logisticregressionanalysis.

OR 95%CI p

Visfatin 0.748 0.632---0.886 0.013 Malegender 30.016 4.355---206.8 0.011 Plateletcount 1.028 1.006---1.050 0.01

intype2diabetes,lipidmetabolismdisorders,endothelial dysfunctionandinﬂammatorydiseasesingeneral.

SCFis consideredavariant ofCAD, butitsexactcause has not been fully elucidated. Several mechanisms have beenproposed,includingmicrovascularvasomotor dysfunc-tion,diffuseatherosclerosis,small-vesselinﬂammation,and endothelialdysfunction.15 _In_this_study,_we_aimed_to

inves-tigatetherelationshipbetweencoronaryslowﬂowandthe

adipocytokinesvisfatinandomentin.

Visfatin is the most recently discovered of the family

of adipocytokines and has been described as an

inﬂam-matory cytokine. Increased expression of visfatin mRNA

has been observed in inﬂammatory conditions including

atherosclerosisand inﬂammatoryboweldisease.16 _Visfatin

isregardedasaninﬂammatorymediator,localizedtofoam

cell macrophages within unstable atherosclerotic lesions,

that potentially plays a role in plaque destabilization.17

Plasma visfatin concentrations increase in patients with

overweight/obesity, type 2 diabetes, metabolic syndrome

and cardiovascular disease, and circulating visfatin level

ispositivelyassociatedwithinsulinresistance.7,9_However,

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has not been investigated. Our ﬁndings show that

vis-fatin levels is signiﬁcantly higher in patients with SCF

(p<0.001).

Omentin is a novel fat depot-speciﬁc adipokine that

was identiﬁed in 2003 from a visceral omental adipose

tissue cDNA library and has anti-inﬂammatory effects.18

The omentin gene is located in the 1q22-q23

chromoso-mal region, which has been linked to type 2 diabetes

in several populations, suggesting that it may be a

candidate gene for type 2 diabetes susceptibility in

humans.19,20

Severalclinicalstudieshave shownthatserumomentin

is signiﬁcantly decreased in obese patients and patients

withpolycysticovarysyndromeordiabetes.21,22_In_addition,

circulating omentin levels are negatively correlated with

metabolicriskfactors,includingBMI,waistcircumference,

andinsulinresistance.21,22_A_negative_correlation_of_omentin

has alsobeen shown withincreased carotidintima-media

thicknessinpatientswithmetabolicsyndrome.23 _De_Souza

Batista et al. showed that omentin gene expression was

decreasedwithobesityanddecreasedomentinlevelswere

associatedwithincreasingobesityandinsulinresistance.24

However,nopreviousstudieshaveclariﬁedtherelationship

ofserumomentinwithSCF.

Inourstudythemeanplasmalevelofomentinwaslower

intheSCFgroupthanincontrols, althoughthedifference

wasnotstatisticallysigniﬁcant(p=0.754).

Study

limitations

Apossiblelimitationofthestudywasthesmallstudy

popula-tion.Theoddsratioofmalegenderwasverylarge,possibly

due tothe small sample size. Further studies withlarger

studypopulationsarerequired.

Conclusion

According to our results, the adipocytokines visfatin and

omentinmayplayaroleinthepathogenesisofslow

coro-naryﬂow.InordertoclarifytheirrelationshipwithSCFand

to investigate their potential as drugtargets in

endothe-lialdysfunctionandinﬂammatorydiseases,thesemolecules

shouldbestudiedinlargergroups.

Ethical

disclosures

Protection of human and animal subjects.The authors

declarethatnoexperimentswereperformedonhumansor

animalsforthisstudy.

Conﬁdentialityofdata.Theauthorsdeclarethatnopatient

dataappearinthisarticle.

Right to privacy and informed consent.The authors

declarethatnopatientdataappearinthisarticle.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

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