High levels of high-sensitivity C-reactive protein and uric acid can predict disease severity in patients with mitral regurgitation

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Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

www.revportcardiol.org

ORIGINAL

ARTICLE

High

levels

of

high-sensitivity

C-reactive

protein

and

uric

acid

can

predict

disease

severity

in

patients

with

mitral

regurgitation

Yasin

Turker

a_,_∗

_,

_Ismail

_Ekinozu

a

_,

_Yasemin

_Turker

b

_,

_Mehmet

_Akkaya

c

a_Department_of_Cardiology,_Duzce_University_Faculty_of_Medicine,_Duzce,_Turkey b_Family_Medicine_Center,_Duzce,_Turkey

c_Department_of_Cardiology,_BezmiAlem_University_Hospital,_Istanbul,_Turkey

Received29July2013;accepted31March2014 Availableonline11November2014

KEYWORDS High-sensitivity C-reactiveprotein; Mitralregurgitation; NYHAclass; Uricacid Abstract

Introduction:Both high-sensitivity CRP (hs-CRP) anduric acid (UA)levels areknown tobe

increased inheart failurepatients and are associated with poorerfunctional capacity and adverseoutcome.Theroleofthesemarkersinpatientswithmitralregurgitation(MR)isless clear.Theaimofthisstudywastoassesstherelationshipbetweenhs-CRP,UAandorganicMR. Wealsoassessedwhetherhs-CRPandUAlevelsarecorrelatedwithsymptomsofMR,severity ofMR,LVremodelingandoutcomeduringfollow-up.

Methods:Atotalof200consecutivepatients(87men[43.5%];meanage61.6±12.5years)with

moderateorsevereisolatedandorganicMRwereincludedinthestudy.Allthepatientswere assessed clinicallyandweremanaged andtreatedwithstandardmedicaltherapyaccording toevidence-basedpracticeguidelines.PatientswerecategorizedaccordingtoNewYorkHeart Association(NYHA)functionalclass.WeassessedandgradedtheseverityofMRusinga multi-parametricapproach.hs-CRPwasmeasuredwithchemiluminescentimmunometricassayusing anIMMULITE®₁₀₀₀_autoanalyzer_(Siemens,_Germany)._Serum_UA_levels_were_analyzed_using_a

Cobas®₆₀₀₀_autoanalyzer_(Roche_Diagnostics,_Mannheim,_Germany).

Results:Mean UA levels increased signiﬁcantly with NYHA class: 4.46±1.58 mg/dl for

patients in NYHA class I, 5.91±1.69 mg/dl for class II, 6.31±2.16 mg/dl for class III and 8.86_±3.17 mg/dl for class IV (p<0.001). Mean UA levels also increased signiﬁcantly with increased severity ofMR (moderate5.62±1.9 mg/dl, moderateto severe 5.56±1.2mg/dl, severe 7.38_±3.4 mg/dl, p<0.001). There was a signiﬁcant correlation between UA level and left ventricular end-diastolic diameter (r=0.40; p<0.001), left ventricular end-systolic

∗_{Corresponding}_author.

E-mailaddress:dryasinturker@hotmail.com(Y.Turker). http://dx.doi.org/10.1016/j.repc.2014.03.014

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diameter(r=0.297;p=0.001)andleftventricularejectionfraction(LVEF)(r=0.195,p=0.036), whereashs-CRPwasnotcorrelatedwith theseparameters.In multivariateCoxproportional hazardsanalysisLVEF,NYHAclassandUAlevelsweretheonlyindependentpredictorsofdeath.

Conclusion:UAandhs-CRPlevelscanhelpidentifypatientswithasymptomaticmoderateor

severemitralregurgitation.UAlevelsmay beusefultoassesstheextent ofleft ventricular remodelingandintheoptimaltimingofmitralvalvesurgeryincertainsubsetsofpatients. ©2013SociedadePortuguesadeCardiologia.PublishedbyElsevier España,S.L.U.Allrights reserved.

PALAVRAS-CHAVE

ProteínaC-reativade altasensibilidade; Regurgitac¸ãomitral; ClassedaNYHA; Ácidoúrico

NíveiselevadosdeproteínaC-reativadealtasensibilidadeedeácidoúricopodem preveraseveridadedadoenc¸aempacientescomregurgitac¸ãomitral

Resumo

Introduc¸ão: ÉconhecidoquetantoaproteínaC-reativadealtasensibilidade(PCR-as)comoo

ácidoúrico(AU)estãoelevadosnosdoentescominsuficiênciacardíacae,estãoassociadosa piorcapacidadefuncionaleapiorprognóstico.Opapeldestesmarcadoresnosdoentescom regurgitaçãomitral(RM)é menosclaro. Oobjetivo desteestudo foiode avaliararelação entrePCR-as,oAUeaRMorgânica.TambémavaliamosseosníveisdePCR-asedeAUestão correlacionadoscom ossintomas daRM, coma severidadedaRM, com aremodelagem do ventrículoesquerdo(VE)ecomoprognóstico,duranteoseguimentoclínico.

Métodos: Umtotalde200pacientesconsecutivos(86homens(43,5%);idademédia61,6±12,5

anos)comRMorgânicaisolada,moderadaousevera,foramincluídosnoestudo.Todososdoentes foramavaliadosclinicamenteetratadoscomaterapêuticamédicastandarddeacordocoma práticadamedicinabaseadanaevidênciaecomasGuidelines.Osdoentesforamclassificadosde acordocomaclassefuncionaldaNewYorkHeartAssociation(NYHA).Avaliamoseclassificamos agravidadedaRMutilizandoomodelomultiparamétrico.APCRdealtasensibilidadefoi quan-tificadacomotesteimunométricoquemilumeniscente,usandoumAutoanalizadorIMMULITE®

1000(Siemens,Germany).OsníveisséricosdeAUforamdeterminadosusandooAutoanalizador COBASsérie6000(Roche®_Diagnostics,_Mannheim,_Germany).

Resultados: Osníveis médiosde AUaumentaram signiﬁcativamentecomaclasse daNYHA:

4,46_±1,58mg/dlparaClasseIdaNYHA,5,91_±1,69mg/dlparaaclasseIIdaNYHA,6,31_±2,16 mg/dlparaClasseIIIdaNYHAe8,86±3,17mg/dlparaClasseIVdaNYHA(p<0,001).Osvalores médiosdoAUtambémaumentaramdeformasignificativacomoaumentodaseveridadeda RM(moderada=5,62±1,9mg/dl,moderadaasevera=5,56±1,2mg/dl,severa=7.38±3.4mg/dl, p<0.001).FoiencontradaumacorrelaçãosignificativaentreosníveisdeAUeoDDVE(r=0.40; p<0.001,Figure5),DSVE(r=0,297;p=0,001)eFEVE(r=0,195,p=0,036),enquantoaPCR-asnão secorrelacionoucomessesparâmetros.NaanálisemultivariáveldeCox,aFEVE,aclasseda NYHAeosníveisdeAUforamosúnicosfatorespreditivosindependentesdemorte.

Conclusão:OsníveisdeAUedePCR-aspodemajudaradistinguirosdoentescomRMmoderada

aseveraassintomática,dossintomáticos.OsníveisdeAUpodemserúteisnadeterminac¸ãoda extensãodaremodelagemventricularedotempomaisadequadoparaarealizac¸ãodacirurgia daválvulamitral,emdeterminadosgruposdedoentes.

Introduction

Primary mitral regurgitation (MR) covers all etiologies in which intrinsic lesions affect one or several components of the mitral valve apparatus.1 _Surgery _is _recommended inpatientswithchronicsevereMR iftheyhave any symp-tomsorinasymptomaticpatientswithleftventricular(LV) dysfunction.1 _When _guideline _indications _for _surgery _are reached,earlysurgeryisassociatedwithbetteroutcomes, sincethedevelopmentofevenmildsymptomsbythetime

ofsurgeryisassociatedwithdeleteriouschangesincardiac functionaftersurgery.2,3 _However,_{difficulties}_in_detecting early LV dysfunction, accurately assessing the severity of valveinvolvement, or recognizingearlycardiac symptoms oftenmake itdifficult todetermine theoptimaltiming of mitralvalvesurgery.4_In_many_patients,_the_development_of symptomsisclear,butinothers,symptomsaredifficultto assess becauseofinactivity.In somepatients,it mayalso beunclearwhethersymptomsarerelatedtosevereMRor tocomorbidities.5,6

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Increasedlevelsofhigh-sensitivityC-reactiveprotein (hs-CRP) are associated with poorer functional capacity and adverse outcomeinpatientswithLVsystolicdysfunction.7 Adelaide et al. reported that CRP elevation is also asso-ciated with the presence and severity of MR and with diastolic dysfunction in acute myocardial infarction. This suggeststhatinflammationisrelatedtoventricular remod-eling processes,independently ofLV systolicfunction.8 _As withhs-CRP,recentfindingssuggestthatthereisalsoa rela-tionshipbetweenchronicheartfailure(CHF)anduricacid (UA)levels.9,10 _Elevated _serum_UA_levels_can _predict_poor survivalinsevereandmild---moderateCHF9,10_and_may_also predictexerciseintoleranceandinflammatoryactivation.11 Nozarietal.showedthatelevatedUAandhs-CRPare associ-atedwithheartfailure(HF)amongpatientswithmyocardial infarction(MI)andtheirserumlevelscouldbeapredictor for the occurrence of severe HF in patients withMI.12 _In addition,Yaziciogluetal.havedemonstratedthatelevated serumUAinpatientswithdilatedHFisrelatedtoseverity offunctionalMR.13

Althoughtheassociationbetweenhyperuricemiaand hs-CRPwithchronicheartfailurehasbeenrecognized,therole ofthesebiomarkersinMR patientsislessclear.We there-fore prospectively investigated the association between hs-CRP, UA and organic MR. We also assessed whether hs-CRP and UA levels are correlated with symptoms and severity of MR, LV remodeling and outcomes at one-year follow-up.

Methods

Studypopulation

Atotalof200consecutivepatientswithisolatedandorganic moderateorsevereMRwereincludedinthestudy.Exclusion criteriawere asfollows:a history of MI,previous cardiac surgery, presenceof other valvedisease(aortic valve dis-ease, moderate or severe mitral stenosis, or significant right-sided organic valve disease), ischemic MR, signifi-cantliverorrenaldisease,chroniclungdisease,malignant or hematologic disease, cardiomyopathies or pericardial diseases and concomitant inflammatory diseases such as infectionsandautoimmune disorders;poor echocardiogra-phic acoustic window; and medication with hypouricemic agents.The study wascarriedoutin accordancewiththe principlesoftheDeclarationofHelsinki andwasapproved by theEthics Committeeof DuzceUniversity.All subjects providedwrittenconsent.

Clinicalassessment

All the patients were assessed clinically and were man-agedandtreatedwithstandardmedicaltherapyaccording to evidence-based practice guidelines. Patients were categorized according to New York Heart Association (NYHA)functionalclass.Clinicalassessmentwasperformed by cardiologists who were blinded to UA and hs-CRP levels.

Echocardiography

Inallparticipants,transthoracicM-mode,two-dimensional, pulsed-wave,continuous-waveandcolor Doppler echocar-diographic examinations were performed usinga General ElectricVingmedVivid7(GEVingmedUltrasoundAS,Horten, Norway) using 2.5---3.5 MHz transducers. Left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) diameter andleft atrial (LA) diameter weredetermined from two-dimensional images, according to the American Society ofEchocardiography guidelines.14 _Left_ventricular_ejection fraction(EF) wascalculated usingthe modified Simpson’s method. Severity of MR was assessed from the regurgi-tant fraction and vena contracta width.15,16 _In _the _case of equivocal findings between thesetwo methods the MR score,asdescribedbyThomasetal.,17_was_calculated_from visualassessmentofMRjetpenetration,mitral continuous-wave Doppler characteristics, LA size, pulmonary venous flowpattern,tricuspidregurgitationvelocity,andproximal isovelocitysurfacearearadius.5,14_Pulmonary_artery_systolic pressure(PAP) was calculatedas the sum of the transtri-cuspidgradient and estimatedright atrial pressure.18 _The echocardiographerswereblindedtopatients’symptom sta-tusandUAandhs-CRPlevels.

Bloodsampling

Venousbloodsamplesweredrawnfromthepatientsduringa routinevisittotheoutpatientclinic.Wholebloodcountand routinebiochemicaltestswereperformed.hs-CRPwas mea-suredwithchemiluminescentimmunometricassayusingan IMMULITE® ₁₀₀₀_autoanalyzer _(Siemens,_Germany). _Serum

UAlevelswereassessedusingaCobas® ₆₀₀₀_series

autoan-alyzer(RocheDiagnostics,Mannheim,Germany).

Follow-up

Clinicalandechocardiographicassessmentswereperformed atleastyearlyduringafollow-upvisit.Patientswhodiedor underwentsurgerywerecensoredthesameday,andthose whoremainedalivewerecensoredattheendoffollow-up.

Statisticalanalysis

The statistical analysis wasperformed using SPSS version 13.0(SPSSInc.,Chicago,IL,USA).Continuousvariablesare expressedasmean±SDormedian(25th---75thpercentile), andcategoricalvariablesarepresentedaspercentagesand frequencies.TheStudent’sttestandone-wayANOVAwere usedtocomparenormallydistributedcontinuousvariables intwoormoregroups.TheTukeytestwasusedasapost-hoc test. The Kruskal-Wallis test was used to compare non-normallydistributedcontinuousvariablesinmorethantwo groupsandtheMann-WhitneyUtestwithBonferroni adjust-ment was used for multiple comparisons. The chi-square testwasusedforcategoricalvariablesbetweentwogroups. Variableswithapvalueof<0.05inunivariateanalysiswere thenentered intoamultivariateCoxproportionalhazards regression model to determine independent predictors of mortality during follow-up. Hazard ratios (HR) with 95%

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Table1 Demographic,clinicalcharacteristicsandlaboratoryparametersofpatientswithmitralregurgitationandcomparison betweenasymptomaticandsymptomaticpatients.

Allpatients (n=200) Asymptomatic (n=54) Symptomatic (n=146) p

Meanage,years 61.6±12.5 53.4±12.8 65.9±10.4 <0.001**

Male,n(%) 87(43.5) 14(25.9) 73(50.0) 0.002* Hypertension,n(%) 148(74.0) 31(57.4) 117(80.1) 0.002** Smoking,n(%) 28(14.0) 10(18.5) 18(12.3) 0.260 Diabetes,n(%) 39(19.5) 7(13.0) 32(21.9) 0.227 BMI(kg/m2₎ _29.4_±5.4 _29.4_±3.4 _29.7_±6.4 _0.710 Atrialﬁbrillation,n(%) 116(58.9) 28(51.9) 88(61.5) 0.257 Echocardiographicﬁndings LVEDD(mm) 51.4±6.3 50.4±4.4 52.4±7.4 0.019* LVESD(mm) 36.2±7.3 34.4±6.8 37.5±8.2 0.013* LA(mm) 43.8±5.0 41.7±5.2 44.2±4.6 0.001** Ejectionfraction(%) 54.1_±11.5 60.2_±9.4 51.0_±12.2 <0.001** PAP(mmHg) 36.5±9.5 33.5±6.8 37.3±10.2 0.013*

Mitralregurgitationseverity

Moderate 106(53.0) 49(90.7) 57(39.0) <0.001** Moderatetosevere 60(30.0) 5(9.3) 55(37.7) Severe 34(17.0) --- 34(23.3) Laboratoryﬁndings Hemoglobin(g/dl) 12.7_±1.2 13.0_±1.0 12.6_±1.4 0.033* BUN(mg/dl) 18.8±7.7 17.8±6.8 19.9±9.3 0.123 Serumcreatinine(mg/dl) 0.92_±0.3 0.87_±0.3 0.95_±0.3 0.076 Fastingglucose(mg/dl) 113.2±42.4 98.7±12.2 104±18.5 0.023* Totalcholesterol(mg/dl) 186.6_±41.6 204_±40 174_±33 <0.001* HDL(mg/dl) 47.7±12.9 48.6±11 45.3±13 0.119 LDL(mg/dl) 107.4±33.6 121±33 98±26 <0.001** Triglycerides(mg/dl) 144.2±59.2 139±50 148±65 0.372 hs-CRP(mg/l) 5.26±6.38 2.56±1.9 5.9±6.8 0.004** Uricacid(mg/dl) 5.99_±2.28 4.5_±1.6 6.5_±2.4 <0.001** Medication Beta-blockers,n(%) 102(51.8) 23(42.6) 79(55.2) 0.150 ACEIs/ARBs,n(%) 152(77.2) 33(63.1) 119(83.2) 0.002** Diuretics,n(%) 97(49.2) 14(25.9) 83(58.0) <0.001** CCBs,n(%) 14(7.1) 4(7.4) 10(7.0) 0.920 Digoxin,n(%) 32(16.2) 6(11.1) 26(18.2) 0.283

ACEIs:angiotensin-convertingenzymeinhibitors;ARBs:angiotensinreceptorblockers;BMI:bodymassindex; CCBs:calciumchannel blockers;hs-CRP:high-sensitivityC-reactiveprotein;LA:leftatrialdiameter;LVEDD:leftventricularend-diastolicdiameter;LVESD:left ventricularend-systolicdiameter;PAP:pulmonaryarterypressure.

Valuesaremean±SD(range)orn(%).

* _p_<_0.05. **_p_<_0.01.

conﬁdenceintervals(CI)forriskfactorsaregiven.Apvalue oflessthan0.05wasconsideredstatisticallysigniﬁcant.

Results

Of the 200 patients with moderate, moderate to severe andsevereMRincludedinthestudy,54wereasymptomatic while 146were symptomatic. Baselinedemographic, clin-icalcharacteristics and laboratory parametersof patients withMRarelistedandcomparedbetweenasymptomaticand symptomaticpatientsinTable1.Meanagewassigniﬁcantly higher in symptomatic than in asymptomatic MR patients

(p<0.05). Malegender andhypertensionweremore preva-lentinthesymptomaticgroupthantheasymptomaticgroup (p<0.05 for both). Treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensinreceptor blocker (ARBs)anddiureticswasalsomoreprevalentinsymptomatic MRpatients(allp<0.05).

PatientsinthesymptomaticgrouphadlowerLVEF,higher PAP, increased LVEDD and LVESD and larger LA diame-ter compared to the asymptomatic group (all p<0.05). Moderate to severe and severe mitral regurgitation was signiﬁcantly more prevalent in the symptomatic group (p<0.001). Hemoglobin, totalcholesterol, andlow-density lipoprotein(LDL)cholesterollevelsweresigniﬁcantlylower,

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hs-CRP (mg/l) hs-CRP (mg/l) hs-CRP (mg/l) NYHA I 10 9 8 7 6 5 4 3 2 1 0

NYHA II NYHA III NYHA IV

Figure1 High-sensitivity C-reactiveproteinlevelsaccordingtoNYHA functionalclass.Topofthebarrepresents medianand whiskersrepresentthe25thand75thpercentileofconcentrations.hs-CRP:high-sensitivityC-reactiveprotein.

P1:NYHAIvs.NYHAII;P2:NYHAIvs.NYHAIII;P3:NYHAIvs.NYHAIV;P4:NYHAIIvs.NYHAIII;P5:NYHAIIvs.NYHAIV;P6:NYHA

IIIvs.NYHAIV.

p1<0.001,p2=0.001,p3<0.001,p4=0.008,p5=0.062,p6=0.794.

whilefastingglucosewashigher,inthesymptomaticgroup (allp<0.05).

hs-CRP was significantly elevated among symptomatic MR patientscompared toasymptomaticpatients (5.9±6.8 vs. 2.56±1.9 mg/l; p=0.004). Median hs-CRP levels were increased significantly withincrease in NYHA class (NYHA class I: 1.50 mg/l [0.90---3.50], class II: 2.73 mg/l [2.59---6.57],classIII: 5.20mg/l[3.30---9.30], andclassIV: 4.07mg/l[4.03---7.92],p<0.001;Figure1).Asimilar corre-lationwasalsofoundwithMRseverity,medianhs-CRPlevels beingsignificantlyincreasedwithmoresevereMR (moder-ate:2.62mg/l[1.70---2.95],moderatetosevere:5.20mg/l [3.30---5.6], and severe: 5.53 mg/l [4.50---9.30], p=0.002; Figure2).

UA levels were signiﬁcantly elevated among symp-tomatic compared to asymptomatic patients (6.5±2.4 vs. 4.5±1.6 mg/dl; p<0.001). Mean UA levels increased

significantly with NYHA class: 4.46±1.58 mg/dl for NYHA class I, 5.91±1.69 mg/dl for class II, 6.31±2.16 mg/dl for class III and 8.86±3.17 mg/dl for patients in class IV (p<0.001; Figure 3). Mean UA levels also increased significantly with increased severity of MR (moderate: 5.62±1.9 mg/dl, moderate to severe: 5.56±1.2 mg/dl, severe:7.38±3.4mg/dl, p<0.001;Figure4). There wasa significantcorrelationbetweenUAlevelandLVEDD(r=0.40; p<0.001, Figure 5), LVESD (r=0.297; p=0.001) and LVEF (r=0.195,p=0.036),whereashs-CRPwasnotcorrelatedwith theseparameters.

Inaddition,hsCRPlevelswerenearlysigniﬁcantlyhigher (5.5±2.5 vs.4.2±3.6mg/l, p=0.053),and UAlevelswere signiﬁcantlyhigher (7.6±2.8 vs. 5.5±1.9mg/dl, p<0.001) in patients who needed surgery than in those who did notaccording to current ESCguidelines onvalvular heart disease.1

Moderate Moderate to severe Severe

p=0.002 10 9 8 7 6 5 4 3 2 1 0 h s-CRP (mg/l)

Figure2 High-sensitivityC-reactiveproteinlevelsaccordingtodegreeofmitralregurgitation.Topofthebarrepresentsmedian andwhiskersrepresentthe25thand75thpercentileofconcentrations.hs-CRP:high-sensitivityC-reactiveprotein.

P1:moderatevs.moderatetosevere;P2:moderatevs.severe;P3:moderatetoseverevs.severe.

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UA (mg/dl)

NYHA I NYHA II NYHA III NYHA IV

U A ( m g /d l) 14 12 10 8 6 4 2 0

Figure3 UricacidlevelsaccordingtoNYHAfunctionalclass. Topofthebarrepresentsmeanandwhiskersrepresentstandard deviations.UA:uricacid.

P1:NYHAIvs.NYHAII;P2:NYHAIvs.NYHAIII;P3:NYHAIvs.

NYHAIV;P4:NYHAIIvs.NYHAIII;P5:NYHAIIvs.NYHAIV;P6:

NYHAIIIvs.NYHAIV.

p1=0.029,p2=0.010,p3<0.001,p4=0.840,p5<0.001,p6=0.001.

Meanfollow-upwas437.1±133.9(20---545)days.During follow-up21(10.5%)patientsdiedand26(13%)underwent surgery. Increased UA levels were signiﬁcantly associated with an increased risk of death during follow-up, along withmalegender,increasedserumcreatinine,reducedLVEF, moresevereMRandhigherNYHAfunctionalclass(Table2). InmultivariateCoxproportionalhazardsanalysisLVEF,NYHA classandUAlevelsweretheonlyindependentpredictorsof death(Table2).

12 P<0.001

Moderate Moderate to severe Severe 10 8 6 4 2 0

Uric acid (mg/dI)

Figure 4 Uric acid levels according to degree of mitral regurgitation.Topofthebarrepresentsmedianandwhiskers representthe25thand75thpercentileofconcentrations.UA: uricacid.

P1:moderatevs.moderatetosevere;P2:moderatevs.severe;

P3:moderatetoseverevs.severe.

p1<0.001,p2<0.001,p3=0.123

Discussion

Wefound asigniﬁcantincrease inUAandhs-CRPlevelsin patientswithhigherdegreesofMRandNYHAclass.Wealso found that increased UA level, reduced LVEF and higher NYHAclassweresigniﬁcantlyassociatedwithanincreased riskofdeathduringfollow-up.

Surgery is indicated in patients who have symptoms duetochronic MRbutnocontraindicationtosurgery.The management of asymptomatic patients is controversial as there are no randomized trials to support any particu-lar course of action.2,19 _In _some _patients, _including_those who are elderly, physically inactive or obese, it is dif-ﬁcult to assess symptoms because of inactivity. On the otherhand,insomepatients,suchasthosewithpulmonary

o o o o o o o o o o oo o o o oo o o oo o o o o o o o o o o oo o o o o o o o 8.00 7.00 6.00 5.00 4.00 .00 2.00 4.00 6.00 8.00 10.00 12.00 UA L VDD r=0.40; p<0.001

Figure5 Relationshipofuricacidlevelswithleftventriculardiastolicdiameterinpatientswithisolatedandorganicmoderate orsevereMR.LVDD:leftventriculardiastolicdiameter;UA:uricacid.

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Table 2 Results of univariate and multivariate Cox proportional hazard analysis of mortality in patients with mitral regurgitation.

Variable Univariateanalysis Multivariateanalysis

HR 95%CI p HR 95%CI p Gender 0.172 0.058---0.511 0.002** _3.521 _{0.764---16.216} _0.216 NYHAclass 10.296 5.136---20.640 <0.001** _3.803 _{1.243---11.637} _0.019* Uricacid 1.043 1.022---1.065 <0.001** _1.050 _{1.015---1.086} _0.005** Serumcreatinine 7.865 2.792---22.154 <0.001** _2.715 _{0.153---17.89} _0.618 Mitralregurgitation 6.469 3.207---13.049 <0.001** _1.436 _{0.391---5.282} _0.586 Ejectionfraction 0.882 0.839---0.927 <0.001** _0.936 _{0.878---0.998} _0.045* NYHA:NewYorkHeartAssociation.

* _p<0.05. ** _p<0.01.

disease,it maybeunclearwhether symptomsarerelated tosevereMRorcomorbidities.5,6_Noninvasive_markers_that show early changes in the cardiovascular system would thereforebehelpfulinassessingpatientswithMR.6_Several studieshave reportedthevalue ofelevated BNPlevelsto identifyasymptomaticMRpatientsat higherriskof devel-oping heart failure, LV dysfunction or death in mid-term follow-up.5,20,21 _A _recent _study _showed _a _significant cor-relation between proadrenomedullin levelsand degree of MRandNYHAfunctional class.22 _It_has_been _reported_that patientswithischemicheartdisease,LVsystolicdysfunction and dilatedcardiomyopathy withelevated hs-CRP have a worseprognosis.23,24_Two_previous_studies_indicated_that_CRP predictsheartfailureanddeathafterMI.25,26_In_our_study, wefoundthaths-CRPlevelsweresignificantlyhigheramong symptomatic than in asymptomatic patients. Additionally, hs-CRPlevelswerefoundtobesignificantlyincreasedwith higherdegreesof MRand NYHAclass.Hence,hs-CRP may beofvalueforidentificationofadvancedstagesofMRwhen other tools arenot available or less informative. We also believethaths-CRPmayhaveapotentialrolefor monitor-ingpatientresponsetomedicationorsurgeryinfollow-up. Inagreementwithourstudy,Arruda-Olsonetal.reported thatthepresenceofdiastolicdysfunctionandmoderateor severeMRwasassociatedwithhigherCRPlevels.After fur-theradjustmentforinfectionwithintwoweekspriortoMI, theassociationbetweenCRPanddiastolicdysfunctionwas nolongersignificant,buttheassociationbetweenCRPand MRremained.8_In_contrast_to_studies_in_HF_patients,_hs-CRP wasnotcorrelatedwithLVdimensionsorLVEF.

PathwaysofUAproductionandmetabolismmayhave a considerableimpactonCHFpathophysiologyanditsclinical picture.27,28 _It _has_been _shown_that _patients_with_CHF_are hyperuricemiccomparedtocontrols,independentlyofthe effectsofdiuretics,renalimpairmentandothermetabolic factors.9 _UA _levels _were _{signiﬁcantly} _correlated _with _LV systolicanddiastolicdysfunctionin patientswithCHF.29,30 Hyperuricemiais a constantﬁndinginCHF, itsprevalence increasing with disease severity.31,32 _Elevated _serum _UA may itself convey prognostic information in CHF.33 _Anker etal.demonstratedanindependentandgradedrelationship betweenserumUAlevelsandsurvivalinpatientswith mod-erate tosevere CHF.10 _It _has _been _shown _that _in_patients withmild tomoderateCHF, elevated serumUAlevelsare

stronglyrelatedtodeath,andthisrelationshipis indepen-dentofCHFseverityandimpairedrenalfunction.33 _In_the samestudy,hyperuricemiawasreportedtopredictexercise intoleranceandwasamarkerofinflammatoryactivationin CHF.SerumUAlevelsincreasedsignificantlyinparallelwith CHFseverityexpressedasNYHAclass.33_In_our_study,_UA_was significantlyhigheramongsymptomaticMRpatientsthanin asymptomatic patients. This may help to identify asymp-tomaticpatientsinfollow-up.WealsofoundthatmeanUA levels increased significantly with NYHA class and higher degreesofMR. These findingssuggest thatUAis a poten-tialbiomarker forthe assessmentof therapeuticresponse toeither medicationor surgicalintervention infollow-up. Inagreement withprevious studiesin patients withheart failure,UAwassignificantly correlatedwithLVEDD,LVESD andLVEF.Therefore,webelieveUAlevelsmaybeusefulto assesstheextentofLVremodelingandintheoptimaltiming ofmitralvalvesurgeryincertainsubsetsofpatients.

Asalimitationofthestudy,wecannotruleouttheimpact ofdiureticdoseonUA.

Conclusion

UAandhs-CRPlevelscanhelptodistinguishpatientswith asymptomatic moderate to severe MR from symptomatic patients.UAlevelsmaybeusefultoassesstheextentofLV remodelingandtheoptimaltiming ofmitralvalvesurgery incertainsubsetsofpatients.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethat the proceduresfollowed were inaccordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or

(8)

subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

References

1.Guidelinesonthemanagementofvalvularheartdisease (ver-sion2012):theJointTaskForceontheManagementofValvular HeartDiseaseoftheEuropeanSocietyofCardiology(ESC)and theEuropeanAssociationforCardio-ThoracicSurgery(EACTS). EurHeartJ.2012.

2.KangDH,KimJH,RimJH,etal.Comparisonofearlysurgery versusconventionaltreatmentinasymptomaticseveremitral regurgitation.Circulation.2009;119:797---804.

3.SamadZ,Kaul P,ShawLK, etal. Impactofearlysurgeryon survival of patients withsevere mitral regurgitation. Heart. 2011;97:221---4.

4.RossJJr.Thetimingofsurgeryforseveremitralregurgitation. NEnglJMed.1996;335:1456---8.

5.Davutoglu V,CelikA, AksoyM,et al. PlasmaNT-proBNPis a potentialmarkerofdiseaseseverityandcorrelateswith symp-tomsinpatientswithchronic rheumaticvalvedisease. EurJ HeartFail.2005;7:532---6.

6.Potocki M, Mair J, Weber M, et al. Relation of N-terminal pro-B-typenatriureticpeptidetosymptoms,severity,andleft ventricularremodelinginpatientswithorganicmitral regurgi-tation.AmJCardiol.2009;104:559---64.

7.Windram JD, Loh PH, Rigby AS, et al. Relationship of high-sensitivityC-reactiveproteintoprognosisandotherprognostic markers in outpatients with heart failure. Am Heart J. 2007;153:1048---55.

8.Arruda-OlsonAM,Enriquez-SaranoM,BursiF,etal.Left ventri-cularfunctionandC-reactiveproteinlevelsinacutemyocardial infarction.AmJCardiol.2010;105:917---21.

9.LeyvaF,AnkerSD,SwanJW,etal.Serumuricacidasanindex ofimpairedoxidativemetabolisminchronicheartfailure.Eur HeartJ.1997;18:858---65.

10.AnkerSD,DoehnerW,Rauchhaus M,etal.Uricacidand sur-vival in chronic heart failure: validation and application in metabolic,functional,andhemodynamicstaging.Circulation. 2003;107:1991---7.

11.Jankowska EA, Ponıkowska B, Majda J, et al. Hyperuri-caemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol. 2007;115: 151---5.

12.NozariY,GeraielyB.Correlationbetweentheserumlevelsof uricacidandHS-CRPwiththeoccurrenceofearlysystolic fail-ureofleftventriclefollowingacutemyocardialinfarction.Acta MedIran.2011;49:531---5.

13.YaziciogluMV,AvciA,AcarG,etal.Elevateduricacidand func-tionalmitralregurgitationindilatedcardiomyopathy.EurRev MedPharmacolSci.2012;49:1637---41.

14.LangRM,BierigM,DevereuxRB,etal.Recommendationsfor chamberquantiﬁcation:areportfromtheAmericanSocietyof Echocardiography’s Guidelinesand Standards Committee and theChamberQuantiﬁcationWritingGroup,developedin con-junctionwiththeEuropeanAssociationofEchocardiography,a branchoftheEuropeanSocietyofCardiology.JAmSoc Echocar-diogr.2005;18:1440---63.

15.Enriquez-Sarano M, Miller FA Jr, Hayes SN, et al. Effective mitralregurgitantoriﬁcearea:clinicaluseandpitfallsofthe proximalisovelocitysurfaceareamethod.JAmCollCardiol. 1995;25:703---9.

16.HallSA,Brickner ME,Willett DL,etal. Assessmentofmitral regurgitationseveritybyDopplercolorﬂowmappingofthevena contracta.Circulation.1997;95:636---42.

17.ThomasL,FosterE,HoffmanJI,etal.Themitralregurgitation index:anechocardiographicguidetoseverity.JAmCollCardiol. 1999;33:2016---22.

18.QuinonesMA,OttoCM,StoddardM,etal. Recommendations forquantiﬁcationofDopplerechocardiography:areportfrom theDopplerQuantiﬁcationTaskForceoftheNomenclatureand StandardsCommitteeoftheAmericanSocietyof Echocardiog-raphy.JAmSocEchocardiogr.2002;15:167---84.

19.RosenhekR,RaderF,KlaarU,etal.Outcomeofwatchful wait-inginasymptomaticsevere mitralregurgitation. Circulation. 2006;113:2238---44.

20.PizarroR,BazzinoOO,ObertiPF,etal.Prospectivevalidationof theprognosticusefulnessofbrainnatriureticpeptidein asymp-tomaticpatientswithchronicseveremitralregurgitation.JAm CollCardiol.2009;54:1099---106.

21.SuttonTM, StewartRA, Gerber IL,et al. Plasmanatriuretic peptidelevelsincreasewithsymptomsandseverity ofmitral regurgitation.JAmCollCardiol.2003;41:2280---7.

22.TurkerY,AslantasY,TurkerY,etal.Anovelindicatorfor assess-mentofmitralregurgitationseverity:pro-adrenomedullin.Int JCardiol.2013;168:2998---3000.

23.Chirinos JA, Zambrano JP, Chakko S, et al. Usefulness of C-reactive protein as an independent predictor of death in patients with ischemic cardiomyopathy. Am J Cardiol. 2005;95:88---90.

24.KanekoK, KandaT, YamauchiY, et al.C-reactive protein in dilatedcardiomyopathy.Cardiology.1999;91:215---9.

25.SuleimanM,AronsonD,ReisnerSA,etal.AdmissionC-reactive protein levels and 30-day mortality in patients with acute myocardialinfarction.AmJMed.2003;115:695---701.

26.SuleimanM,KhatibR,AgmonY,etal.Earlyinﬂammationand riskoflong-termdevelopmentofheartfailure andmortality insurvivorsofacutemyocardial infarctionpredictive roleof C-reactiveprotein.JAmCollCardiol.2006;47:962---8. 27.DoehnerW,AnkerSD.Uricacidinchronicheartfailure.Semin

Nephrol.2005;25:61---6.

28.Hare JH, Johnson RJ. Uric acid predicts clinical outcomes inheart failure:insights regarding therole ofxanthine oxi-dase and uric acid in disease pathophysiology. Circulation. 2003;107:1951---3.

29.SakaiH,TsutamotoT,TsutsuiT,etal.Serumlevelofuricacid, partlysecretedfromthefailingheart,isaprognosticmarker in patients with congestive heart failure. Circ J. 2006;70: 1006---11.

30.CicoiraM,ZanollaL, RossiA, etal.Elevatedserumuricacid levelsareassociatedwithdiastolicdysfunctioninpatientswith dilatedcardiomyopathy.AmHeartJ.2002;143:1107---11. 31.DoehnerW,RauchhausM,FloreaVG,etal.Uricacidin

cachec-ticandnon-cachecticCHFpatients---relationtolegvascular resistance.AmHeartJ.2001;141:792---9.

32.Leyva F, Chua TP, Anker SD, et al. Uric acid in chronic heartfailure:ameasureofanaerobicthreshold.Metabolism. 1998;47:1156---9.

33.JankowskaEA,PonikowskaB,MajdaJ,etal.Hyperuricaemia predicts poor outcome in patients with mild to moderate chronicheartfailure.IntJCardiol.2007;115:151---5.