Relationship
Between
Prodromal
Angina
Pectoris
and
Neutrophil-to
Lymphocyte
Ratio
in
Patients
With
ST
Elevation
Myocardial
Infarction
Murat
Gok,
MD
a*,
Harun
Kundi,
MD
a,
Emrullah
Kiziltunc,
MD
a,
Mert
Evlice,
MD
b,
Mustafa
Cetin,
MD
a,
Muhammed
Suleymanoglu,
MD
c,
Alparslan
Kurtul,
MD
d,
Ender
Ornek,
MD
aaDepartmentofCardiology,AnkaraNumuneEducationandResearchHospital,Ankara,Turkey
bDepartmentofCardiology,KartalKosuyoluHighSpecialityTrainingandResearchHospital,Istanbul,Turkey cDepartmentofCardiology,TurkeyHighSpecialityTrainingandResearchHospital,Ankara,Turkey dDepartmentofCardiology,AnkaraEducationandResearchHospital,Ankara,Turkey
Received5January2017;receivedinrevisedform15February2018;accepted8April2018;onlinepublished-ahead-of-print18April2018
Introduction
Ithasbeenshownthatinflammationplaysanimportantrole inthedevelopmentandcourseofcardiovasculardiseases[1]. Myocardial ischaemia/reperfusion injury is, in fact, an inflammatory processcharacterisedbyrecruitmentof neu-trophilsintotheischaemicmyocardium[2].
Discoveryoftheischaemicpreconditioningphenomenon hasfocussedattentionontheabilityofthemyocardiumto protectitself.Ithasbeenwelldemonstratedinanimalmodels thatbriefischaemicepisodesprecedingprolongedcoronary occlusion cause a significant reduction of infarct size [3]. Prodromalangina(PA),definedaschestpainepisodes lim-itedtothe24hoursbeforeinfarction,couldberegardedas
©2018AustralianandNewZealandSocietyofCardiacandThoracicSurgeons(ANZSCTS)andtheCardiacSocietyofAustraliaandNewZealand(CSANZ). PublishedbyElsevierB.V.Allrightsreserved.
*Correspondingauthor.Tel.:+905075228886,Fax:+905075228886.Email:drmuratg@hotmail.com
Background Theaimofthisstudywastoinvestigatetherelationshipbetweenprodromalangina(PA)with neutrophil-to-lymphocyteratio(NLR)inpatientswithST-segmentelevationmyocardialinfarction(STEMI).
Methods Thestudygroupincluded145patientswithSTEMIwhounderwentemergencycoronaryangiography(CA) within24hoursofsymptomonset.DatawerecollectedregardingwhetherpatientshadexperiencedPA beforeacutemyocardialinfarction.Seventy-three(73)patients(50.3%)hadprodromalangina.Prodromal anginapositiveandnegativegroupswerecomparedfordemographiccharacteristics,completebloodcount parametersincludingNLR,bloodbiochemistryparametersandleftventricularejectionfraction(LVEF).
Results Neutrophilcount,NLR,andtroponinIlevelsweresignificantlyhigherinthePAnegativegroup.LVEFafter reperfusionandlymphocytecountwerelowerinthePAnegativegroup.Inmultivariateregressionanalysis, NLR(
b
= 0.419,p<0.001)andLVEF(b
=0.418,p<0.001)werefoundtobesignificantlyassociatedwith thepresenceofPAinSTEMIpatients.Conclusions AbsenceofPAwassignificantlyandindependentlyassociatedwithincreasedNLRandimpairedLVEF afterreperfusion,andincreasedNLRwasfoundasasignificantpredictorforbothlackofPAandimpaired LVEFinSTEMIpatients.
Keywords Neutrophil-to-lymphocyteratio Prodromalangina ST-segmentelevationmyocardialinfarction
theclinical correlateof ischaemicpreconditioning[4–8]. It hasbeendemonstratedthatischaemicpreconditioninghas anti-inflammatoryeffects[9–11].
Neutrophil-to-lymphocyte ratio (NLR) is a non-specific, frequently used marker for acute inflammatory response. IncreasedNLRhasbeenassociatedwithimpairedleft ven-tricularfunctionandadverseoutcomesinpatientswithacute myocardialinfarction(AMI)[12–15].However,nostudies,to date,haveinvestigatedtherelationshipbetweenNLRwith thepresence/absenceofPAinAMIcases.
In this study, we aimed to investigate the relationship betweenPAandNLRinpatientswithST-segmentelevation AMI(STEMI).
Materials
and
Methods
Study
Design
ThepatientswhowereadmittedtoourhospitalwithSTEMI, andunderwentemergencycoronaryangiography(CA)after diagnosisbetweenMarchandJuly2014wereincludedinour study.ThelocalethicscommitteeofAnkaraNumune Edu-cationandResearchHospitalapprovedthestudyprotocol, andallpatientsprovidedtheirwritteninformedconsents.
ST-segmentelevation wasconsidered when thepatients had symptoms of AMI for 30minutes, accompanied by >1mm (0.1mV) ST-segment elevation in two consecutive leads. Thediagnosiswaslaterconfirmedbyanincrease in troponinIlevel.
Prodromalanginawasdefinedastypical chestpain epi-sode(s) that persisted<30minuteseither atrest orduring effort24hoursbeforetheonsetofAMI.Patientswithactive infectious or inflammatory diseases (n=10), haematologic disorders(n=5),severerenalorliverdisease(n=25), pre-viousstroke(n=5),rheumatologicdiseases(n=4),diabetes mellitus (n=35), malignancy(n=3),previous myocardial infarctionandnon-STEMI(NSTEMI)(n=45)wereexcluded fromthestudy.Afterevaluationforinclusionandexclusion criteria,145patientswithSTEMIremainedforfinalanalysis (Figure1).
Complete blood counts and differentials were studied from the peripheral venous blood samples obtained on admission of the patients to the emergency department. Bloodsampleswerecollectedin calcium-ethylenediaminete-traacetic acid (EDTA) tubes. Blood counts were measured withanauto-analyser.Neutrophil-to-lymphocyteratiowas calculatedastheratioofneutrophilstolymphocytesinthe peripheralblood.Otherroutinelaboratoryparameterswere
alsomeasuredinourhospital’s laboratory,fromtheblood samplesobtainedonadmissionofthepatients.
Transthoracic echocardiography was performed within 72hoursofhospitaladmission.Leftventricularejection frac-tion(LVEF)wascalculatedusingSimpson’smethod.
ThepatientswereaskedwhethertheyhadPAbeforeAMI. Thentheyweredividedintotwogroupsastheonesthathad PA(PApositivegroup)andtheonesdidnothavePA(PA negative group).All study data were recorded ina study formincludingstatusofPA,bloodtests,echocardiography findingsandCAdata.
All patients were orally pretreated with acetyl salicylic acid300mg.STEMIpatientsweregiven600mgclopidogrel at thetimeofdiagnosis, andbefore CA. BaselineCA was performedthroughthefemoralarterybystandardJudkins techniquewith6or7FcathetersusingtheSiemensAxiom (SiemensAxiomArtisZee2011;SiemensHealthcare, Erlan-gen, Germany) SensisXP. Coronaryangiography and bal-loon dilation/stent application were performed within 60minutesafteradmissionofthepatients.
Statistical
Analysis
SPSS22.0statisticalsoftware(IBMCorp.,Armonk,NY,USA) was usedtoperformstatisticalanalysis.Kolmogorov–Smirnov test wasused toexamine the distributionpattern ofdata.
Continuous variableswere presentedas medianand inter-quartile range (IQR) or meanstandard deviation (SD). Theeffectsofage,LVEF,smoking,meancorpuscularvolume (MCV),NLR;whitebloodcell(WBC),neutrophil,lymphocyte, monocyteandplateletcounts;andlevelsofhaemoglobin,peak troponin I,totalcholesterol, low-densitylipoprotein(LDL), high-densitylipoprotein(HDL),creatinine,stentsize,andtotal bilirubinonPAwerecomputedinunivariateanalysis. Varia-blesthathadunadjustedpvalue<0.10inlogisticregression analysiswereidentifiedaspotentialriskmarkers(WBC, lym-phocyteandneutrophilcounts,NLR,LVEF,troponinIlevel), andthey were included inthe multiple logisticregression analysis.Apvalue<0.05wasconsideredasstatistically sig-nificantataconfidenceintervalof95%.
Receiveroperatingcharacteristics(ROC)curvewasusedto showthesensitivityandspecificityofNLR,andtheoptimal cut-offvalueforpredictingPA.
Results
Thebaselineclinicalcharacteristicsandlaboratory parame-tersofthestudypopulationarepresentedinTable1.There were145patientsinthestudygroup,73ofthem(50.3%)with PA.Gender,age,smokingstatus,levelsoftotalcholesterol,
Table1 Baselinecharacteristicsofthepatientswithandwithoutprodromalangina.
Overall n=145(100%) Negative n=72(49.7%) Positive n=73(50.3%) P-value Gender Male,n(%) 111(100%) 53(47.7%) 58(52.3%) 0.41 Female,n(%) 34(100%) 19(55.9%) 15(44.1%) 0.22 Age,years 60.614 6214 5915 0.21 Leftventricularejectionfraction,% 48(40–60) 42(37–50) 50(45–60) <0.001*
Smoking,n(%) 88(60.6%) 45(51.2%) 43(49.8%) 0.26 Whitebloodcellcount,103/mL 9.26.3 11.64.1 7.24.2 <0.001* Haemoglobin,g/dL 14.1(12.6–15.5) 14(12.1–15.2) 14.2(13–16) 0.32 Neutrophilcount,103/mL 8.463.80 9.23.9 5.863.88 <0.001* Lymphocytecount,103/mL 1.791.15 1.601.16 2.291.32 <0.001* Monocytecount,103/mL 0.80.04 0.80.01 0.080.01 0.74 PeaktroponinI,ng/ml 25(5–51) 27(6.8–51) 20(3.2–50) <0.001* Plateletcount,103/mm3 220(192–257) 218(198–266) 225.5(184–255) 0.44
Meancorpuscularvolume,fL 87(83.7–90) 86(82–89) 88(84–90) 0.15 Neutrophil-to-lymphocyteratio 4.5(2.8–8.2) 7.9(3.9–10.4) 3.4(2.1–5.5) <0.001*
Totalcholesterol,mg/dL 19344 19143 19645 0.56 Lowdensitylipoprotein,mg/dL 12239 12241 12237 0.96 Highdensitylipoprotein,mg/dL 4113 4213 4016 0.73 Creatinine,mg/dL 0.980.07 0.970.06 1.070.09 0.32 Totalbilirubin,mg/dL 0.560.33 0.550.33 0.570.33 0.87 Anteriorinfarctlocation,n% 42(58.3%) 44(61.1%) 38(52.1%) 0.16 Time-to-reperfusion(h) 4.21.9 4.22.4 4.01.8 0.25 Stentdiameter,mm 3(2.75–3) 3(2.5–3) 3(2.5–3) 0.65 Stentlength,mm 15(12.5–18) 15(13–18) 15(12–19) 0.38
LDL,HDL, creatinineandtotalbilirubin,monocytecount, haemoglobin (Hb), platelet count, MCV, stent length and stentdiameterweresimilarbetweenPApositiveand nega-tivegroups.
PeaktroponinIlevels,WBCcounts,NLR,andneutrophil countsweresignificantly higherinthePAnegativegroup. Ontheotherhand,LVEFandlymphocytecountswere sig-nificantly higher in the PA positive group (Table 1). The comparisonofNLRlevelsbetweenPApositiveandnegative groupsisalsoshowninFigure2.
Whensixvariablesfoundsignificantlydifferentbetween PA positive and negative groups on univariate analysis (Table1)(peaktroponinIlevel,WBCcount,NLR,neutrophil count, LVEF,and lymphocyte counts) were included ina multivariateanalysis,NLR(
b
= 0.419,p<0.001)andLVEF (b
=0.418,p<0.001)werefoundtobeindependently asso-ciatedwiththepresenceofPA(Table2).Finally,ROCanalysiswasperformedtodeterminethe cut-offvalueofNLRtopredicttheabsenceofPA.Thecut-off valueofNLRtopredictabsenceofPAinallstudy popula-tionsonadmissionwasfoundas4.5,with73.8%sensitivity and68.1%specificity(areaunderthecurve0.750,p<0.001,
Figure3).
Then,thepatientsweredividedintotwogroupsonthe basisofNLRcut-offvalue4.5.PatientswithNLR4.5were older when compared to the patients with NLR<4.5
(p=0.014).Inaddition,WBC count,peaktroponinIlevel, and the number of patients with PA were significantly higher in NLR4.5 group, but LVEF was significantly lower(Table3).
Discussion
Inthisstudy,wehaveshownthatSTEMIpatients without PAhadhigherNLR valuesonadmission,andlowerLVEF afterreperfusion.
Previousstudies haveshown that preconditioned myo-cytes tolerateischaemiabyreducingenergy demand, pre-serving ATP and slowing down the development of the osmoticload andacidosis.Theclinicalcorrelateof ischae-micpreconditioningisPA;itdelayscardiacmyocytedeath, and hasacardioprotective effectagainst ischaemicinjury beforereperfusion.Murryetal.werethefirsttoshowthe phenomenon of ischaemic preconditioning [3], and they reported that intermittent periods of coronary ischaemia separated by periodsof reperfusion precedingmore pro-longedmyocardial ischaemiaresultedinasignificant car-dioprotectiveeffect[16].
Afterthisstudy,severalclinicalstudiesreportedthatPA occurringshortlybeforetheonsetofAMIhada cardiopro-tectiveeffect.Inthepercutaneouscoronaryinterventionera, thepresenceofPAwasfoundtoberelatedtosmallerinfarct
Figure2 Graphdemonstratingsignificantdifferencesforneutrophil-to-lymphocyteratioinprodromalanginapositiveand negativepatients.
size[17,18],improvedleftventricularfunction,and favour-ableshort-andlong-termprognosisafterAMI[7,8].
Inflammatoryreactionplaysanimportantroleinmyocardial ischaemia/reperfusion injury [12]. Release ofinflammatory cytokines andaggregationand infiltration ofinflammatory cellsarethekeystepsininflammation.Ischaemicinjuryseems tobeinduced,inpart,byneutrophilactivation,andprevious
studiesreportedthelinkbetweenneutrophilsandischaemia/ reperfusioninjury.Removalofneutrophilsordruginhibition ofneutrophilactivityhasbeenshowntoreduceischaemia/ reperfusioninjury[19,20].Studieshavealsoshownthatlow lymphocytecountsareassociatedwithmoreseverecoronary arterydiseaseinthesettingsofstableanginaandpoor progno-sisinpatientswithAMI[21,22].Infact,NLRhasastronger
Table2 Multiplelogisticregressionanalysisshowingtherelationshipoftheprodromalanginawith neutrophil-to-lymphocyteratioandleftventricularejectionfraction.
Paramerters Standardised CoefficientsBeta
P-value
Whitebloodcellcount(/mL) 0.002 0.14
Lymphocytecount(/mL) 0.002 0.24
Neutrophilcount(/mL) 0.076 0.068
Neutrophil-tolymphocyteratio 0.419 <0.001 Leftventricularejectionfraction(%) 0.418 <0.001
TroponinI(ng/ml) 0.116 0.15
Figure3Receiver-operating characteristic(ROC)curveanalysis ofneutrophil-to-lymphocyteratio(NLR) datafor pro-dromalangina.
predictivevalue since itis measured byproportioningtwo inflammatorymarkers,neutrophilsandlymphocytes.
Recently,Alfakryetal.reportedthathighserum neutro-philmarkers, namelymyeloperoxidase,matrix metallopro-teinase (MMP)-8, tissue inhibitor of metalloproteinase (TIMP)-1concentrations,andMMP-8⁄TIMP-1ratioreflected increasedriskofrecurrentacutecoronarysyndrome, espe-ciallyinpatientswithoutperiodontaldiseaseandnot receiv-inganti-microbialmedication[23].Later,itwasshownthat NLR was associated with the severity and complexity of stable and unstable angina as reflected by SYNTAX and Gensini scores [21,24,25]. Neutrophil-to-lymphocyte ratio wasalsofoundtobeassociatedwiththeseverityofchronic heartfailureinpatientswithidiopathicdilated cardiomyop-athy [26]. It was alsoreported that increased NLR wasa predictorforlargeinfarctsizeandimpairedLVfunctionafter reperfusiontherapyinpatientswithAMI[27].Kurtuletal. showedthatincreasedNLRisindependentlyassociatedwith risk of contrast-induced nephropathy in non-ST-segment elevationacutecoronarysyndromepatientstreatedby per-cutaneouscoronaryintervention[28].
As seen in the aforementioned studies, NLR has been studiedinanumberofcardiovasculardiseases,butno stud-iesuptodateinvestigatedtherelationshipbetweenPAand NLR in patients with STEMI. Therefore, we hypothesised thatincreasedNLRmighthavearelationshipwithabsenceof prodromalAPbasedonthepathophysiologicalrolesofthe ischaemicpreconditioning and inflammation in AMI, and found lower NLR valueson admission, and higherLVEF afterreperfusioninSTEMIpatientswithPA.
STEMIoftenoccursbecauseofplaqueruptureorerosion, whichiscalledvulnerableplaque.Vulnerableplaqueswere thoughttorepresentamildtomoderateluminalstenosisin thepast[29].Previousstudiesrevealedthatmildtomoderate coronary lesions exhibited a higher risk for AMI than anatomically and physiologically severe lesions [30,31]. Inflammationisassociatedwithmorepositiveremodelling andlessangiographicstenosisbutisassociatedwithmore plaqueruptureandmorerupture-stimulatedthrombus for-mationoftherupturedplaque[31].Asweknow,NLRisnot
onlyelevatedduetothestressoftheacuteMI (lymphopae-nia)butalsoelevatedinflammatorystatus(neutrophilia)in thesettingofSTEMI.IfNLRisonlyelevatedduetothestress oftheAMIthen allbiginfarctswillhavehigherNLRthan smallerinfarcts.Inaddition,itwouldhavebeenbetterifwe could have pre-MI NLR levels, but we could not assess whether NLRwaselevatedbefore MI.Giventhatelevated NLRduringSTEMIisrelatedtotheabsenceofPAaccording toourstudyresults,wecanspeculatethatitsmechanismis that PAhas an anti-inflammatory effect or that increased plaqueinflammation(asreflectedbyNLR)mightberelated tolessseverestenosisbeforeAMIandthereforelessPA.
ThemechanismsoftherelationshipbetweenabsenceofPA andincreasedNLRarenotclear.Themostprobable mecha-nismisanti-inflammatoryeffectofPAreducingneutrophil accumulation,andattenuatingneutrophil-mediated ischae-mia/reperfusioninjury.Therefore,itispossiblethat neutro-philic inflammation, and hence NLR, decreases in the presence of PA.In addition,our resultsindicatedabetter LVEFafterreperfusioninSTEMIpatientswithPAandlower NLR.
Our study has some limitations. First, this is a single centreandnon-randomisedstudythatincludedarelatively small patient group. The effect of PAon the abortion of STEMI,which was mostlikely tooccurin patientsin the veryearlygroup,wasnotassessed.Wecouldnotreachthe data related tothe badinfarct areasuchas collateralson initialCAandthrombolysisinmyocardialinfarction(TIMI) flowpostpercutaneouscoronaryintervention(PCI).Lastly, NLRwasnotcomparedwithotherinflammatorymarkers, such as C-reactive protein, interleukin 6, fibrinogen or myeloperoxidase.
Conclusions
Tothebestofourknowledge,thisisthefirststudyinthe literatureshowing therelationship betweenabsenceofPA andincreasedNLR.Ourfindingssuggestedthatasignificant relationship between lack ofPAand impairedLVEFafter
Table3 ClinicalcharacteristicsofthestudypatientsinrelationwiththeNLRvaluesinpatientswithST-segment elevationmyocardialinfarction.
Overall(n=145)(100%) NLR4.5 (n=74)(51%)
NLR<4.5 (n=71)(49%)
P-value
PatientswithPA,n(%) 73(50.3) 50(67.5) 23(32.3) <0.001 Age,years 6114 6414 5812 0.014 Female,n(%) 34(24) 17(24) 17(24) 0.850 Whitebloodcellcount,103/mL 9.26.3 11.94.8 7.43.2 0.012
Plateletcount,103/mm3 220(192–257) 218(187–251) 226(193–265) 0.390 PeaktroponinI,mg/dL 25(5–51) 35(12–51) 11(2.5–41) 0.045 Leftventricularejectionfraction,(%) 48(40–60) 45(37–50) 55(45–60) <0.001
reperfusion, andincreasedNLRwasfoundas an indepen-dent predictorfor both lackof PAandimpaired LVEFin STEMI patients. Neutrophil-to-lymphocyte ratio could be usedasasimpleandeasy-to-obtainmarkerforclinicalrisk assessmentinSTEMIpatientsontheiradmissiontohospital.
Acknowledgements
Allauthorshavesubstantialcontributionstoconceptionand design,oracquisitionofdata,andanalysisandinterpretation ofdata,draftingthearticleorrevisingitcriticallyfor impor-tantintellectualcontent,andfinalapprovaloftheversionto bepublished.
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