Usefulness of Right Ventricular and Right Atrial Two-Dimensional Speckle Tracking Strain to Predict Late Arrhythmic Events in Adult Patients with Repaired Tetralogy of Fallot

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www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

ORIGINAL

ARTICLE

Usefulness

of

right

ventricular

and

right

atrial

two-dimensional

speckle

tracking

strain

to

predict

late

arrhythmic

events

in

adult

patients

with

repaired

Tetralogy

of

Fallot

Ana

T. Timóteo

∗

_,

_Luísa

_M.

_Branco,

_Sílvia

_A.

_Rosa,

_Ruben

_Ramos,

_Ana

_F.

_Agapito,

Lídia

Sousa,

Ana

Galrinho,

José

A. Oliveira,

Mário

M. Oliveira,

Rui

C. Ferreira

CardiologyDepartment,SantaMartaHospital,CentroHospitalarLisboaCentral,Lisboa,Portugal Received25February2016;accepted26July2016

Availableonline9December2016

KEYWORDS Repairedtetralogy ofFallot; Arrhythmias; Strain Abstract

Objective: Todeterminewhetherrightventricularand/oratrialspeckletrackingstrainis asso-ciatedwithpreviousarrhythmiceventsinpatientswithrepairedtetralogyofFallot.

MethodsandResults: We studied right ventricular and atrial strain in 100 consecutive patients withrepairedtetralogyofFallotreferred forroutineechocardiographicevaluation. Patientsweredividedintotwogroups,onewithpreviousdocumentationofarrhythmias(n=26) andonewithout arrhythmias,inamedianfollow-up of22 years.Patientswith arrhythmias were older (p<0.001) and had surgical repair at an older age (p=0.001). They also had significantly reduced right ventricular strain (-14.7±5.5 vs.-16.9±4.0%, p=0.029)andright atrial strain(19.1±7.7% vs.25.8±11.4%, p=0.001). Neither rightventricular norright atrial strainwereindependentpredictorsofthepresenceofahistoryofdocumentedarrhythmias, whichwas associatedwithageatcorrectionandwiththepresenceofresidualdefects.In a subanalysis afterexcluding23patientswhohadhadmorethanonecorrectivesurgery,right ventricularstrainwasanindependentpredictorofthepresenceofpreviousarrhythmicevents (OR1.19, 95%CI 1.02-1.38,p=0.025).Right atrialstrain wasalso anindependent predictor afteradjustment(OR0.93,95%CI0.87-0.99,p=0.029).Theidealcut-offforrightventricular strainwas-15.3%andforrightatrialstrain23.0%.

Conclusions: Comparedwithconventionalechocardiographic parameters,strain measuresof therightheartareassociatedwiththepresenceofarrhythmicevents,andmaybeusefulfor riskstratificationofpatientswithrepairedtetralogyofFallot,althoughaprospectivestudyis required.

∗_{Corresponding}_author.

E-mailaddress:anatimoteo@yahoo.com(A.T.Timóteo).

http://dx.doi.org/10.1016/j.repc.2016.07.005

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PALAVRAS-CHAVE TetralogiadeFallot reparada;

Arritmias;

Strain

Utilidadedostrainbidimensionalporspeckletrackingdaaurículaeventrículodireito parapredizerarritmiastardiasemdoentesadultoscomTetralogiadeFallotcorrigida Resumo

Objetivo:Avaliarseostrainporspeckletrackingdaaurículae/ouventrículodireitoseassocia comeventosarrítmicospréviosemdoentescomtetralogiadeFallotreparada.

Métodoseresultados: Analisámosostrainauriculareventriculardireitoem100doentes con-secutivos com tetralogiade Fallot reparada em ecocardiograma de rotina.Dividiram-se os doentes num grupo com documentação prévia de arritmias (n=26) e outro sem arritmias, num seguimento medianode 22 anosapós cirurgia.Os doentescom arritmias tinhammais idade(p<0,001)ecirurgiareparadoranumaidademaior(p=0,001).Apresentamtambémum strainventriculardireitosignificativamentereduzido(-14,7±5,5versus-16,9±4,0%,p=0,029) tal como ostrain auriculardireito (19,1±7,7%versus25,8±11,4%, p=0,001). Contudo, nem ostrainauricular,nemoventricularforampreditoresindependentesdapresençadehistória préviadearritmiasdocumentadas.Estasassociaram-seàidadedarealizaçãodacorreçãoecom apresençadedefeitosresiduais.Numasub-análiseapósexclusãode23doentesquetiveram maisdoqueumacirurgiacorretiva,ostrainventriculardireitofoipreditorindependenteda presençapréviadearritmias(OR1,19,IC95%1,02-1,38,p=0,025).Ostrainauriculardireito étambémpreditorindependenteapósajustamento(OR0,93,IC95%0,87-0,99,p=0,029).O limiaridealparaostrainventriculardireitoéde---15,3%eparaostrainauriculardireitode 23,0%.

Conclusões:Comparativamente com os parâmetros ecocardiográficos convencionais, as

avaliações do strain do coração direito associam-se à presença de eventos arrítmicos previamentedocumentadosepoderáserútilnaestratificaçãoderiscoemdoentescom tetralo-giadeFallotreparada,emborasejanecessárioumestudoprospetivo.

Introduction

Firstdescribed in1671 by NielsStensen,tetralogy of Fal-lot (TOF) is the most common cyanotic congenital heart defect.1,2_Before_the_development_of_surgical_palliation_and correction,about50%ofpatientswithTOFdiedinthefirst few years of life and it was unusual for any to survive for more than 30 years.3 _Early _surgical _repair _enabled _a dramaticimprovement in the outcome of TOF, withmost patientsreachingadulthood.1,4,5

Previously,somepatientsreceivedpalliativesurgeryby construction of a systemic-to-pulmonary arterial shunt, balloondilation,or placementofastentintheright ven-tricular(RV) outflow tract in infants, deferring repair for laterin life.1 _A _staged _approach_was_then _suggested, _but thishas potentialdisadvantages such aslong-lasting right ventricular pressure and/or volume overload and persis-tent cyanosis. However, even after early surgical repair, complicationsmayoccur,mainlyinadulthood,suchas signif-icantpulmonaryvalveregurgitation,aorticrootdilationand arrhythmias.1 _Arrhythmias_are_in_fact_a_considerable clini-calprobleminadultswithrepairedTOF,withrecentstudies showing incidences of sustained tachyarrhythmiasas high as43%.6

Ventricularandatrial dilationanddysfunctionare asso-ciatedwitharrhythmias.The goldstandardfor rightheart evaluation is cardiac magnetic resonance,1,2 _because _it enablesbetterglobalandregionalfunctionalanalysisofthe right heart. However, it is often not available in clinical practice,andechocardiographyisstillthemostcommonly

usedtechnique.Two-dimensionalspeckletracking echocar-diography is an early marker of ventricular dysfunction and can thus be useful in the routine evaluation of TOF patients.8---11

Left ventricular (LV) longitudinal function by two-dimensionalspeckletrackingechocardiographyisa predic-toroflife-threateningventriculararrhythmiasanddeathin patientswithheartdisease,includingadultswithrepaired TOF.8,9 _Since_the _disease _mainly _involves _the _right _heart, we aimed to determine if RV and right atrial (RA) strain evaluatedbytwo-dimensionalspeckletracking echocardiog-raphyisassociatedwithpreviouslydocumentedarrhythmic events (ventricularand supraventricular) in patients with repairedTOF.

Methods

AllpatientswithrepairedTOFfollowedattheadult congen-italheartdiseaseoutpatientclinicofSantaMartaHospital (Lisbon, Portugal) who underwent routine transthoracic echocardiography between 2008 and 2015 with digitally stored images of sufficient quality were prospectively includedinthestudy.Clinicalcharacteristicswereobtained by reviewof medicalfilesandincluded age, gender, date andtypeofsurgicalprocedures,electrocardiographic(ECG) data, and New York Heart Association functional classat thetimeoftheechocardiogram.Theprimaryendpointwas documentation of supraventricular or ventricular arrhyth-miasby12-leadECG,ambulatoryECG monitoringorother rhythmmonitoringdevicesatanytimeinthefollow-upafter

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Figure1 Rightatrial(A)andrightventricular(B)strainmeasurementsbytwo-dimensionalspeckletrackingechocardiography.

surgicalcorrection.Singleorpairedprematurebeatswere notconsideredasanendpoint.

Echocardiography

A complete standard echocardiographic study was per-formed including M-mode, two-dimensional and Doppler study.Italsoincludedaspecificechocardiographic evalua-tionoftherightheart,usingcommerciallyavailablesystems (Vivid7TM_and_Vivid₉TM_,_General_Electric_Healthcare)._The studywasperformedwiththepatientinleftlateralposition using a 3.5 MHztransducer. For RV study,fractional area change wascalculatedfromapical4-chamber viewasthe percentagechangeinRVend-diastolicandend-systolicarea. RV end-diastolic diameter was assessed at the mid level oftheRVcavityin4-chamberview.RAvolumeand tricus-piddiastolicandsystolicflowwerealsoevaluatedinapical 4-chamberview.Tricuspidannularplanesystolicexcursion (TAPSE)wasdefinedasthemaximumsystolicmotionofthe lateral tricuspid annulus along its longitudinal plane. RV myocardialperformancewasmeasuredaccordingtotheTei index.12_Tissue_Doppler_{echocardiography}_was_used_to_assess longitudinalmyocardialvelocitiesatthemitralandtricuspid annulus.

Imageswereacquiredinapical4-chamberview,andthe transducer settings of the B-mode image were adjusted toachieve a framerateof at least 55 framesper second (fps) (preferably 60-80 fps). The grayscale definition was changed as necessary to optimize two-dimensional endo-cardialandmyocardialright heartdefinition.Images were digitally stored in cineloop format with three sequential beatsandtransferredtoaworkstationforsubsequentoffline analysisusingacustomized softwarepackage (EchoPACTM_, GeneralElectricHealthcare).Withthissoftware,the endo-cardialborderoftheright ventricleandrightatriumwere manuallytracedandtheprogramautomaticallygenerated additional lines nearthe epicardium. Speckles were then tracked, frame by frame, during the cardiac cycle. The regionofinterestwasalsoadjustedmanuallybythe oper-atorwhenevernecessary.Manualcorrectionwasperformed intheeventofinsufficientorincorrectlytrackedsegments.

The right ventricle and right atrium were automatically dividedintosixsegmentsandmeanpeaklongitudinalstrain wasaveraged from all six segments of the free wall and septum(Figure1).Peaksystoliclongitudinalstrainwas syn-chronizedwiththeECGcorrespondingwithpulmonaryvalve closure.Strainmeasurementsweremadebyasingle opera-torblindedtothepatient’s arrhythmicstatus. Inpatients withatrial fibrillation or atrial flutter, RA strain was not analyzed.

Statistical

analysis

Continuous variables are presented as mean or median, standard deviation or interquartile range (25th-75th per-centile), as required. Normality and homogeneity of variance were tested with the Kolmogorov-Smirnov test and Levene’s test, respectively. Categorical variables are reportedas percentages. Differences between groups for categoricalvariablesweretested withthechi-squaretest orFisher’sexacttest, asappropriate.Thetwo-tailed Stu-dent’sttestwasusedtocomparecontinuousvariableswith normaldistributionandtheMann-Whitneytesttocompare non-normallydistributedvariables.Theassociationbetween continuous variables was analyzed with Person’s correla-tion.Discriminativeabilitywasassessedbytheareaunder thereceiveroperatingcharacteristic(ROC)curve.Thebest cut-off points of both parameters (RV and RA strain) for arrhythmic events were selected by identification of the minimumEuclideandistanceinROCcurveanalysis.

Multivariate logistic regression models were used to assesstheassociationofRVandRAstrainwitharrhythmic events.Factorsthatremainedsignificantatthe0.05levelin univariateanalysiswereconsideredtobesignificant contrib-utorsandwereincludedinthefinalmodel.Multicollinearity wasalsoassessedandwhenidentified,thosevariableswere removedfromthefinalmultivariatemodel.Estimatesofthe associationbetweenpredictorsandendpointsarepresented asoddsratios (OR)with95%confidence interval(CI).The model’spredictive ability wasassessed with the Hosmer-Lemeshowtest.

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Table1 Characteristicsofthestudypopulation.

Overall(n=100) Arrhythmias(n=26) Noarrhythmias(n=74) p

Age(years) 35±11 44±14 32±8 <0.001

Male(%) 66.0 73.1 63.5 0.376

Previouspalliativesurgery(%) 29.0 23.1 31.1 0.439

Ageatcorrectivesurgery(years) 6(4-12) 12(5-23) 6(3-9) 0.001

Secondcorrectivesurgery(%) 23.0 38.5 17.6 0.029

Sinusrhythm(%) 95.0 80.8 100.0 <0.001

RBBB(%) 99.0 100.0 98.6 0.551

NYHAclass(%) 0.347

I 76.0 69.2 78.4

II 24.0 30.8 21.6

Timecorrection-echo(years) 22(4-12) 29(20-34) 24(21-28) 0.093

echo:echocardiographicassessment;NYHA:NewYorkHeartAssociation;RBBB:rightbundlebranchblock.

To establishand quantifythe reproducibilityof RVand atrialstrain,agreementandintra-andinterobserver repro-ducibility were assessed using the interclass correlation coefficient and reliability coefficients (Cronbach’s alpha) withtwo-waymixedeffectsmodels.Meandifferencesand limitsofagreementwereanalyzedwithBland-Altmanplots. Fifteenconsecutivepatientswereselectedfor reproducibil-ityanalysisandthetwooperatorswereblindedforpatient statusandpreviousresults.

IBMSPSSStatisticssoftware,version19.0.0.2(SPSSInc., Chicago,IL)andRstatisticalsoftware,version2.15.0,were usedfor all statistical analyses. All statistical tests were two-sided witha criticalvalue of 0.05 for statistical sig-nificance.

Results

Thestudyincluded100consecutivepatientswithrepaired TOF.Another12patientswereexcludedduetoinadequate images for off-line analysis. Mean age was 35±11 years and 66% were male. At a median follow-up of 22 years, therewere26patientswithdocumentedarrhythmicevents (16withsupraventriculararrhythmias,fivewithventricular arrhythmiasandfivewithboth).Patientswitharrhythmias wereolder,hadsurgicalrepairatanolderage,moreoften hadasecondcorrectivesurgeryandwerelessofteninsinus rhythmat assessment (Table1).In the echocardiographic assessment,thesepatientsmoreoftenhadresidual ventri-cularseptaldefect(VSD)andpulmonaryvalveprosthesis(all replacedinasecondrepairsurgery),moreseveretricuspid regurgitation,moreenlargedrightventricleandrightatrium andlowerRVandatrialstrain(Table2).

Reproducibility data for RV and atrial strain are pre-sented inTable 3. Reproducibilitywas significantlybetter forRV strainthan for RAstrain.RV strain correlatedwith other RV function parameters such as RV fractional area change, TAPSE and tricuspid s’, as well as with RV end-diastolicdimensionandRAstrain (Table4).RAstrain also correlatedwithRVfunctionparameters(tricuspids’,TAPSE andTeiindex)andRAvolume.RVstrainshowedareasonable predictive accuracy for the association with arrhythmias (area under the curve [AUC] 0.660, 95% CI 0.530-0.791), with a cut-off of -13.8% (sensitivity 54% and specificity 76%).RAstrainhada similaraccuracy (AUC0.670,95%CI

0.560-0.781), witha cut-off of 23.0% (sensitivity 58% and specificity69%).Inunivariateanalysis,RAstrain(OR0.94, 95% CI0.89-0.98,p=0.009)andRVstrain(OR1.12, 95%CI 1.01-1.24,p=0.032)werebothassociatedwitharrhythmias. Othermajorpredictorsofarrhythmiaoccurrencewereage at correction (OR 1.05, p=0.006), residual VSD (OR 4.17, p=0.020)andthepresenceofapulmonaryvalveprosthesis (OR5.17,p=0.001).NoneoftheotherRVfunctionmeasures could predict the presence of arrhythmias: RV fractional areachange(OR0.013,p=0.080),TAPSE(OR0.91,p=0.080), Tei index (OR 6.23, p=0.313) and tricuspid s’ (OR 0.83, p=0.075).

Intheoverallpopulationandin multivariateregression analysis,neitherRVnorRAstrainwereindependent predic-torsofthepresenceofpreviousarrhythmias(Table5).The maindeterminantswereageatcorrectionandthepresence ofaresidualVSDandpulmonaryvalveprosthesis,whichisa surrogateforsubsequentrightheartoverloadafterthefirst repair.Sincethisrightheartoverloadmightbiasouranalysis andthesepatientshadasecondcorrectivesurgery,we per-formed a subanalysisafter excluding the23 patientswith a subsequentcorrective surgery(18 withpulmonary valve prosthesisimplantationandthe remainderwithclosure of asignificant residualVSD). Themeanageof thissubgroup was 35±10 years, and 16 patients had documentation of arrhythmias(supraventricularin10patients,ventricularin three and both in three). In this subgroup, after adjust-mentforpatients’ageatrepairandpresenceofaVSD,RV strainremainedan independentpredictorof thepresence ofarrhythmicevents(OR1.19,95%CI1.02-1.38,p=0.025) (Table6).RAstrainwasalsoanindependentpredictorafter adjustment(OR0.93,95%CI0.87-0.99,p=0.029).ROCcurve analysis showed similar predictive accuracy for both RV strain(AUC0.696,95%CI0.532-0.860,cut-off-15.3%, sen-sitivity62%andspecificity 74%)andRAstrain(AUC0.699, 95%CI0.571-0.827,cut-off23.0%,sensitivity59%and speci-ficity 67%)(Figure2). Inall models,thepredictive ability ofthecompletemultivariatemodelwassignificantlyhigher, comparedtoeachsinglevariable.

Discussion

TOF is the most common form of cyanotic congeni-tal heart defect (approximately 10% of all congenital

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Table2 Echocardiographicdata.

Overall(n=100) Arrhythmias(n=26) Noarrhythmias(n=74) p

NormalLVfunctiona_(%) _97.0 _88.5 _100.0 _0.003

ResidualVSD(%) 13.0 26.9 8.1 0.014

Pulmonaryvalveprosthesis(%) 25.0 50.0 16.2 0.001

Pulmonaryregurgitation≥2(%) 49.0 46.2 50.0 0.419 Tricuspidregurgitation≥2(%) 16 34.6 9.5 0.026 MitralE/e’ 8.9(7.2-12.1) 9.8(7.8-14.9) 8.3(6.9-9.9) 0.061 RVdiastolicarea(cm2₎ _29.1±8.3 _30.3±6.8 _28.6±8.8 _0.375 RVsystolicarea(cm2₎ _18.2±5.9 _19.7±4.5 _17.7±6.3 _0.145 RVFAC(%) 0.37±0.09 0.34±0.09 0.38±0.09 0.076 RVdimension(mm) 34.9±9.5 40.0±7.8 33.2±9.4 0.008 RAvolume/BSA(ml/m2₎ _27.8_(22.2-42.9) _41.6_(29.5-57.6) _24.4_(20.9-32.4) _0.007 Tricuspide’(cm/s) 9(7-12) 8(6-11) 10(7-12) 0.132 Tricuspids’(cm/s) 8(8-10) 7(6-9) 8(7-18) 0.051 TricuspidE(cm/s) 81±25 73±11 85±29 0.051 TricuspidE/e’ 9.1(5.9-11.2) 9.9(6.4-11.8) 8.7(5.5-10.8) 0.418

Peakpulmonarygradient(mmHg) 18(12-26) 22(13-37) 17(12-24) 0.097

RV/RAgradient(mmHg) 30(24-37) 34(25-41) 30(24-35) 0.141 PASP(mmHg) 19(14-25) 17(13-24) 19(13-26) 0.473 TAPSE(mm) 17.8±4.4 16.5±4.4 18.3±4.4 0.077 Teiindex 0.22(0.12-0.26) 0.22(0.10-0.27) 0.22(0.12-0.26) 0.972 RVstrain(%) −16.4±4.6 −14.7±5.5 −16.9±4.0 0.029 RAstrain(%)b _24.1±10.9 _19.1±7.7 _25.8±11.4 _0.001

BSA:bodysurfacearea;FAC:fractionalareachange;LV:leftventricular;PASP:pulmonaryarterysystolicpressure;RA:rightatrial;

RV:rightventricular;TAPSE:tricuspidannularplanesystolicexcursion;VSD:ventricularseptaldefect.

a _Normal_left_ventricular_function_was_defined_as_ejection_fraction_>55%.

b _Five_patients_with_atrial_{fibrillation/flutter}_were_excluded_from_RA_strain_analysis.

Table3 Reproducibilityresultsforrightventricularandrightatrialstrain. ICC(consistency) ICC(agreement) Reliability

coefficienta Mean difference (absolute) Limitsof agreement (absolute) RVstrain(intraobserver) 0.98(0.94-0.99) 0.98(0.93-0.99) 0.989 −0.42 ±2.04 RVstrain(interobserver) 0.93(0.81-0.98) 0.93(0.82-0.98) 0.966 −0.35 ±3.84 RAstrain(intraobserver) 0.85(0.62-0.95) 0.86(0.63-0.95) 0.921 −0.71 ±9.14 RAstrain(interobserver) 0.85(0.62-0.95) 0.83(0.55-0.94) 0.919 2.29 ±9.48

ICC:interclasscorrelationcoefficient;RA:rightatrial;RV:rightventricular.

a _Cronbach’s_alpha.

Table4 Correlationsbetweencontinuousvariables.

RVstrain(r) p RAstrain(r) p RVstrain - - −0.573 <0.001 RAstrain −0.573 <0.001 - -RVFAC −0.432 <0.001 0.321 0.001 RVdiastolicarea/BSA 0.139 0.169 −0.143 0.155 RV/BSA 0.319 0.006 −0.177 0.078 Tricuspide’ −0.068 0.509 0.151 0.137 Tricuspids’ −0.395 <0.001 0.259 0.010 RV/RAgradient −0.001 0.991 −0.042 0.679 PASP −0.154 0.129 −0.018 0.858

Peakpulmonarygradient 0.100 0.320 −0.008 0.937

TAPSE −0.317 0.001 0.258 0.010

Teiindex 0.147 0.253 −0.281 0.027

BSA:body surfacearea; FAC:fractional areachange; LV: left ventricular;PASP: pulmonary arterysystolicpressure;r: correlation

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1.00 0.75 0.50 0.25 0.00 0.00 0.25 0.50 1 - specificity

Right atrial strain

A

Sensitivity 0.75 1.00 1.00 0.75 0.50 0.25 0.00 0.00 0.25 0.50 1 - specificity

Right ventricular strain

B

Sensitivity

0.75 1.00

Figure2 Receiveroperatingcharacteristiccurvesofrightatrial(A)andrightventricular(B)strainforthepresenceofdocumented arrhythmiasinthesubanalysispopulation(n=77).

Table 5 Multivariate logistic regression analysis in the overallpopulation. OR 95%CI p Model1a Ageatcorrection 1.05 1.01-1.09 0.014 ResidualVSD 4.01 0.98-16.35 0.053 Pulmonaryprosthesis 5.18 1.68-15.93 0.004 RVstrain 1.08 0.96-1.22 0.187 Model2b Ageatcorrection 1.05 1.01-1.09 0.022 ResidualVSD 5.16 1.69-15.81 0.004 Pulmonaryprosthesis 0.95 0.91-1.01 0.082 RAstrain 0.95 0.91-1.01 0.082

CI:confidenceinterval;OR:oddsratio;RA:rightatrial;RV:right

ventricular;VSD:ventricularseptaldefect.

Predictivecapacity(univariate)byAUC:ageatcorrection(0.72),

residual VSD (0.59), pulmonary prosthesis (0.67), RV strain

(0.66),RAstrain(0,67).Overallmultivariatemodelpredictive

capacity:model1(0.80),model2(0.80).

a_{Hosmer-Lemeshow}_p=0.447.

b _{Hosmer-Lemeshow}_p=0.184.

heart defects --- similar to a previous report by our cen-ter, which has a long experience in congenital heart disease).2,13 _The _prognosis _of _TOF _has_improved _markedly in recent years due to advances in surgical techniques andearly repair.Inthe1990s,32-yearsurvivalofpatients who survived corrective surgery was 86%,4 _whereas cur-rent long-term survival of repaired TOF is estimated to be>90%(30-yearsurvival of92%).5 _There_can_however_be importantlatecomplicationsfollowingTOFrepairincluding arrhythmias,heart failureand death.5 _At _35-year follow-up,symptomatic arrhythmiashave acumulativeincidence of17%.5_Previous_studies_showed_an_incidence_of supraven-triculararrhythmiasrangingbetween4%and20%,depending on the duration of follow-up.6,13---17 _Repaired _TOF _is _also associated with subsequent ventricular tachyarrhythmias, mortalityandmorbidity.15,18_The_incidence_of_sudden_death is6%over30years,principallyin thefirstfew yearsafter repair.Themainpredictorsofarrhythmiceventsareolder ageatrepairandresidualRVstructuralabnormalitiessuch

Table6 Multivariatelogisticregressionanalysisinthe sub-setofpatientswithoutasecondcorrectivesurgery(n=77).

OR 95%CI p Model1a Ageatcorrection 1.05 1.01-1.10 0.014 ResidualVSD 1.97 0.35-11.09 0.441 RVstrain 1.19 1.02-1.38 0.025 Model2b Ageatcorrection 1.04 1.00-1.09 0.039 ResidualVSD 2.03 0.36-11.61 0.424 RAstrain 0.93 0.87-0.99 0.029

CI:confidence interval;OR: oddsratio;RV:right ventricular;

RA:rightatrial;VSD:ventricularseptaldefect.

Predictivecapacity(univariate)byAUC:ageatcorrection(0.72),

residualVSD(0.57),RVstrain(0.70),RAstrain(0.70).Overall

predictivecapacityofmultivariatemodel:model1(0.77),model

2(0.77).

a _{Hosmer-Lemeshow}_p=0.486.

b _{Hosmer-Lemeshow}_p=0.198.

as outflow aneurysms or significant pulmonary regurgita-tion and severe RV dilation with right or left ventricular dysfunction.9,14---16 _{Long-standing} _pulmonary _{regurgitation} has deleterious effects on RV size and function, which increasestheriskofseverearrhythmiasandsuddendeath becauseRVfunctionisamajorprognosticfactorinpatients withoperated TOF.9,14---16 _After_35-year_follow-up, _44%_will require some type of reintervention,and at a median of 24 years after initial correction 40% will need pulmonary valvereplacement.5

Due to the complicated geometry of the right ventri-cle,two-dimensionalmeasurementsofRVfunctionmaybe inadequate and assessment is challenging. For this rea-son, cardiac magnetic resonance imaging (CMRI) is still the gold standard non-invasive technique for right heart structuralandfunctional assessmentin patientswith con-genitalheartdisease,includingTOF.19_However,_its_limited availability,costandcontraindicationsareimportant limi-tationsfor itsapplication in clinical practice,particularly for regular long-term follow-up of these patients, and

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echocardiography will remain the main tool for routine assessmentofTOFpatients.

Previous studies have validated TAPSEand tricuspid s’ measured by echocardiography against RV ejection frac-tion measured by CMRI, and both are currently used as measuresofRVfunction.19_However,_they_did_not_take_into accountthe multisegmental natureof contractility.Other parameterssuchasRVfractionalareachangein4-chamber view,fractionalshorteningoftheRVoutflowtractandTei index,althoughindicatorsofRVdysfunction,arelessused.7 In a previous paper, our group showed the usefulness of newechocardiographicimagingtechniques,particularly tis-sueDopplerimaging,inpatientswithrepairedTOFandits association with arrhythmias.20 _However,_RV _function _was only assessed at the atrioventricular valve annular level. Recentlyit has alsobeen demonstratedthat LV longitudi-nal strain measured by two-dimensional speckle tracking echocardiography is an important indicator of mortality risk.8 _This _technique _is _not _{angle-dependent} _and _is _not affectedbytetheringeffects.ItcanalsobeappliedtoRV functionalassessmentinpatientswithright heartdisease, includingpatientswithrepairedTOF.21_It_has_been_tested_in patientswithpulmonaryhypertension,pulmonaryembolism and atrial septal defects.22---24 _However, _very _few _studies haveassessedRVfunctionbytwo-dimensionalspeckle track-ingechocardiographyinadultpatientslateafterTOFrepair, and none hasanalyzed right atrial function. In ourstudy, we performed a specific study of the right heart using conventionaltwo-dimensional, Dopplerand tissueDoppler methods, and also studied right atrial and ventricular function bypeak longitudinal strain withtwo-dimensional speckletrackingechocardiography.Thiswasmeasuredina singleplane,byaveragingsixsegmentsofthefreewalland septum.

Apilotstudyperformedatourcentershowedthe poten-tial value of these new technologies appliedto the right hearttoassesstheassociationwitharrhythmiasinpatients withrepaired TOF.25 _We _therefore _decided_to_enlarge _the studysampletoimprovethestatisticalpowerofour conclu-sions. In the present study sample, 26% had a history of arrhythmias(ventricularin10%andsupraventricularin21%), whichisclosetopreviousreports.Thesepatientswereolder andhadcorrectivesurgeryatanolderage.Theyalsomore often underwent a second corrective surgery, mainly for pulmonaryvalvereplacement.Thisconfirmstheimportant role of residual defectsthat lead to overload and hence enlargement and dysfunctionof the right heart chambers afterthefirstcorrectivesurgery,whichareknowntocause arrhythmias.In our study population, RVsystolic function asassessedbytraditionalmethods,suchasfractionalarea change, TAPSE, Tei index and tricuspid s’, were similar between groups. Although strain correlated with conven-tionalRVfunctionmeasures,wefoundsignificantreductions inbothRAandRVstraininpatientswitharrhythmicevents, confirming thatthistechnique candetect contractile dys-functionearlierinthecourseofthedisease.

RA and RV strain showed reasonable predictive abil-ity,withan AUC>0.65. Thecut-off obtainedfor RVstrain was-13.8% withreasonable specificity and sensitivity. RA strain cut-off was 23.0%, also with reasonable sensitivity andspecificity.Rightheartchamberstrainisapredictorfor the presence of arrhythmias. However, after multivariate

analysis with adjustment for other important predictors suchasageat correction or thepresence ofresidual VSD or pulmonary valve prosthesis (as a surrogate for previ-oussignificantpulmonaryregurgitation),itwasnolongera predictor.However,the predictiveabilityof thecomplete multivariate model was significantly higher, compared to eachindividualvariable.

Althoughstrainandstrainrateimprovesignificantlyand acutelyaftercorrectionoflong-standingpulmonary regur-gitationandresidualstenosis,wedonotknowwhetherthis improvement is maintained in long-term follow-up.26 _We thereforeexcludedpatients whounderwentasecond cor-rectivesurgerywithpulmonary valvereplacement (dueto severepulmonaryregurgitation)andclosureofasignificant non-restrictiveVSD.Thesepreviousdefectsareasurrogate markerforpreviouslong-standingrightheartoverloadthat mayhavebeenthecauseforthedetectedarrhythmias.We thenperformed asubanalysisof the77patientswithonly asinglecorrectivesurgery (20.8%withprevious historyof arrhythmia).Inthisgroup,16.9%hadaresidualVSD,which washoweverrestrictiveinallcases.Inthissubanalysis,we confirmedthe independentpredictive value ofRA andRV strainforthepresenceofpreviousarrhythmias.

Limitations

Sincethearrhythmiaswerediagnosedbeforethe echocar-diographic assessment, this is considered a retrospective study.Thus,the present study cannotestablish a definite causal relationship between strain and arrhythmias. In addition,theinvestigation anddocumentationof arrhyth-mias was symptom-driven, that is, only patients with symptomssuggestiveofarrhythmiasunderwentsubsequent investigation.

A prospective study on the association of right heart myocardialstrain withfuturearrhythmicevents wouldbe moreinteresting. However,sincemostevents occurred in latechildhoodorearlyadulthood,suchastudywouldhave to be performed in a pediatric cardiology setting. Also, the annual event rate is relatively low; this is a major difficulty in studies attempting to improve risk stratifica-tion in TOF patients, particularly with the use of recent technology,sinceitwouldrequirealargesampleandlong follow-up.

Thenumberofpatientswitharrhythmiaswasrelatively small,anditwasnotpossibletostudythetypesof arrhyth-miaseparately due tolow statistical power. Nonetheless, weperformedapreliminaryanalysisinthesubstudy popu-lation,whichshowedthatRVstrainistheonlypredictorof ventriculararrhythmias(OR1.36,95%CI1.07-1.73,p=0.011) andthatRAstrainisanindependentpredictorof supraven-triculararrhythmias (OR0.93, 95% CI 0.86-0.99, p=0.039) adjustedforageatcorrectionandresidualVSD(theother predictorsinunivariateanalysis).None oftheother meas-uresofrightventricularoratrialfunctionwerepredictorsof eithertypeofarrhythmia.Thisindicatesthatthereisscope forfurtherprospectivestudies.

Two-dimensional speckle tracking echocardiography strain was measured with non-dedicated software --- we usedanadaptationfromLVtwo-dimensionalspeckle track-ingechocardiographystrainanalysis.Thiscouldexplainthe

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resultsof ourreproducibility analysis.Although the inter-class correlation coefficient was excellent for RV strain and very good for RA strain (better for intraobserver variability),thelimitsofagreementbyBland-Altman analy-siswereratherwide.The use ofnon-dedicated software, with frequent use of manual corrections, may partially explain these results. The other possible explanation is relatedtoimage quality.Measurementswere more repro-ducible when image quality was good. This suggests that follow-up assessments should be performed by the same operator and preferably with the same software,as rec-ommendedin a recent position paper fromthe European AssociationofCardiovascularImaging.27_In_a_study_by_Diller etal.,TAPSEandRVtwo-dimensionalsystolicstrainwerenot relatedtosuddencardiacdeathorlife-threatening arrhyth-mia,incontrasttoourresults.9_One_explanation_is_that_that studyonlyfocusedonventriculararrhythmias,whichinour studywerefound inonly10patients(38%).Another possi-bleexplanationis theuse of differentsoftwarefor strain quantification,sincestrainresultsarenotinterchangeable betweendifferenttypesofequipment.27

Ananalysisofstrainratemighthave beenmore appro-priate,becauseit islessvolumedependent.However,our speckletrackinganalysissoftwaredidnot enableregional strainrateanalysis.

Recently described prognostic parameters, such as detailedtwo-dimensionalassessmentoftheRVoutflowtract orRVdyssynchronybystrain,werenotanalyzed,duetothe retrospectivenatureofourstudyandtheneedforspecific images.7,28_Also,_we_used_LV_strain_analysis_software,_which isnotyetvalidatedforuseinanalysisofRVdyssynchrony.

Conclusions

InpatientswithrepairedTOF,ageatcorrectionandresidual defectsaresignificantlyassociatedwithprevious documen-tation of arrhythmias. RA and RV strain are particularly usefulinpatientswithoutsignificantresidualdefectsafter correctivesurgery,becausebothareindependently associ-atedwiththeoccurrenceofarrhythmias.Theyseemtobe an earliermarker ofdysfunction thanconventional meas-ures.However,duetotheretrospectivenatureofourstudy wecould notconfirm adirect causalrelationship;further prospective long-term studies are needed, and this pre-dictive value needs to be supported by more extensive prospectivelong-termdata.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Financial

support

This researchreceived nospecific grantfromany funding agency,commercialornot-for-profitsectors.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

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