Original papers<br>The role of insulin-like growth factor-1 in development of coronary no-reflow and severity of coronary artery disease in patients with acute myocardial infarction

The role of insulin-like growth factor-1 in development of coronary no-reflow and severity of coronary artery disease in patients with acute myocardial infarction

Ibrahim Faruk Akturk¹, Ahmet Arif Yalcin¹, Ismail Biyik², Nihan Turhan Caglar³, Nilgun Isiksacan⁴, Cetin Sarikamis¹, Fatih Uzun¹, Omer Celik¹, Ilker Murat Caglar⁵

1DepartmentofCardiology,MehmetAkifErsoyThoracicandCardiovascularSurgeryTrainingandResearchHospital,Halkali,Istanbul,

Turkey

2DepartmentofCardiology,UsakStateHospital,Usak,Turkey

3DepartmentofCardiology,IstanbulEducationandResearchHospital,Istanbul,Turkey

4DepartmentofBiochemistry,MehmetAkifErsoyThoracicandCardiovascularSurgeryTrainingandResearchHospital,Halkali,Istanbul,

Turkey

5DepartmentofCardiology,BakirkoyDrSadiKonukEducationandResearchHospital,Bakirkoy,Istanbul,Turkey

PostepKardiolInter2014;10,1(35):12–17

DOI:10.5114/pwki.2014.41460

A b s t r a c t

Introduction: Insulin-likegrowthfactor-1(IGF-1)hasatheroprotectiveeffectsviareductioninoxidativestress,cellularapoptosis,

pro-inflammatorysignaling,andendothelialdysfunction.

Aim: WehypothesizedthatlowlevelsofIGF-1maybeassociatedwiththeseverityandextentofcoronaryarterydiseaseand

developmentofthecoronaryno-reflowphenomenoninpatientswithacuteST-elevationmyocardialinfarction(STEMI)andinvesti- gatedtheroleoftheIGF-1moleculeinthecoronaryno-reflowphenomenonandseverityofcoronaryarterydisease(CAD)inpatients

withacuteSTEMIinatertiaryhospital.

Material and methods: Thestudywasconductedamong113patientsundergoingprimarypercutaneouscoronaryintervention

(PPCI)forSTEMI,ofwhom49patientsdevelopedtheno-reflowphenomenon.Coronaryno-reflowwasdefinedasThrombolysisIn

MyocardialInfarction(TIMI)flowgrade2orlessafterintervention.Insulin-likegrowthfactor-1levelsweremeasuredinbothgroups.

TheseverityandextentofCADwereevaluatedaccordingtotheGensiniandSyntaxscores.

Results: AlthoughIGF-1levelswerelowerintheno-reflowgroup,therewasnotastatisticallysignificantdifferencebetween

theno-reflowgroupandthecontrolgroup(116.65±51.72vs.130.82±48.76,p=0.130).GensiniandSyntaxscoreswerehigherin

theno-reflowgroup.TherewasnoassociationbetweenGensiniandSyntaxscoresandIGF-1levels(r=–0.071,r=0.479,r=–0.158,

p=0.113).

Conclusions: Inthisstudy,IGF-1levelswerenotstatisticallydifferentbetweenpatientsdevelopingtheno-reflowphenomenon

andcontrols.Therewasnoassociationbetweendevelopmentoftheno-reflowphenomenonandseverityofCADorIGF-1levels.

Nevertheless,largescalestudiesareneededtoverifytheseresults.

Key words: insulin-likegrowthfactor-1,no-reflow,coronaryarterydisease,ST-elevationmyocardialinfarction.

Introduction

Insulin-likegrowthfactor-1(IGF-1)hasanti-inflamma- toryandpro-repairingpropertiesthatmakeitantiathero- genic[1,2].CirculatingIGF-1ismainlyreleasedbytheliv- erundertheregulationofgrowthhormoneandexecutes

allofitsphysiologicaleffectsviabindingtoitsreceptor

[2].Todate,severalstudieshavealreadydescribedthe

Corresponding author:

Ismail Biyik MD, Asc. Prof., Department of Cardiology, Usak State Hospital, Ușak Devlet Hastanesi, Kardiyoloji Klinig˘i, 64100 Ușak, Turkey, phone: +905424173209, e-mail: ismailbiyikmd@yahoo.com

Received: 1.12.2013, accepted: 9.01.2014.

importanceofIGF-1onatherosclerosiswithitslargebi- ologicaleffectsandtherapeuticpotential.Althoughthe

resultsofthesetrialsareinconclusive,ingeneral,thereis

aninverserelationbetweenIGF-1levelsandatheroscle- rosis[2,3].Insulin-likegrowthfactor-1reducesoxidative

stress, inflammation and atherogenesis in the vascula- tureandplaysamajorroleinvasodilatoryresponsesby

regulatingnitricoxide(NO)productionintheendotheli-

um[2].No-reflowisanimportantcomplicationofprimary

percutaneouscoronaryintervention(PPCI)withpoorclin- icaloutcomes,occurringmorefrequentlyinthesetting

of acute ST-elevation myocardial infarction (STEMI) [4].

The angiographic no-reflow phenomenon is defined as

severelyimpairedforwardcoronaryflow(Thrombolysisin

MyocardialInfarction(TIMI)<3)intheabsenceofresidu- alstenosis,dissectionorthrombosis[5–9].Althoughthe

underlyingmechanismsofno-reflowremainobscure,mi- crovascularplugging,thromboticdebris,cellularedema,

reperfusioninjury,endothelialdysfunction,coronaryva- sospasmandmicrovascularspasmarelikelytobeclosely

related [4, 6, 7, 10]. The prevalence of no-reflow varies

from2%upto50%,dependingonthedefinition,recog- nition methods and selected patient population [6, 11].

Patients with no-reflow tend to experience more early

post-infarction complications, heart failure, cardiogenic

shock and death [4, 6, 10, 11]. According to our knowl- edge, there is no study investigating the interactions

betweenIGF-1levelsanddevelopmentoftheno-reflow

phenomenoninEnglishliterature.

Aim

Thus, we hypothesized that low levels of IGF-1 may

beassociatedwiththeseverityandextentofcoronary

artery disease (CAD) and development of the coronary

no-reflowphenomenoninpatientswithacuteST-eleva- tion myocardial infarction and investigated the role of

theIGF-1moleculeinthecoronaryno-reflowphenome- nonandseverityofCADinpatientswithacuteSTEMIin

atertiaryhospital.

Material and methods Study patients

This is an observational, case-control comparative

study.PatientswithSTEMIwhounderwentPPCIwithin

90 min after first medical contact were included. A to- tal of 113 patients were selected for enrollment in the

trial.Forty-ninepatientsdevelopedno-reflow(group1).

Sixty-four patients did not (group 2). All patients were

given similar medical treatment according to related

guidelinedirectedmedicaltreatmentapproachesexcept

for no-reflow treatment. Exclusion criteria were cardio- genic shock, complete AV block on admission, rescue

percutaneous coronary intervention (PCI), intervention

onveingrafts,coronarydissection,angiographicallyvisi- bledistalembolization,severeheartfailure,severebron- chospasticdisease,patientswithpreviouspercutaneous

revascularization and/or myocardial infarction, severe

renalfailure(creatinine>3mg)andliverfailure.Diabetic

patientsoninsulintherapyorpoorlycontrolleddiabetic

patients(suchasdiabeticketoacidosisandhyperosmolar

nonketotic coma), patients with acromegaly or growth

hormonedeficiency,patientsonsteroidtherapyandpa- tientswithknownmalignancywerealsoexcluded.

All patients provided written informed consent and

thestudyprotocolwasapprovedbytheethicscommit- teeofthehospitalinaccordancewiththeDeclarationof

HelsinkiandGoodClinicalPracticeguidelines.

Insulin-like growth factor-1 measurement Arterialblood(20ml)wascollectedfromthefemo- ralarterysheathaftercompletingprimarypercutaneous

intervention. After the collection, the tubes were cen- trifuged at 3000 rpm for 10 min and the serum trans- ferredtocappedtubesforstorage.Allaliquotswerean- onymizedandstoredfrozenat–40°Cfor6monthsuntil

analyzed. All analyses were performed using Siemens

Immulite IGF-I assay with solid-phase enzyme labeled

chemiluminescentimmunometricassay[12].Hemolyzed,

lipemic and icteric serums were not used for analysis.

TheresultoftheIGF1testwasgiveninng/ml.

Coronary angiography

All angiograms were performed with 7 Fr guiding

catheterswithoutsideholesataspeedof30framesper

second.Coronaryangiographywascarriedoutbyanau- tomaticmechanicalinjector(ACISTCVi,BraccoImaging

S.p.A. Italy). All observations were performed by an in- terventional cardiologist who was blinded to the study

groups.TheTIMIflowscorewasdefinedbythedegree

of flow into the epicardial artery as follows: grade 0,

completeabsenceofflowbeyondthepointofobstruc- tion;grade1,somecontrastmaterialflowsdistaltothe

obstruction but complete arterial visualization is not

achieved;grade2,delayedopacificationoftheentirear- tery;andgrade3,fullpromptvisualizationoftheentire

artery[13].

Coronary artery disease scoring

The severity and extent of CAD were evaluated ac- cording to the Gensini score and Syntax score. Gensini

scoredependsonthedegreeofthecoronaryarteryste- nosisanditsgeographicimportance[14].Thedegreeof

luminalnarrowing,concentricityandeccentricityofthe

plaquesareevaluated.1pointisgivenfor1–25%steno- sis, 2 points for 26–50%, 4 points for 51–75%, 8 points

for 76–90%, 16 points for 91–99%, and 32 points for

100%stenosis.Further,eachlesion’spointismultiplied

bythecoefficientwhichisgivenforeachprincipalvas- cular segment due to the functional significance (the

leftmaincoronaryartery×5;theproximalsegmentof

theleftanteriordescendingcoronaryartery(LAD)×2.5;

theproximalsegmentofthecircumflexartery×2.5;the

mid-segmentoftheLAD×1.5;therightcoronaryartery,

thedistalsegmentoftheLAD,theposterolateralartery

andtheobtusemarginalartery×1;andothers×0.5),and

thesumofallgivesthetotalscore[14].TheSyntaxscore

correspondingtothelesioncomplexitywasmeasuredby

thecoronarytreecharacteristicsandthelesionlocations

andspecifics[15].Thescoreismeasuredusingtheopenly

accessible web based score calculator (http//www.syn- taxscore.com). Scorings were performed and averaged

bytwoobserverswhowereblindedtothestudygroups.

Statistical analysis

StatisticalcalculationswereperformedwithNumber

Cruncher Statistical System 2007 Statistical Software

program for Windows (Utah, USA). Besides standard

descriptive statistical calculations (mean and standard

deviation,median,interquartilerange),forthevariables

that showed a normal distribution, the unpaired t test

wasusedinthecomparisonofgroups,forthevariables

not having a normal distribution, the Mann-Whitney

U testwasusedinthecomparisonofgroups,andtheχ² testwasperformedduringtheevaluationofqualitative

data.ThePearsoncorrelationtestwasusedtodetermine

the relationships between the variables. The statistical

significancelevelwasestablishedatp <0.05.

Results

Patient and control groups were similar in terms of

sex,age,bodymassindex,presenceofdiabetesandhy- pertensionandfamilyhistoryofcoronaryarterydisease.

Patients’ characteristics, differences and study results

arepresentedinTableI.AlthoughIGF-1levelstendtobe

lowerinno-reflowpatients,resultswerenotstatistically

different between the no-reflow group and the control

group(116.65±51.72vs.130.82±48.76,p=0.130).In-hos- pitalmortalitywashigherintheno-reflowgroup(8.77%

vs.0%,p=0.016).GensiniandSyntaxscoreswerelow- erinthecontrolgroup.However,therewasnocorrela- Table I. Clinical,demographicandinterventionalcharacteristicsofbothgroups

Parameter No-reflow

(n = 49)

Lack of no-reflow (n = 64)

Value of p

Age [years] 58.16 ±12.35 55.03 ±8.98 0.111

Sex, n (%) Male 41 (83.67) 56 (87.50) 0.596

Female 8 (16.33) 8 (12.50)

BMI [kg/m²] 28.13 ±4.13 27.75 ±4.98 0.732

Diabetes mellitus, n (%) 10 (20.41) 10 (15.63) 0.680

Hypertension, n (%) 15 (30.61) 20 (31.25) 0.942

Hyperlipidemia, n (%) 12 (24.49) 11 (17.19) 0.471

Alcohol use, n (%) 4 (8.16) 13 (20.31) 0.127

Smoking, n (%) 21 (42.86) 49 (76.56) 0.005

Family history of CAD, n (%) 19 (38.78) 31 (48.44) 0.404

In-hospital mortality, n (%) 5 (10.20) 0 (0.00) 0.031

IGF-1 116.65 ±51.72 130.82 ±48.76 0.130

Gensini score 67.4 ±26.85 47.13 ±24.8 0.0001

Syntax score 25.48 ±10.3 17.94 ±8.03 0.0001

Number of stents 1.45 ±0.71 1.16 ±0.6 0.019

Stent diameter 3.33 ±0.47 2.98 ±0.86 0.013

Stent length 30.04 ±16.14 23.5 ±12.13 0.015

Glucose 177.16 ±94.42 144.87 ±74.78 0.041

Total cholesterol 193.73 ±37.53 204.24 ±48.3 0.204

Triglyceride 109.87 ±61.58 151.52 ±87.44 0.005

LDL 126.61 ±33.59 141.43 ±42.72 0.044

HDL 45.93 ±12.43 39.66 ±9.78 0.004

Creatinine 0.93 ±0.32 0.84 ±0.17 0.04

Troponin max. 16.02 ±14.95 6.52 ±8.04 0.0001

EF 41.5 ±9.75 51.05 ±8.84 0.0001

RDW 13.3 ±1.08 13.1 ±1 0.301

Platelet count 248.05 ±61.81 258.19 ±56.09 0.350

MPV 8.21 ±0.86 8.47 ±0.83 0.096

Neutrophil count 10325.18 ±3950.56 8754.76 ±3428.08 0.022

Lymphocyte count 1681.25 ±1027.61 2150.08 ±914.42 0.01

NLR 8.57 ±7.25 5.29 ±3.94 0.002

tionbetweenGensiniandSyntaxscoresandIGF-1levels

(r=–0.071,r=0.479,r=–0.158,p=0.113respectively).

Interestingly,currentsmokingwashigherinthecontrol

group than in the no-reflow group. The number, length

and diameter of stents used were lower in the control

group.Onadmission,serumcreatinineandbloodglucose

levelswerelowerinthecontrolgroup.Serumlowdensity

lipoprotein(LDL)andtriglyceridelevelswerehigherinthe

controlgroup.Initialtroponinlevelswerenotstatistically

differentbetweenthegroups(5.41±7.78vs.3.14±6.46,

p=0.086).Peaktroponinlevelsweresignificantlyhigher

intheno-reflowgroupthaninthecontrolgroup(16.02

±14.95vs.6.52±8.04,p=0.0001).Neutrophilcountand

neutrophiltolymphocyteratio(NLR)werehigherinthe

no-reflowgroup(8754.76±3428.08vs.10325.18±3950.56

and5.29±3.94vs.8.57±7.25,p=0.02,p=0.002respec- tively). There was no difference between the groups in

platelet count or mean platelet volume (p = 0.350 and

p=0.096respectively).

Discussion

Inthisstudy,theno-refloworslowflowphenomenon

wasmostlyseeninpatientswhohavemorediffuseand

severe coronary artery disease, with higher Gensini and

Syntax scores. The major finding of this study was that

IGF-1 levels were not different between the no-reflow

group and the control group. Thus, there was no asso- ciation between the no-reflow phenomenon and IGF-1

levels. There was also no association between Gensini

and Syntax scores and IGF-1 levels. Previously published

studieshavealreadydemonstratedtheeffectofIGF-1on

vascularhomeostasis[2,3,16].Nitricoxideplaysanim- portantroleintheregulationofendothelialfunctiondue

toitspotentvasodilatoreffectandsensitivityofredoxsta- tusoftheendothelium[2].Increasingevidenceindicates

thatIGF-1preservesendothelialfunctionandplaysama- jor role in vasodilatory responses by increasing NO pro- duction and decreasing oxidative stress and attenuating

endothelin-1inducedcontractileresponsesinthevascular

endothelium[2].Endothelialdysfunction,coronaryvaso- spasm and microvascular spasm may play a role in the

pathogenesis of the no-reflow phenomenon. Although

IGF-1 levels tended to be lower in no-reflow patients in

ourstudy,therewasnostatisticallysignificantassociation

betweendevelopmentoftheno-reflowphenomenonand

IGF-1,whichhaspotentialvasodilatoreffectsonvascular

function.Althoughmicrovasculardysfunctionisoneofthe

possiblepathophysiologicalmechanismsfortheno-reflow

phenomenon [4, 6, 7, 10], thrombus burden and athero- scleroticdebrisburdenmayplayamoreeffectiverolein

developmentoftheno-refloworslowflowphenomenon.

Accordingtotheresultsofourstudy,IGF-1maynothave

significantcontributiontothedevelopmentofno-reflow

or slow flow in patients with STEMI. Insulin-like growth

factor-1 also has positive effects on the development of

cardiac structures, myocardial contraction, heart beats

and ejection fraction and increases cardiac performance

and decreases wall tension [17]. Animal studies have

shownthatIGF-1hastheabilitytoreducetheatheroscle- roticburdenbyitspleiotropic,antioxidantandantiinflam- matoryeffects[1,2].LowIGF-1expressionand/orbioavail- abilitymayplayaroleinoxidizedLDLinducedcytotoxicity

andapoptosisinvascularsmoothmusclecellsthathelp

plaquedestabilizationandrupture[3].HighIGF-1,withits

receptorandbindingproteins,mayprotecttheatheroscle- roticplaqueagainstdestabilizationandrupture[16].The

receptorofIGF-1createsahybridreceptorwiththeinsulin

receptor,resultinginmoreIGF-1expression,whichmakes

vascularsmoothmusclecellsinsensitivetoinsulin[2].Low

levels of IGF-1 are associated with chronic insulin resis- tanceandimpairedglucosetolerance[16,18].Insulin-like

growthfactor-1levelsarealsolowerinpatientswithpoorly

controlleddiabetes[1].Accordingtoseveralstudies,IGF-1

levels are correlated with cardiovascular disease risk in

thegeneralpopulation[16].Ithasbeenreportedthatlow

levelsofIGF-1maybeanindependentriskfactorformyo- cardial infarction, coronary artery disease and increased

carotid intima-media thickness, and interfere with obe- sity,insulinresistance,impairedglucoseintoleranceand

leftventricularhypertrophy[18].However,clinicalstudies

have produced conflicting results regarding the relation

betweenIGF-IanddifferentformsofCAD[1,18–20].Spalla- rossa et al. observed decreased IGF-1 levels in patients

withadvancedCAD[21].Burchardtet al.determinedhigher

IGF-1levelsinpatientswithadvancedCADthanpatients

withhemodynamicallyinsignificantCAD[16].Theystated

thathighIGF-1levelsareaphysiologicalregulatorymech- anismagainstCAD.PatientswithhighIGF-1levelsexperi- encemorestableanginathanacutecoronarysyndromes

[22].Ruotoloet al.demonstratedanindependentassocia- tionbetweenIGF-1levelsandprogressionofCADinyoung

malesurvivorsofMI[23].However,Botkeret al. couldnot

showanassociationbetweenIGF-1levelsandCAD[24].

Similarly,Lawloret al.couldnotshowanyassociationbe- tweenIGF-1levelsandcoronaryarterydisease[25].Inour

study,therewasnoassociationbetweenIGF-1levelsand

theextentandseverityofCAD.Therewasnoassociation

betweentheno-reflowphenomenonandIGF-1levels,also,

despitethereportsassertingthatIGF-1playsanimportant

roleinarterialvasodilatationbycontrollingendothelialNO

productionandreducesinflammationandoxidativestress

[2,17].Changesinlipidprofileafteracutecoronarysyn- dromehavebeenknownforatleast50years[26].While

totalcholesterol,LDLandHDLlevelstendtodecreaseby

0–20%, triglyceride levels increase by 20–30% [26, 27].

Stress-inducedmyocardialdamagealertsadrenergicacti- vationassociatedlipolysisandmobilizesfreefattyacids

[26,27].Likewise,LDLlevelswerelowerinpatientswith

no-reflowthancontrolsinourstudy.Highercreatininelev- elsdetectedintheno-reflowgroupmaybeassociatedwith

impairedcoronaryflow.Interestingly,currentsmokershad

theno-reflowphenomenonlessofteninourstudy.Accord- ingtoourstudy,neutrophilcountandNLRmayalsopre- dict no-reflow, which may be explained by an excessive

inflammatoryresponseinno-reflowpatients.TheNLRin- dexisknowntospecifytheinflammatorystatus[28].The

NLRhasrecentlybeenshownasapredictorofmortalityin

patientswithacutemyocardialinfarction,stablepatients

with CAD and in patients undergoing PCI and all other

conditions [28, 29]. In-hospital mortality was higher in

theno-reflowgroup,whohavehigherlevelsofneutrophil

countsandNLRinthisstudy.Thenumber,lengthanddiam- eterofstentsusedwerehigherinno-reflowpatients,also.

Study limitations: Since this was a single-center

study limited to PPCI of native vessels, the number of

patients was small, representing the major limitation.

Anotherlimitationofourstudyisthatunfortunatelywe

donothaveenoughsounddataaboutballooninflation

pressures and patients’ previous medications. Another

issue is the high frequency of the no-reflow phenome- noninourstudypopulation,approximately50%ofallpa- tients.Itishighascomparedtodataofotherlargescale

studies,evenonSTEMIpatientsonly[30].Thismaybe

relatedtothemethodologyofevaluationanddefinition

ofno-reflow.Sincetheno-reflowgroupincludedpatients

withhigherGensiniandSyntaxscores,theslowerflow

might be related to some residual stenoses within the

infarct-relatedartery.Unfortunately,wewerenotableto

usethrombusaspirationcathetersduringthestudyperi- od;manualthrombusaspirationmighthavechangedour

results.IntheCathPCIRegistry,Harrisonet al.reported

thatolderage,STEMI,prolongedintervalfromsymptom

onset to intervention, cardiogenic shock, longer lesion

length, higher risk class C lesions, bifurcation lesions,

andperiproceduralTIMIflowgradewereclinicalandan- giographic variables independently associated with de- velopmentoftheno-reflowphenomenon[30].Sincethe

no-reflow phenomenon was blindly evaluated, possible

differencesdonotchangethevalueofresults.Howev- er, large scale multicenter studies may reveal different

results.

Conclusions

In this study, although no-reflow or slow flow was

mostly seen in patients with more diffuse and severe

CAD,therewasnoassociationbetweendevelopmentof

the no-reflow phenomenon and the severity of CAD or

IGF-1levels.However,largescalestudiesareneededto

verifytheseresults.

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