Preoperative values of inflammatory markers predict clinical outcomes in patients after CABG, regardless of the use of cardiopulmonary bypass

Original Article

Preoperative values of inflammatory markers predict clinical outcomes in patients after CABG, regardless of the use of cardiopulmonary bypass

Dariusz Plicner

^a,

*, Jarosław Stolin´ski

^a

, Marcin Wa˛sowicz

^b

, Bugusław Gawe˛da

^a

, Hubert Hymczak

^c

, Bogusław Kapelak

^a,d

, Rafał Drwiła

^c

, Anetta Undas

^d

aDepartmentofCardiosurgery,JohnPaulIIHospital,Krakow,Poland

bDepartmentofAnesthesia,TorontoGeneralHospital,UniversityofToronto,Toronto,Canada

cDepartmentofAnesthesia,JohnPaulIIHospital,Krakow,Poland

dInstituteofCardiology,JagiellonianUniversityMedicalCollege,Krakow,Poland

Whatisalreadyknown?

The influence of systemic inflammatory markers on clinical outcomes after CABG surgery remains a matter of scientific debate.

Whatthisstudyadds?

High levelsof inflammatory markers before surgerycouldbe helpful in prediction of unfavorable early post-CABG clinical outcomes. Thisstudyalso confirms theconceptthat CABG is

associatedwithsystemicinflammatory responseregardless of theuseofCPB.

1. Introduction

Systemicinflammatory responsetogetherwithmicroemboli- zation is responsible for most of themorbidity afteron-pump coronaryarterybypassgraftsurgery(CABG).Inspiteofimprove- mentsinanesthesia aswellassurgicaltechniques,CABGisstill associatedwithenhancedinflammation.¹Toreducetheseeffects, reintroduction of off-pump coronary artery bypass surgery (OPCAB)hasbecomeincreasinglymorecommoninrecentyears.² Theinfluence ofOPCAB on reductionof systemic inflammation remainsamatterofscientificdebate.Asmallnumberoftrialshave correlatedthebiochemicalfindingsofsystemicinflammationwith theclinicaloutcomesofpatientsafterCABG.^2–5

ARTICLE INFO

Articlehistory:

Received12March2016 Accepted18October2016 Availableonline26October2016

Keywords:

Cardiopulmonarybypass Coronaryarterybypassgrafting Inflammation

ABSTRACT

Objective:The impact of systemic inflammation on clinical outcomes after CABG surgery is still controversial.Inthisstudy,weevaluatedtheimpactofthemarkersofinflammation,endothelialdamage andplateletactivationonclinicaloutcomesafteron-andoff-pumpCABG.

Methods:Agroupof191consecutiveon-andoff-pumpCABGpatientswereprospectivelystudied.Blood samplesweredrawnbeforesurgery,18–36haftertheprocedureand5–7dayspostoperativelyand analyzed for 8-iso-prostaglandin F2a (8-iso-PGF2a), asymmetric dimethylarginine (ADMA)and b- thromboglobulin(b-TG).WhitebloodcountandC-reactiveproteinweremeasuredtwice,firstbefore andthenduringthefirst18–36hafterCABG.Theprimaryclinicalend-pointswere:lowcardiacoutput syndrome(LCOS),postoperativemyocardialinfarction(PMI)andin-hospitalcardiovasculardeath.

Results:Elevationof8-iso-PGF2a,ADMAandb-TGbeforesurgerywasassociatedwithanincreasedrisk ofmorbidityandmortalityafterCABG.Therewerenodifferencesinanalyzedmarkersandclinical outcomesbetweentheon-andoff-pumpgroups.Evenduringtheuncomplicatedpostoperativecourse theinflammatoryresponsewasenhancedandstillremainedhigherthanbaseline5–7daysaftersurgery.

Conclusion:Linksbetweenpreoperative8-iso-PGF2a,ADMAandb-TGandunfavorableearlypost-CABG outcomessuggestthatthesemarkerscouldbeusefulinidentifyingpatientswithincreasedriskofLCOS, PMIandin-hospitalcardiovasculardeathfollowingelectiveCABG.

ß2016PublishedbyElsevierB.V.onbehalfofCardiologicalSocietyofIndia.Thisisanopenaccessarticle undertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Correspondingauthorat:JohnPaulIIHospital,80Pra˛dnickaSt.,31-202Krako´w, Poland.

E-mailaddress:plicner@pro.onet.pl(D.Plicner).

ContentslistsavailableatScienceDirect

Indian Heart Journal

j our na lho me p a ge : w ww . e l se v i e r . com / l oc a te / i h j

http://dx.doi.org/10.1016/j.ihj.2016.10.002

0019-4832/ß2016Publishedby ElsevierB.V.onbehalf ofCardiologicalSociety ofIndia.This isan openaccessarticleunder theCCBY-NC-NDlicense(http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Inthis prospective,cohortstudyweevaluatedtheimpactof CABGandOPCABregarding:(1)oxidativestress,(2) endothelial cells,(3)platelets,(4)C-reactiveprotein(CRP)and(5)whiteblood count(WBC).

Oxidativestressiscausedbyanimbalancebetweenfreeradical generation and elimination. Evidence indicates that oxidative stresscontributestomyocardialischemia-reperfusioninjury.⁶8- iso-prostaglandinF2a(8-iso-PGF2a)wasanalyzedasamarkerof oxidativestress.⁷

Bytheproductionofvarioussubstances,thevascularendothe- liumis a significantregulatorof cardiovascularfunction. Nitric oxide(NO)isproducedinendothelialcellsandplaysanimportant role in various cardioprotective effects including: inhibition of superoxideradicalsandinhibitionofplateletactivation.⁸Oxidative stressduringmyocardialreperfusionaftercardiacsurgeryreduces thebioavailabilityofNO.Fortheassessmentofendothelialinjury we chose asymmetric dimethylarginine (ADMA) as a natural inhibitorofNOsynthase.^9,10

A variety of agonists secreted by platelets and other cells contribute to activation of platelets during surgery. Platelet secretedcytokinesmaybeinvolvedintheinflammatoryresponse tocoronarysurgerybecauseofthestrongactivationofplatelets.¹¹

b

-thromboglobulin(

b

-TG)standsforagroupofplateletproteins, which are released in large amounts subsequent to platelet activation.¹²

Therefore, in this study we evaluated the influence of cardiopulmonary bypass (CPB) on systemic inflammatory re- sponse,endothelialdamageandplateletactivation.Inaddition,we correlatedthepre-aswellaspostoperativevaluesofinflammatory markerswiththeclinicaloutcomesafterCABGsurgery.

2. Materialsandmethods

StudyprotocolwasapprovedbythelocalResearchEthicsBoard and all participating patients signed an informed consent.The study was performed in accordance with the Declaration of Helsinki and with the consensus guidelines expressed by the STROBEstatement.

2.1. Patients

The studywas compromisedof 191 consecutively recruited patients undergoing isolated, elective on- or off-pump CABG procedurebetweenJanuaryandMarch2008.IndicationsforCABG wereconsistentwiththeEuropeanSocietyofCardiologyandthe European Associationfor Cardio-ThoracicSurgery guidelineson myocardialrevascularization.¹³Exclusioncriteriawerehistoryof previouscardiacsurgery,orpercutaneouscoronaryintervention (PCI)within1monthpriortosurgery,renalinsufficiencyandliver dysfunction. All data was collected prospectively. The primary clinical endpoints were low cardiac output syndrome (LCOS) withoutpostoperativemyocardialinfarction(PMI),PMIand in- hospitalcardiovasculardeath.

LCOS was diagnosed if the patient required an intra-aortic balloonpumptobeweanedfromCPBorbecauseofhemodynamic compromisewhileintheintensivecareunit(ICU).LCOSwasalso diagnosed if thepatient requiredinotropic therapy (dopamine, dobutamine,milnirone,orepinephrine)tomaintainthesystolic bloodpressure>90mmHgandcardiacoutput>2.2L/min/m²for

30minintheICU,aftercorrectionofalloftheelectrolyteand blood gas abnormalities and after adjusting the preload and afterloadtoitsoptimalvalue.Patientswhoreceivedalowdoseof dopamine (3

m

g/kg/min) were not considered to have LCOS.

Patientswhorequiredvasoconstrictingmedicationsbecauseofa highcardiacoutput(2.5L/min/m²)andlowperipheralresistance werealsonotconsideredtohaveLCOS.¹⁴

PMIwasdefinedasaserumcreatinekinase-myocardialband (CK-MB) value 5 times greaterthan the upperlimit of normal (>85U/L)withnewQwavespresent,oraCK-MBlevel10times greaterthantheupperlimitofnormal(<170U/L),(withorwithout Qwaves),ornewregionalwallmotionabnormalitiesdemonstrat- edbytransesophagealechocardiography.¹⁵

In-hospitalcardiovasculardeathwasdefinedasdeathoccurring duringthesamehospitalizationperiodastheCABGsurgerydueto heart failure,PMI,stroke, cardiovascularhemorrhageorsudden cardiacdeath.

2.2. CABGprocedure

All patients underwent standardized anesthesia. CABG was carried out through median sternotomy. All patients were operated on by consecutive surgeons according to their own preference,includinguseofCPBandthetypeofcardioplegia.CPB was carried out with a 40

m

m arterial blood filter (Jostra Medizintechnik AG, Hirrlingen, Germany) and a nonpulsatile roller pump (Jostra Medizintechnik AG, Hirrlingen, Germany).

BesidesheparincoatedCPBcircuitwedidnotmakeanyspecial measurestoreduceinflammationduringsurgery.Meanarterial pressurewasmaintained between40 and60mmHgand blood flow was kept at 2.0–2.4L/min per m². Moderate systemic hypothermia (esophageal temperature, 32–348C) was applied.

Myocardialpreservationwasachievedwithaorticrootinfusionof intermittentwarmbloodorcoldcrystalloidcardioplegia,accord- ingtothesurgeon’spreference.Anticoagulationwasachievedby administrationofheparin(500IU/kg)beforetheonsetofCPBand wasmonitoredbymeansoftheactivatedclottingtime(>400s).

After all anastomoses were completed, anticoagulation was reversed by protamine chloride to a normal activated clotting time.Allpatientsreceivedstandardizedpostoperativecare.

OPCABprocedureswereperformedbythesameheparinization protocolasdescribedabove.TherevascularizationintheOPCAB patientswasperformedonthebeatingheartusingtheOctopusIV system(MedtronicInc.,Minneapolis,USA)andacoronaryflow- shuntwasalwayspassedintothecoronaryarteriotomy.

2.3. Laboratoryinvestigations

Blood samples were drawn from an anticubital vein with minimal stasis after an overnight fast, before the start of any anesthesia andsurgeryprocedures,18–36haftertheprocedure and5–7dayspostoperativelyandanalyzedfor8-iso-PGF2a,ADMA and

b

-TG.Commerciallyavailableenzyme-linkedimmunosorbent assays were used to measure plasma 8-iso-PGF2a (Cayman Chemicals,AnnArbor, MI)and plasma

b

-TG(Diagnostica Stago, Asnieres,France).ADMAmeasurementwasperformedbyisocratic high-performanceliquidchromatographyasdescribedbyTeerlink et al.¹⁶Routinelaboratoryvariables, includingbloodcellcount, CRP and myocardial necrosis markers, were determined using standard laboratory techniques. WBC and CRP weremeasured preoperativelyand18–36hafterCABG.NormalvaluesofWBCand CRPwere3.8–10.010⁹/Landbelow5mg/Lrespectively.CK-MB valuesweremeasuredat6,12,18,and24haftersurgery.TheCK- MB levelof 17U/Lwasconsidered theuppernormal value.All measurements were performed by technicians blinded to the origin of the samples. Intra- and inter-assay coefficients of variationwere<7%.

2.4. Statisticalanalysis

Continuous variables werepresented as meanand standard deviation()orasmedianwith25th,75thpercentilesinter-quartile range (IQR) as it concerned postoperative drainage and CRP.

Categoricalvariableswerepresentedasnumbersandpercentages.

TheShapiro–Wilktestwasusedtotestthenormalityofcontinuous variables. In order to examine the differences between the two independent groups, Student’s t-test (for continuous normally distributedvariables)ortheMann–WhitneyU-test(fornon-normally distributedvariables)wereused.The

x

²testorFisher’s exacttest wereusedtocomparedistributionsofcategoricalvariablesbetween independent groups. To assess the linear correlation between variables,thePearsoncorrelationcoefficientfornormallydistributed variablesorSpearman’srankcorrelationcoefficientfornon-normally distributedvariableswerecalculated.Theassociationbetweenthe8- iso-PGF_2a,ADMA,

b

-TG,WBC,CRPlevelsandLCOS,PMIorin-hospital deathwasevaluatedbylogisticregressionanalysis.Nomultivariate logisticregressionmodelingwasperformedowingtoalownumberof LCOSevents(13cases),PMIevents(19cases)andin-hospitaldeaths (7 cases). Statistical analysis was performed with Statistica 10.0 (StatSoft, Tulsa, OK, USA). Two-sided p-values of <0.05 were consideredstatisticallysignificant.

3. Results

3.1. Peri-andpostoperativedata

Table1showspatient’sdemographicdata.Baseline variables such as age, gender, risk factors for coronary artery disease, preoperativeejectionfraction,EuroSCOREIandmedicationswere comparable among groups. 158 patients underwent on-pump CABGand33wereoperatedwithoutCPB.Thegroupsdidnotdiffer intermsoftotaltransfusionaswellasLCOS,PMI,ICUlengthofstay andin-hospitaldeath,whereaspostoperativedrainagewasslightly higherforpatients withCPB(Table2). Meanbaselinevalues of studiedparametersareshowninTable3.

Inallpatients8-iso-PGF2aincreasedby30%at18–36hpost- CABG(p=0.05)andthendecreasedby11%5–7-daysaftersurgery (p<0.0001). Similarly, ADMA increased by 70% 18–36h after CABG(p=0.0001)andthendecreasedby21%in5–7postoperative days (p=0.0001).

b

-TG increased by 44% 18–36h post-CABG (p<0.001) and decreased by 19% 5–7days afterthe procedure (p=0.001) (Table3). There was a positive correlation between ADMA and 8-iso-PGF2a at all-time points (r=0.71 at baseline, r=0.73 at 18–36h and r=0.70 in 5–7 postoperative days, p<0.001forallcomparisons)andbetween

b

-TGand8-iso-PGF2a (r=0.62 at baseline, r=0.68 at 18–36h and r=0.61 in 5–7

postoperativedays,p<0.001forallcomparisons).WBCincreased by 45% and CRP increased by 6320% 18–36h after CABG (p=0.016 and p=0.024 respectively)(Table 3). No differences, intermsofanalyzedmarkers,werenotedforthedifferenttypesof CABG (on-pump CABG versus OPCAB) (Fig. 1). There were no correlations between postoperative 8-iso-PGF2a, ADMA,

b

-TG, WBCorCRPandcross-clamptimeorCPBtime.

3.2. Lowcardiacoutputsyndromewithoutpostoperativemyocardial infarction

Ofthe191patients,6.8%developedLCOSwithoutPMI,6.3%

patients from the on-pump CABG group and 9.1% from the OPCABGpatients(p=0.567)(Table2).Therewerenodifferences in the baseline demographicor clinicalvariables between the LCOS subgroup and remaining subjects (data not shown). All studiedparameters before CABG, exceptfor the baseline CRP, were statistically higher in patients with LCOS (Table 3).

Postoperative values of analyzed markers were significantly higher in the LCOS subgroup, regardless of the use of CPB.

Regression analysis showed a significant correlation between preoperative 8-iso-PGF2a, ADMA and

b

-TG levels, and LCOS (p=0.024,p=0.017andp=0.021respectively).

3.3. Postoperativemyocardialinfarction

9.9%patientsdevelopedPMI,8.2%patientsfromtheon-pump CABG group and 18.2% from the OPCABG group (p=0.082) (Table2).TherewerenosignificantdifferencesbetweenthePMI patientsandtheremainingsubjectswithregardtodemographic data (data not shown).Baseline 8-iso-PGF2a,ADMA and

b

-TG levels weresignificantlyhigherin thePMIsubgroup(Table3).

Aftersurgery,allanalyzedmarkerswerestatisticallyhigherinthe PMI subgroup, irrespective of use of CPB. Regression analysis showed a significant correlation between preoperative 8-iso- PGF2a,ADMAand

b

-TGlevels,andPMI(p=0.045,p=0.012and p=0.001respectively).

3.4. In-hospitalcardiovasculardeath

3.7%patientsdiedduringtheearlypostoperativeperioddueto extensivePMI.Thesewere3.8%patientsfromtheon-pumpCABG group and 3.0% from the OPCABG group (p=0.831), (Table 2).

Table1

BaselinecharacteristicsofCABGpatients.

Variable Allpatientsn=191 PatientswithCPBn=158 PatientswithoutCPBn=33 p

Age(years) 64.98.1 65.28.2 63.57.4 0.282

Female,n(%) 43(22.5) 35(22.2) 8(24.2) 0.794

Peripheralvasculardisease,n(%) 31(16.2) 25(15.8) 6(18.2) 0.738

Diabetesmellitus,n(%) 59(30.9) 46(29.1) 13(39.4) 0.245

Insulin,n(%) 28(14.7) 22(13.9) 6(18.2) 0.529

Hypertension,n(%) 158(82.7) 127(80.4) 31(93.9) 0.061

Hypercholesterolemia,n(%) 126(66.0) 101(63.9) 25(75.8) 0.192

Previousmyocardialinfarction,n(%) 154(80.6) 128(81.0) 26(78.8) 0.769

PreviousPCI,n(%) 23(12.0) 19(12.0) 4(12.1) 0.998

Currentsmoking,n(%) 54(34.2) 44(32.6) 10(43.5) 0.309

COPD,n(%) 11(5.8) 9(5.7) 2(6.1) 0.942

Atrialfibrillation,n(%) 11(6.8) 10(7.2) 1(4.3) 0.610

BMI,kg/m² 28.03.9 28.03.9 28.04.0 0.791

LVEF,% 52.09.3 52.19.4 51.39.2 0.648

EuroSCOREI 2.91.9 3.01.9 2.62.0 0.329

Aspirin,n(%) 38(20.1) 31(19.9) 7(21.2) 0.862

ACEinhibitors,n(%) 168(88.0) 137(86.7) 31(93.9) 0.246

b-blockers,n(%) 172(90.1) 141(89.2) 31(93.9) 0.412

Lipid-loweringstatin,n(%) 171(89.5) 141(89.2) 30(90.9) 0.776

Valuesaredisplayedasmeanstandarddeviationornumber(percentage).

ACE,angiotensin-convertingenzyme;BMI,bodymassindex;COPD,chronicobstructivepulmonarydisease;LVEF,leftventricularejectionfraction;PCI,percutaneouscoronary interventions.

Thesepatients didnot differfromtheremainingsubjectswith respecttodemographicandclinicalvariables(datanotshown).

As in the case of LCOS and PMI, this small subgroup was characterizedbyhigher8-iso-PGF2a,ADMA,and

b

-TGlevelsat

baseline (Table 3). After CABG all studied markers were significantly higherin this subgroup of patients, regardless of the use of CPB. Regression analysis showed a significant correlation between preoperative 8-iso-PGF2a, ADMA and Table2

OperativeandpostoperativecharacteristicsofCABGpatients.

Variable Allpatientsn=191 PatientswithCPBn=158 PatientswithoutCPBn=33 p

Aorticcross-clamptime,minutes 40.114.0 40.114.0 – –

CPBtime,minutes 89.232.2 89.232.2 – –

Transfusion(redcells/platelets/plasma)2units,n(%) 126(66) 105(66.5) 21(63.6) 0.137

Postoperativedrainage,mL 700(480–975) 850(540–1150) 685(480–920) 0.017

LCOS,n(%) 13(6.8) 10(6.3) 3(9.1) 0.567

PMI,n(%) 19(9.9) 13(8.2) 6(18.2) 0.082

ICUlengthofstay2days,n(%) 82(43.2) 62(39.2) 20(62.5) 0.511

In-hospitalcardiovasculardeath,n(%) 7(3.7) 6(3.8) 1(3.0) 0.831

Valuesaredisplayedasmeanstandarddeviation,number(percentage)ormedianwith25th–75thpercentilesinter-quartilerange.

CPB,cardiopulmonarybypass;ICU,intensivecareunit;LCOS,lowcardiacoutputsyndrome;PMI,postoperativemyocardialinfarction.

Table3

Changesofstudiedinflammatoryresponseparametersinpatientswithanalyzedclinicalend-points.

Variable Allpatients

n=191

Patientswith LCOSn=13

Patients without LCOSn=178

p Patientswith PMIn=19

Patients without PMIn=172

p In-hospital deathn=7

Survivors n=184

p

Baseline8-iso-PGF2a,(pg/mL) 358.639.3 392.156.2 356.136.8 0.001 386.552.5 355.536.5 <0.001 385.853.9 357.038.1 0.011 18–36hpost

CABG8-iso-PGF2a,(pg/mL)

468.143.4 526.275.1 463.436.4 0.015 505.366.4 463.437.4 0.017 543.450.2 464.740.4 0.021

5–7dayspost

CABG8-iso-PGF2a,(pg/mL)

417.048.2 528.958.9 409.336.8 0.001 500.770.7 409.537.9 0.005 549.310.6 412.243.2 0.004

BaselineADMA,(mmol/L) 0.560.06 0.650.08 0.560.05 0.001 0.640.09 0.550.09 <0.001 0.620.11 0.560.06 0.041 18–36hpost

CABGADMA,(mmol/L)

0.950.10 1.130.17 0.930.09 0.002 1.060.16 0.930.08 0.002 1.170.14 0.930.10 0.031

5–7dayspostCABGADMA, (mmol/L)

0.750.12 1.040.12 0.730.09 <0.001 0.960.15 0.730.10 0.002 1.100.06 0.740.10 0.003

Baselineb-TG,(IU/mL) 58.810.0 70.412.6 56.99.2 0.002 68.212.5 56.79.1 <0.001 64.815.3 57.59.7 0.025 18–36hpostCABGb-TG,

(IU/mL)

84.621.5 109.328.2 82.619.7 0.007 100.426.9 82.620.0 <0.001 108.024.2 83.520.7 <0.001

5–7dayspostCABGb-TG, (IU/mL)

68.517.3 107.616.7 65.813.8 <0.001 94.924.1 66.114.5 0.006 114.015.0 66.714.7 0.005

BaselineWBCcount,(10⁹/L) 7.32.1 8.83.9 7.21.9 0.009 8.23.5 7.21.9 0.252 8.21.5 7.32.2 0.215 18–36hpost

CABGWBCcount,(10⁹/L)

10.63.9 15.57.2 10.13.1 0.032 14.16.3 10.03.1 0.016 15.75.9 10.53.7 0.039

BaselineCRP,(mg/L) 2.5(1.5–4.8) 4.0(1.8–9.1) 2.4(1.5–4.7) 0.342 3.9(1.7–8.9) 2.4(1.5–4.5) 0.748 2.6(2.4–8.2) 2.4(1.5–4.7) 0.356 18–36hpostCABGCRP,

(mg/L)

160.5 (125.9–188.5)

180.7 (170.9–258.8)

152.9 (124.0–187.1)

0.009 175.8 (170.6–230.2)

152.8 (123.8–187.5)

0.025 254.8 (201.4–256.2)

153.1 (124.5–186.3)

0.030

Valuesaredisplayedasmeanstandarddeviationormedianwith25th–75thpercentilesinter-quartilerange.

8-iso-PGF2a,8-iso-prostaglandinF2a;ADMA,asymmetricdimethylarginine;b-TG,b-thromboglobulin;CABG,coronaryarterybypassgrafting;CPB,cardiopulmonarybypass;CRP, C-reactiveprotein;WBC,whitebloodcounts.

0.1 1 10 100 1000

8-iso-PGF2α, (pg/mL)

ADMA, (μmol/L)

β-TG, (IU/mL) WBC, (x109/L) CRP, (mg/L)

Baseline - pts. with CPB Baseline - pts. without CPB

18–36 h post CABG -pts. with CPB 18–36 h post CABG -pts. without CPB 5–7 days post CABG -pts. with CPB 5–7 days post CABG -pts. without CPB

0.960 0.636

0.533

0.725 0.229

0.457

0.429 0.530 0.327

0.255

0.360 0.728

0.773

Fig.1.LevelchangesofstudiedparametersinpatientswithandwithoutCPB.Nostatisticaldifferences,intermsofanalyzedmarkers,werenotedforthedifferenttypesof CABG(on-pumpCABGversusOPCAB).pValuesareshownabovethecolumnsofthediagram.

8-iso-PGF2a,8-iso-prostaglandinF2a;ADMA,asymmetricdimethylarginine;b-TG,b-thromboglobulin;CABG,coronaryarterybypassgrafting;OPCAB,off-pumpcoronary arterybypasssurgery;CPB,cardiopulmonarybypass;CRP,C-reactiveprotein;pts.,patients;WBC,whitebloodcounts.

b

-TG levels, and in-hospital cardiovascular death (p=0.037, p=0.043andp=0.014respectively).

4. Discussion

WedemonstratedforthefirsttimeinalargenumberofCABG patientsthesimultaneouslevelchangesof8-iso-PGF2a,ADMA,

b

- TG,WBC and CRP. We showedthat clinical outcomesin early postoperative course are associated with these markers of inflammation,oxidativestressand plateletactivation.Themost importantfindingofourstudyis that elevationof8-iso-PGF2a, ADMAand

b

-TGbeforesurgeryisassociatedwithanincreasedrisk of morbidity (LCOS and PMI) and mortalityafter CABG, which expands ourprevious observations made in smaller groups of patients that suggested a prognosticrole of theseprocesses in patientsundergoingCABG.^17,18Postoperativelyallstudiedparam- eters, including WBC and CRP, increased statistically higher in patientswithprimaryclinicalendpoints,regardlessofuseofCPB.

Evenduringtheuncomplicatedpostoperativecoursetheinflam- matoryresponsewas enhanced and still remainedhigher than baseline5–7 days aftersurgery. On-pump aswellas off-pump surgerywereassociatedwithasimilarincreaseofstudiedmarkers.

Additionallytherewasnocorrelationbetweenanalyzedpostop- erativemarkersandtimeofCPBorevenwithaorticcross-clamp time. Our findings are consistent with other studies that demonstratedthatcardiacsurgeryresultsinextensiveoxidative stressresponseirrespectiveofwhetherCABGwasperformedwith orwithoutCPB.^19,20Incontrasttoourresultsseveralstudieshave shownthatwithOPCAB,thedegreeofinflammatoryresponseis significantly less expressed.² Because of the small number of patients in these trials, no significant difference in clinical outcomesbetweengroupswasobserved.

Wehavealreadyreportedthatoxidativestress,measuredby8- iso-PGF2a,isassociatedwithADMAincreaseafteron-pumpCABG andpre-procedurehighlevelsofthesemarkersareassociatedwith PMI and in-hospital cardiovascular death.¹⁷ In this study we demonstratethatalsoinOPCAB,baselineADMAaswellas8-iso- PGF_2aarepredictorsofunfavorablepostoperativeoutcomesinthe samedegreeasinon-pumpCABG.AlsobaselineADMAelevation cannotbeexplainedbyrenal dysfunction,asrenalinsufficiency wasanexclusioncriterioninthisreport.Theseresultscorroborate findingsobtainedbyKaruetal.whoobservedthatcardiacsurgery results in extensive oxidative stress response and a marked increaseinADMA,regardless of themethodortype ofsurgical procedureused.^19,21

This study demonstrates that the occurrence of LCOS, PMI andin-hospitaldeathafterelective,isolatedCABGisalsoassociated withincreasedplateletactivation,measuredby

b

-TG.Wereported previously that platelet activation and oxidative stress are significantlyenhancedinpatientsundergoingCABGsurgeryand preoperative elevated levels of

b

-TG are associated with an increasedriskofPMI.¹⁸Ourcurrentstudyshowsthattheactivation ofplateletsincreasetothesamedegreeinon-pumpCABGasin OPCABandincreasedlevelof

b

-TGatbaselineisassociatedwith unfavorableearlypostoperativeoutcomes,includingaswellPMI, LCOSandin-hospitalcardiovasculardeath.Molleretal.observed thatplateletsafterOPCABweremoreeasilyactivatedintheearly postoperativeperiodthaninon-pumpCABG.²²

Inflammatory markers such as CRP and WBC were raised similarlyafteron-pumpCABGaswellasafterOPCAB.Thereare widenumberofstudiesshowingcontroversialresultsofinflam- matorymarkersincomparisonofOPCABversusonpumpCABG.As confirmedinourstudy,Karuetal.showedthatCRPconcentrations still remained higher than baseline by the end of the first postoperativeweek.ThisCRPresponsewasirrespectiveofwhether CABGsurgerywasperformedwithorwithoutCPB.¹⁹Ontheother

hand,Rajaetal.publishedafewstudiesinwhichtheincreasesof CRPlevelsandWBCweregreaterandpersistedforalongertime afteron-pumpCABGwithrespecttoOPCAB.²Neverthelessinour studypreoperativelevelsofCRPandWBCwerenotassociatedwith anyclinicalendpoints.

Wereportedpreviouslythattheinflammatoryresponseduring cardiac surgery is at least in part related to the genetic characteristics of any given individual and the candidates are genes for tumor necrosis factor alpha and interleukin 6 as evidenced previously.^23,24 These findings are consistent witha studybyLehmannetal.whoalsodemonstratedageneticinfluence on systemic inflammatory response to CABG.²⁵ In our study, elevation of 8-iso-PGF2a, ADMA and

b

-TG before surgery is associatedwithanincreasedriskofmorbidityandmortalityafter CABGandhighbaselinelevelsofthesemarkersarelikelyofgenetic origin.ThedataregardinginflammatoryresponsetoCPBarestill inconsistent.Ourfindingssuggestthat8-iso-PGF2a,ADMAand

b

- TGdeterminedbeforeon-pumpCABGaswellasOPCAB,couldbe helpfulinidentifyingpatientsatriskofLCOS,PMIandin-hospital death. In addition, this study validate the concept that other mechanisms rather than CPB and myocardial ischemia during aorta cross-clamp are responsible for increased postoperative inflammatoryresponse.

Thisstudyhassomelimitations.Themostimportantlimitation ofourstudyisthelackofcontrolgroup.Comparisonofsystemic inflammatoryresponse,endothelialdamageandplateletactivation betweenpatientshavingclassicalfullsternotomycardiacsurgeryto thesamesurgeryperformedbyminithoracotomyortothesimple sternotomy in non cardiac surgery could help to answer the questionofhowimportantaroleininflammatoryresponseplays range of surgical trauma. It is a retrospective analysis of prospectivelycollecteddataatasinglecenter.Thesamplesizeof thestudygroupwaslimitedandrestrictedtoCABGpatients.8-iso- PGF2

a

,ADMAand

b

-TGlevelsweremeasuredonlyatthreetime points.Windowsofpostoperativemeasurementswerewide.Using astrictermeasurementregimencouldalsogivelessvariationinthe results.Itisprobablethatmeasurementsperformedmoreoften, especiallyduringthefirst24haftertheprocedure,couldprovide newinformationontheeffectofCABGoninflammatoryresponse, endothelialdamageandplateletactivationmarkersformationand elimination.EuroSCOREIvalueswerelowasonlyelective,isolated CABG patients,without previous history of cardiac surgeryand withoutrenalfunctionimpairmentwererecruited.Theresultsof this study cannot be extrapolated to high-risk patients. Other factors such as dietmight alsoaffect preoperativelevels of the variablesstudiedespeciallyoxidativestress.^26,27Thelowincidence oftheprimaryclinicalendpointsmayimpactthepoweravailable for this study and could introduce unexpected bias into the outcomes.Atlast, ourstudywas limitedtothe hospital stay.It would be of interest to assess analyzed markers and clinical endpoints,withinthefirstpostoperativemonths.

5. Conclusion

Linksbetweenpreoperativelevelsof8-iso-PGF2a,ADMAand

b

-TG andunfavorableearly post-CABGoutcomessuggest that thesemarkerscouldbeusefulinidentifyingpatientsatincreased riskofLCOS,PMIandin-hospitalcardiovasculardeathfollowing elective surgery. Our results validate the concept that CABG surgery is associated with systemic inflammatory response, endothelial damage and platelet activation regardless of the useofCPB.

Conflictsofinterest

Theauthorshavenonetodeclare.

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