Yao Wu , Feifei Si , Li Luo , Qijian Yi 1 year of of heart failure in children with medianage levels of Serum melatonin may contribute to thepathogenesis ORIGINAL ARTICLE

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www.jped.com.br

ORIGINAL ARTICLE

Serum levels of melatonin may contribute to the

pathogenesis of heart failure in children with median age of 1 year ^夽

Yao Wu

^a^,^b^,^c

, Feifei Si

^a^,^b^,^c

, Li Luo

^a^,^b^,^c

, Qijian Yi

^a^,^b^,^c^,∗

aKeyLaboratoryofPediatricsinChongqing,Chongqing,China

bChongqingInternationalScienceandTechnologyCooperationCenterforChildDevelopmentandDisorders,Chongqing,China

cChildren’sHospitalofChongqingMedicalUniversity,DepartmentofCardiovascularMedicine,Chongqing,China

Received15February2017;accepted14June2017 Availableonline28October2017

KEYWORDS Melatonin;

Myeloperoxidase;

Capsase-3;

Heartfailure;

Pediatricpatients

Abstract

Objective: Melatoninhasaprotectiveroleinadultswithcardiovasculardisease,buttheeffects ofmelatonin in children with cardiacdysfunction arenot wellunderstood. Thisstudy was designed to explore the variations inmelatonin, myeloperoxidase, andcaspase-3 levelsin childrensufferingfromheartfailure.

Methods: Seventy-twopediatricpatientswithheartfailureandtwelvehealthychildrenwere enrolledinthis study.A modiﬁed Rossscoring systemwas usedto evaluateclinicalcardiac function.Patientswithascoreof>2pointswereincludedinthestudyandweredividedinto threegroupsaccordingtoseverityofheartfailure:mild(score:3---6),moderate(score:7---9), andsevere(score:10---12).Echocardiographicparameters,laboratorydata,andserumlevels ofmelatonin,myeloperoxidase,andcaspase-3weremeasuredandanalyzedinallpatients.

Results: Comparedwithpatientswithmildandmoderateheartfailure,patientsinthesevere heart failuregrouphadsigniﬁcantlydecreased leftventricular ejectionfraction (p<0.001), and signiﬁcantly increased serum melatonin levels (p=0.013) and myeloperoxidase levels (p<0.001).Serum melatonin levels were positively correlated with serum caspase-3 levels (p<0.001).Theoptimalcutoffvaluesofserummelatoninlevelsforthediagnosisofsevereheart failureandprimarycardiomyopathyinpediatricpatientswithheartfailurewere54.14pg/mL and32.88pg/mL,respectively.

夽 Pleasecitethisarticleas:WuY,SiF,LuoL,YiQ.Serumlevelsofmelatoninmaycontributetothepathogenesisofheartfailurein childrenwithmedianageof1year.JPediatr(RioJ).2018;94:446---52.

∗Correspondingauthor.

E-mail:[email protected](Q.Yi).

https://doi.org/10.1016/j.jped.2017.06.023

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Conclusions: Serum melatonin and myeloperoxidase levelswere increasedin children with severeheart failure.Itislikelythatincreasingmelatoninlevelsmayactasacompensatory mechanisminpediatricchildrenwithheartfailure.

4.0/).

PALAVRAS-CHAVE Melatonina;

Mieloperoxidase;

Caspase3;

Insuﬁciência cardíaca;

Pacientespediátricos

Níveisséricosdamelatoninapodemcontribuirparaapatogênesedeinsuﬁciência cardíacaemcrianc¸ascomidademédiade1ano

Resumo

Objetivo: Amelatoninapossuiumpapelprotetoremadultoscomdoençacardiovascular,porém osefeitosdamelatoninaemcriançascomdisfunçãocardíacanãosãobementendidos.Oestudo foiprojetadoparaexploraravariaçãonosníveisdemelatonina,mieloperoxidaseecaspase3 emcriançasquesofremdeinsuficiênciacardíaca.

Métodos: 72pacientespediátricoscominsuficiência cardíacae12criançassaudáveis foram inscritosnoestudo.UmsistemadeclassificaçãodeRossmodificadafoiutilizadoparaavaliar afunçãocardíacaclínica.Ospacientescomescorede>2pontosforamincluídasnoestudo eforamdivididosem trêsgruposde acordocomagravidadedainsuficiência cardíaca:leve (escore:3-6),moderada(escore:7-9)egrave(escore:10-12).Osparâmetrosecocardiográficos, dadoslaboratoriaiseníveisséricosdemelatonina,mieloperoxidaseecaspase3forammedidos eanalisadosemtodosospacientes.

Resultados: Em comparação aos pacientes com insuficiência cardíaca de gravidade leve e moderada, ospacientesnogrupodeinsuficiência cardíacagraveapresentaram redução sig- nificativa dafraçãodeejeçãodoventrículoesquerdo(p<0,001)eaumentosignificativonos níveisséricosdemelatonina(p=0,013)eníveisdemieloperoxidase(p<0,001).Osníveisséri- cos de melatoninaforampositivamentecorrelacionados comosníveis séricos decaspase 3 (p<0,001).Osvalores de corteideais dosníveis séricos demelatonina paradiagnóstico de ICecardiomiopatiaprimáriaempacientespediátricoscominsuficiênciacardíacaforam54,14 pg/mLe32,88pg/mL,respectivamente.

Conclusões: Osníveisséricosdemelatoninaemieloperoxidasemostraramaumentoemcrianças cominsuficiênciacardíacagrave.Especulamosseoaumentonosníveisdemelatoninapodeagir comoummecanismocompensatórioemcriançaspediátricascominsuficiênciacardíaca.

0/).

Introduction

The prevalence of heart failure (HF) is rising; it poses an increasing burden in terms of both healthcare costs andmortality,especiallywhenitoccursinyoungchildren.

Consequently, a better understanding of the best way to evaluateandmanageHFisrequired.Whileadvancesindiag- nosisandtreatmentofHFinadultshavebeenmade,similar awarenessislackingforpediatricpatientswithHF.¹

Melatonin (N-acetyl-5-methoxytryptamine),a secretory product of the human pineal gland, is well known for its inﬂuence on the cardiovascular system. Mela- tonin has a protective action on the heart that occurs throughbothreceptor-mediatedandreceptor-independent mechanisms.² The receptor-mediated mechanism involves theclassicmelatoninmembranereceptors(MT1andMT2);

however, the precise localization of these receptors has notbeencompletelyelucidated.³Thereceptor-independent mechanism of melatonin occurs through its function

as a potent antioxidant and free radical scavenger.⁴ Melatonin has been shown to reduce hypertension,⁵ pro- tecttheischemic/reperfusedheart,⁶andresisttheprocess of atherosclerosis.⁷ Cardiomyocyte hypertrophy initially occursasacompensatoryresponse,buteventuallybecomes pathologicalandcanleadtoHF.Melatoninaffectshemody- namicoverload,nitricoxide(NO)availability,freeradicals, and lipid proﬁles that may also modify cardiomyocyte hypertrophy.⁸

TheassociationbetweenmelatoninandpediatricHFhas notbeen fullyunderstood.The authorsperformed astudy toinvestigatethecirculatinglevelsofmelatonininchildren withHF.

Methods

This single-center pediatric study was approved by the EthicsCommittee.Allpatient-derivedbloodsampleswere

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collectedafterwritteninformedconsentwasobtainedfrom parentsorguardians.

Collectionofbloodsamplesandclinicdata

Blood samples from 72 children diagnosed with HF and 12 healthy children undergoing routine health examina- tionwerecollectedbetweenDecember2014andDecember 2015 at the Clinical Examination Center.The median age of children with heart failure was1 year (range 0---11.75 years),with44 patientsagedless than1year (61.1%),16 patients between 1 and 3 years (22.2%), three patients between4 and 7 years(4.2%), andnine patients aged>8 years (12.5%). Heart defects included: ventricular septal defects (n=11), atrial septal defects (n=3), tetralogy of Fallot(n=1),patentductusarteriosus(n=3),complexcon- genital heart disease (n=20), aorta stenosis (n=1), and single ventricle (n=3). Other diseases included: primary cardiomyopathy (n=20), myocarditis (n=4), arrhythmias (n=4), pneumonia (n=1), and leukemia(n=1). All serum sampleswerecollectedbetween8:00and10:00am,around the timethat the children also underwent clinical examination. Based on the modiﬁed Ross criteria for cardiac function,⁹HFwasdividedintomild(score:3---6),moderate (score:7---9),orsevere(score:10---12).Toanalyzetheasso- ciationbetweenrelevantclinicdataandtheincidenceofHF inchildren,dataon72childrenwithHFwereretrospectively collected.Dataincludedeachpatient’sage,gender,length ofhospitalstay,echocardiographicexamination,laboratory values, diagnosis, and heart rates detected when admit- tedtothehospital.The concentrationsofMB,TnI,CK-MB andBNPweremeasuredbychemiluminescentimmunoassay (Siemens^®,Munich,Germany)byadocimasterintheclini- callaboratory of thehospital. The clinical characteristics for all 84 children who were evaluated and the patholo- giesofthe72pediatricpatientswithHFaresummarizedin Table1.

Melatonin,myeloperoxidase,andcaspase-3 analysis

Allserumsampleswerestoredinafreezerat---80^◦Cbefore testing. Melatonin, myeloperoxidase (MPO), and caspase- 3 levelswere measured usingthe humanmelatonin ELISA kit(Arigo,Taiwan),thehumanMPOELISAkit(eBioscience^® Thermoﬁsher, CA, USA), and the human caspase-3 ELISA kit (Westang Bio-tech^®, Shanghai, China), respectively.

All assays were performed following the manufacturers’

instructions.

Statisticalanalysis

All statistical analyses were performed with SPSS soft- ware (IBM SPSS Statistics for Windows, version 19.0. NY, USA). All data are shown as mean±SD, with the excep- tionofdatathatwerenotnormallydistributed,whichare shownasmedian(range).Fornormallydistributedvariables, between-groupcomparisonswereevaluatedusingtheone- wayanalysisofvariance(ANOVA)test.Theleastsigniﬁcant difference(LSD)methodwasutilizedtoestimatepairwise comparisons.Fornon-normallydistributedvariables,inter- group comparisonswereassessed usingtheKruskal---Wallis Htest,andthechi-squaredtestwasusedforcomparisons.

Linearregressionanalysiswasperformedtodeterminethe association betweenserummelatoninlevelswithejection fraction(EF)andwithlevelsofcaspase-3andMPOinpedi- atric patients with HF. Pearson correlation analysis was usedtodetermine whethertherewasalinearassociation between serum melatonin concentration and these data mentionedabove.Todeterminetheappropriatecutoffvalue ofserummelatonintodiagnosesevereHFandprimarycar- diomyopathy inpediatricpatientswithHF,theareaunder the receiver operating characteristic (ROC) curve (AUC), sensitivity,speciﬁcity,positivepredictivevalue(PPV),negative predictive value (NPV), and Youden index (J) were

Table1 Clinical,echocardiographic,andlaboratoryvalues,andserummelatoninlevelsofpediatricpatientswithheartfailure andhealthycontrols.

Control(n=12) MildHF(n=26) ModerateHF(n=33) SevereHF(n=13) F p Age(years) 0.55(0.17---12.9) 0.54(0.06---11.33) 0.58(0.0---11.67) 0.94(0.14---11.75) 1.852 >0.05

Gender(male/female) 7/5 12/14 19/14 10/3 4.24 >0.05

Hospitallengthofstay (days)

14.15±9.92^a 22.24±16.43 13.23±8.59^a 3.648 0.031 Echocardiographic

parameters

n=24 n=28 n=10

EF(%) 62.24±14.23^b 60.61±14.98^c 46.4±17.34 4.262 0.019

FS(%) 33.67±9.55 32.04±9.88 26.6±9.89 1.868 >0.05

Laboratorydata

SerumMB(␮g/L) 25.93(12.45---332.75) 25.12(0.01---520.9) 28.95(12.3---135.28) 1.108 >0.05 SerumTropI(␮g/L) 0.1(0.01---0.71) 0.07(0---76.93) 0.2(0.01---2.91) 1.765 >0.05 SerumCK-MB(pmol/L) 3.96(0.88---11.98) 3.33(0.41---8.8) 2.37(0.36---13.79) 1.124 >0.05 SerumBNP(ng/L) 106.7(7.75---18700) 85.39(0.58---35000) 260.53(4.46---1586.65) 0.455 >0.05 EF,ejectionfraction;FS,fractionalshortening;MB,myoglobin;TropI,highlysensitiveTroponin-I;CK-MB,creatinekinase-MB;BNP,brain natriureticpeptide.Valuesareexpressedasmean±SDormedian(range).

ap<0.05comparedwiththemoderateHFgroup.

b p<0.01comparedwiththesevereHFgroup.

c p<0.05comparedwiththesevereHFgroup.

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analyzed. A p value of <0.05 was considered statistically signiﬁcantforalltests.

Results

Serumlevelsofmelatonin,MPO,andcaspase-3 TheEFinthegroupwithsevereHFwasthelowestamongthe fourgroups (p=0.019).Length of hospitalstay (p=0.031) was also found to be different between the four groups (Table1).AsshowninFig.1A,themedianserummelatonin levelwas188.3pg/mL,witharangeof10.06---666.7pg/mL inthesevereHFgroup,whichwasthehighestmedianamong thefourgroups(p=0.031).Fig.1BplotstheserumMPOlev- els;inthegroupwithsevereHF,themedianMPOvaluewas 304.200pg/mL, with a range of 61,880---1,402,700pg/mL, whichwasthehighestamongthefourgroups(p<0.001).No signiﬁcantdifferenceswerefoundincaspase-3levelsamong thefourgroups(p>0.05;Fig.1C).Therewasnorelationship betweencirculatingmelatoninlevelsandage,gender,hospitallengthofstay,EF,orHFetiology(allp>0.05;Fig.1D---H).

Correlationsbetweenmelatoninandcaspase-3, MPO,EFandheartrate

Therewasasigniﬁcantpositivecorrelationbetweenserum melatonin level and serum caspase-3 level (p=0.003;

Fig.2A).Incontrast,serummelatoninlevelswerenotcor- relatedwithMPO(p>0.05;Fig.2B),EF(p>0.05;Fig.2C), ortheheartratesofpatientsdetectedatadmissiontothe hospital(p>0.05;Fig.2D).

ROCcurvesofserummelatoninconcentrationsin pediatricpatientswithHF

Serum melatonin concentrations ranging from 1.1851 to 667.6936pg/mL were used to generate ROC curves and define the optimal value of serum melatonin todiagnose severeHFinpediatricpatients.TheAUC,sensitivity,specificity, PPV, NPV, and J value were assessed. Among all pediatricpatientswithHF,acutoffvalueof54.1404pg/mL yieldedthehighestJ(0.545),withsensitivityof0.833,speci- ficityof0.712,PPVof0.37,andNPVof0.94,indicatingthat thismaybetheoptimalcutoffvaluefor diagnosingsevere HF(Fig.3A).

ROC curvesfor concentrations ofcirculating melatonin were used to deﬁne the optimal value of serum melatonin to diagnose primary cardiomyopathy in pediatric patientswithHF.Among allHFchildren,acutoffvalueof 32.8805pg/mLyieldedthehighestJvalue(0.429),withsen- sitivityof0.9,speciﬁcityof0.529,PPVof0.43,andNPVof 0.93,indicating thatthismaybetheoptimal cutoffvalue for diagnosing primary cardiomyopathy in these patients (Fig.3B).

Discussion

HF is a serious syndrome and is the terminal phase of manypediatriccardiovasculardiseases,especiallyprimary cardiomyopathyorcongenitalheartdisease.¹⁰However,the

molecularmechanismisnotfullyunderstood.Cardiovascu- lardiseaseshavebeenassociatedwithtemporalrhythmicity and seasonal affective disorder.¹¹ Hypertension, myocardial ischemia, arrhythmia, angina, and sudden death due toHFoftenhaveahigherincidenceinthemorning,espe- cially between 6:00 am and 12:00 pm.¹² Cardiovascular diseaseshavealsobeenshowntovaryinseveritywithsea- sonalalterations.¹³Melatoninissecretedbythepinealgland withdiurnalrhythmicity.Lightexposure,especiallyduring daytime, inhibits the secretion of melatonin.¹⁴ Nonethe- less, the role of melatonin in the rhythmicity-associated pathophysiology of HF in pediatric patients remains unclear.

Researchhasdemonstratedthatlowermelatoninlevels areobservedintheNewYorkHeartAssociation(NYHA)class III subgroup of adult patients with HF.¹⁵ A separate study revealed that serummelatonin levels in HF patients suf- feringfromhypertensivecardiomyopathywerelowerthan in individuals without HF.¹⁶ The present data contradicts thatwhich isobserved inadults,and shows thatcirculat- inglevelsofmelatoninweresigniﬁcantlyhigherinchildren withmoresevere HF. Thedatasuggest thattheremaybe a separate mechanism in pediatric patients with HF that affectsmelatoninlevels.Melatoninplaysaprotectiverole incardiovascular diseases asan antioxidantand powerful radicalscavenger.¹⁷Itislikelythattheincreasedmelatonin concentrationinpediatricpatientswithsevereHFmaybea compensatorymechanism;thisspeculationwarrantsfurther investigation.

Numerousstudieshave suggested thatexcessiveoxida- tivestress islinkedtoapoptosisof myocardialcells¹⁸ and thepathologicalprocessthatleadstoHF.¹⁹ In thepresent study,MPOlevelswereincreasedinpatientswithsevereHF, indicatingthatexcessivestressfromreactiveoxygenspecies isinvolvedinthepathologicaldevelopmentofpediatricHF.

Thoughnosigniﬁcantdifferenceswerefound intheserum levelsofcaspase-3amongthegroups,thecirculatinglevels of melatoninwere found to bepositively associated with serumcaspase-3, suggesting a possible role of melatonin intheapoptoticprocessleadingtopediatricHF.Previously studieshavedemonstratedthatserummelatoninconcentra- tionsvariedwithage,withyoungerchildren havinghigher melatonin levels under healthy conditions; however, the present study did not ﬁnd a relationship between mela- toninandage,gender,hospitallengthofstay,EF,heartrate detectedatadmission,orHFetiology.Thisdifferencefrom previousstudiesmaybeduetothefactthatserumsamples inthe previousstudies weretaken fromhealthychildren, whereasthepresentstudyexaminedchildrenwithpediatric HF.

Theplasma levelsofbrainnatriureticpeptide(BNP)or N-terminalpro-brainnatriureticpeptide(NT-proBNP)have been proven tobeuseful in the diagnosis, prognosis,and management of children with heart failure.²⁰ A negative correlationhasbeenfoundbetweenplasmaconcentrations ofBNPorNT-proBNPandagesininfantsandchildrenwith cardiacdysfunction.^21,22 In the present study,such a correlation between the serumlevelsof melatonin and ages inchildrenwithHFwasnotdetected.However,theseval- ues of melatonin in diagnosing children with HF are far better than BNP or NT-proBNP. In adults, melatonin has been suggested not only as a diagnostic biomarker, but

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Figure1 Serumlevelsofmelatonin(A),MPO(B),andcaspase-3(C)inpatients,bydegreeofcardiacdysfunction.Serummelatonin levelsinpediatricspatientsstratiﬁedbyage(D),gender(E),lengthofhospitalstay(F),ejectionfraction(%)(G),andheartfailure etiology(H).VSD,ventricularseptaldefects;ASD,atrialseptaldefects;TOF,tetralogyofFallot;PDA,patentductusarteriosus.

**p<0.01comparedwithsevereheartfailuregroup.

also as a potential therapeutic option for the cardiovas- culardiseases.¹⁷ Thus, learningthelevelsof melatoninin cardiac children is needed to demonstrate the true ben- eﬁt of melatonin in the management of children with HF.

Inconclusion,thecirculationlevelsofmelatoninandMPO wereelevatedinpediatricpatientswithsevereheartfail- ure. Additionally, serummelatoninlevelswere correlated withserumcaspase-3levels.Furtherstudiesareneededto investigatetheroleofmelatonininchildrenwithHF.

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0 200 400 600 800 0

10 20 30

Caspase-3 (ng/l)

40 N=59

R=0.383 P=0.003

Melatonin(pg/ml)

A

0 200 400 600 800

0 5 10

15 N=80

R=0.159 P> 0.05

Melatonin(pg/ml)

MPO (X 100 pg/ml)

B

0 200 400 600

0 20 40 60 80

100 N=61

R=0.097 P>0.05

Melatonin(pg/ml)

EF(%)

C

0 200 400 600 800

0 100 200

300 N=68

R=0.17 P > 0.05

Melatonin(pg/ml)

Heart rate(bpm)

D

Figure2 Relationship betweenserum melatonin leveland caspase-3(A), MPO (B),ejection fraction (%)(C),and heart rate detectedatadmission(D).

Sensitivity Sensitivity

1-specificity 1-specificity

A 1.0 B

1.0 0.8

0.8 0.6

0.6 0.4

0.4 0.2

0.2 0.0

1.0

0.8

0.6

0.4

0.2

0.0

0.0 0.0 0.2 0.4 0.6 0.8 1.0

Figure3 Comparisonofreceivingoperatorcharacteristic(ROC)curvesforthediagnosticperformanceofmelatonininidentifying severeheartfailure(HF)(A)andprimarycardiomyopathy(B)inpediatricpatientswithHF.(A)Areaunderthecurve(AUC)=0.780for melatonin(p=0.002).Themaximalcut-offvaluewas54.1404pg/mLformelatonin(sensitivity=0.833,speciﬁcity=0.712,PPV=0.37, NPV=0.94,andJ=0.545).(B)AUC=0.683formelatonin(p=0.017).Themaximalcut-offvaluewas32.8805pg/mLformelatonin (sensitivity=0.900,speciﬁcity=0.529,PPV=0.43,NPV=0.93,andJ=0.429).PPV,positivepredictivevalue;NPV,negativepredictive value;J,Youdenindex.

Ethical approval and informed consent

This study was approved by the Ethics Committee. All patient-derivedbloodsampleswerecollectedafterwritten informedconsentwasobtainedfromparentsorguardians.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

Acknowledgements

TheauthorswouldliketothankFengchuanJingandDanyi Peng for providinginformationandfor the supportduring thisstudy.

References

1.MacicekSM,Macias CG,JefferiesJL, KimJJ,PriceJF.Acute heart failure syndromes in thepediatric emergency depart- ment.Pediatrics.2009;124:e898---904.

2.ReiterRJ,TanDX,ManchesterLC,PilarTM,FloresLJ,Koppisepi S.Medicalimplications ofmelatonin:receptor-mediated and receptor-independentactions.AdvMedSci.2007;52:11---28.

3.Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, DubocovichML,etal.MT(2)melatoninreceptorsare present and functional in rat caudal artery. J Pharmacol Exp Ther.

2002;302:1295---302.

4.Ghosh G, DeK, Maity S, Bandyopadhyay D,Bhattacharya S, ReiterRJ,etal.Melatoninprotectsagainstoxidativedamage andrestoresexpressionofGLUT4geneinthehyperthyroidrat heart.JPinealRes.2007;42:71---82.

(7)

5.Cagnacci A, CannolettaM,RenziA,BaldassariF,AranginoS, Volpe A. Prolonged melatonin administrationdecreases noc- turnal blood pressure in women. Am J Hypertens. 2005;18:

1614---8.

6.PetrosilloG,ColantuonoG,MoroN,RuggieroFM,TiravantiE, DiVenosaN,etal.Melatoninprotectsagainstheartischemia- reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol.

2009;297:H1487---93.

7.AbujaPM,LiebmannP,HaynM,SchauensteinK,EsterbauerH.

Antioxidantroleofmelatonin inlipidperoxidationofhuman LDL.FEBSLett.1997;413:289---93.

8.Reiter RJ, Manchester LC, Fuentes-Broto L, Tan DX. Car- diac hypertrophy and remodelling: pathophysiological conse- quences and protective effects of melatonin. J Hypertens.

2010;28:S7---12.

9.RossRD. TheRoss classiﬁcationfor heartfailure in children after25years:areviewandanage-stratiﬁedrevision.Pediatr Cardiol.2012;33:1295---300.

10.BrosigCL,BearL,AllenS,HoffmannRG,PanA,FrommeltM, etal.Preschoolneurodevelopmentaloutcomesinchildrenwith congenitalheartdisease.JPediatr(RioJ).2017;183,80---86.e1.

11.Sheng CS,ChengYB,WeiFF,YangWY,GuoQH, LiFK,etal.

Diurnalbloodpressurerhythmicityinrelationtoenvironmental andgeneticcuesinuntreatedreferredpatients.Hypertension.

2017;69:128---35.

12.Nakashima H, Mashimo Y, Kurobe M, Muto S, Furudono S, Maemura K. Impact of morning onset on the incidence of recurrentacute coronarysyndrome and progression ofcoro- nary atherosclerosis in acute myocardial infarction. Circ J.

2017;81:361---7.

13.FarrajAK,WalshL,Haykal-CoatesN,MalikF,McGeeJ,Winsett D,etal.Cardiaceffectsofseasonalambientparticulatematter andozoneco-exposureinrats.PartFibreToxicol.2015;12:12.

14.PereiraJC,PradellaHM,AlvesRC.Secondarytoexcessivemela- toninsynthesis,theconsumptionoftryptophanfrom outside

the blood---brain barrier and melatonin over-signaling in the parstuberalismaybecentraltothepathophysiologyofwinter depression.MedHypotheses.2017;98:69---75.

15.DzidaG,PrystupaA,Lachowska-KotowskaP,KadasT,Kamie´nski P,KimakE,etal.Alterationindiurnalandnocturnalmelatonin serumlevelin patientswithchronic heartfailure.Ann Agric EnvironMed.2013;20:745---8.

16.Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. The potentialusefulnessofserummelatoninleveltopredictheart failureinpatientswithhypertensivecardiomyopathy.IntJCar- diol.2014;174:415---7.

17.¸ehirliS AÖ, KoyunD,Tetik¸,S ÖzsavcıD,Yi˘ginerÖ,C¸etinel¸,S etal.Melatoninprotectsagainstischemicheartfailureinrats.

JPinealRes.2013;55:138---48.

18.SungHK,ChanYK,HanM,JahngJW,SongE,DanielsonE,etal.

Lipocalin-2(NGAL) attenuatesautophagy to exacerbate car- diacapoptosisinducedbymyocardialischemia.JCellPhysiol.

2017;232:2125---34.

19.SchrutkaL, Distelmaier K,Hohensinner P,Sulzgruber P,Lang IM, Maurer G, et al. Impaired high-density lipoprotein anti- oxidativefunctionisassociatedwithoutcomeinpatientswith chronicheartfailure.JAmHeartAssoc.2016;5:e004169.

20.¸ahinS M, PortakalO,Karagöz T,Hasc¸elikG, ÖzkutluS.Diag- nostic performance of BNP and NT-ProBNP measurements in childrenwithheartfailurebasedoncongenitalheartdefects andcardiomyopathies.ClinBiochem.2010;43:1278---81.

21.LinCW,ZengXL,ZhangJF,MengXH.Determiningtheoptimal cutoffvaluesofplasmaN-terminalpro-B-typenatriureticpep- tidelevelsforthediagnosisofheartfailureinchildrenofage upto14years.JCardFail.2014;20:168---73.

22.CantinottiM,LawY,VittoriniS,CrocettiM,MarcoM,MurziB, etal. Thepotentialand limitationsofplasmaBNPmeasure- mentinthediagnosis,prognosis,andmanagementofchildren withheartfailureduetocongenitalcardiacdisease:anupdate.

HeartFailRev.2014;19:727---42.

Yao Wu , Feifei Si , Li Luo , Qijian Yi 1 year of of heart failure in children with medianage levels of Serum melatonin may contribute to thepathogenesis ORIGINAL ARTICLE

ORIGINAL ARTICLE

Serum levels of melatonin may contribute to the

pathogenesis of heart failure in children with median age of 1 year 夽

Yao Wu

, Feifei Si

, Li Luo

, Qijian Yi

Introduction

Methods

Results

Discussion

Ethical approval and informed consent

Conﬂicts of interest

Acknowledgements

References

pathogenesis of heart failure in children with median age of 1 year ^夽