Prediction of new onset of resting pulmonary arterial hypertension in systemic sclerosis.

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Availableonlineat

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CLINICAL

RESEARCH

Prediction

of

new

onset

of

resting

pulmonary

arterial

hypertension

in

systemic

sclerosis

Facteurs

prédictifs

d’apparition

d’hypertension

artérielle

pulmonaire

chez

les

patients

atteints

de

sclérodermie

systémique

Damien

Voilliot

a

,

Julien

Magne

a

,

Raluca

Dulgheru

a

,

Seisyou

Kou

a

,

Christine

Henri

a

,

Luis

Caballero

a

,

Carla

De

Sousa

a

,

Muriel

Sprynger

a

,

Béatrice

Andre

a

,

Luc

A. Pierard

a,∗

_,

_Patrizio

_Lancellotti

b,∗

a_University_of_Liège_Hospital,_GIGA_{Cardiovascular}_Sciences,_Department_of_Cardiology,

HeartValveClinic,UniversityHospitalSartTilman,Liège,Belgium

b_Gruppo_Villa_Maria_Care_and_Research,_Anthea_Hospital,_Bari,_Italy

Received25April2015;receivedinrevisedform13 November2015; accepted18November 2015

Availableonline15February2016

KEYWORDS Scleroderma; Exercise echocardiography; Pulmonaryarterial hypertension; Nailfold videocapillaroscopy Summary

Background.—Earlydetectionofpulmonaryarterialhypertension(PH)iscrucialinsystemic scleroderma.However, predictorsofnew onsetofrestingPH duringfollow-up (FUPH)have beenpoorlyexplored.

Aim.—Todeterminewhethernailfoldvideocapillaroscopy(NVC)gradeandexercise echocar-diographicvariablesarepredictorsofFUPH.

Methods.—Weprospectivelyenrolled40patientswithsystemicsclerosis(age54±13years; 68% women). All patients underwent graded semisupine exercise echocardiography and NVC. Baseline resting PH and FUPH were deﬁned as systolic pulmonary arterial pressure (sPAP)>35mmHg,andexercise-inducedPH(EIPH)asexercisesPAP>50mmHg.

Results.—SeventeenpatientsdevelopedEIPH(43%).Duringfollow-up(FU)(25±15months),11 patientswithoutbaselinePHdevelopedFUPH(28%),allfromtheEIPHgroup.PatientswithFUPH

Abbreviations: BNP,B-typenatriureticpeptide;CI,conﬁdenceinterval;EIPH,exercise-inducedpulmonaryarterialhypertension;FUPH, newonsetofrestingpulmonaryarterialhypertensionduringfollow-up;HR,hazardratio;LV,leftventricular;NVC,nailfold videocapil-laroscopy;OR,oddsratio;PH,pulmonaryarterialhypertension;sPAP,systolicpulmonaryarterialpressure.

∗_{Corresponding}_authors.

E-mailaddresses:lpierard@chu.ulg.ac.be(L.A.Pierard),plancellotti@chu.ulg.ac.be(P.Lancellotti).

http://dx.doi.org/10.1016/j.acvd.2015.11.014

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weresigniﬁcantlyolder(60_±14vs50_±12years;P=0.04),hadhigherrestingandexercisesPAP (30±4vs22±5and60±12vs40±11mmHg,respectively;P<0.0001)andahigherexercise E/e’ratio(9.4_±0.7vs5.8_±0.4;P=0.0003)andpresentedmorefrequentlyNVCgrade>2(90% vs35%;P=0.0009).Afteradjustmentforage,restingsPAP,exercisesPAPandNVCgrade>2were associatedwithmaximalrestingsPAPduringfollow-upandFUPH(P<0.05).Patientswithboth EIPHandNVCgrade>2hadaveryhighincidenceofFUPH(82%),andbothvariablesremained strongly associated withFUPH after adjustmentfor age(hazard ratio11.6, 95%conﬁdence interval2.4—55.3;P=0.002).

Conclusion.—Exercise echocardiographyand NVC can identify a subgroup of patients with systemicsclerosiswhoareatriskofdevelopingFUPH.

MOTSCLÉS Sclérodermie; Échocardiographie d’effort; Hypertension artérielle pulmonaire; Capillaroscopie Résumé

Contexte.—Lesfacteursprédictifsd’apparitiond’HTAPpendantlesuivi(HTAPsuivi),dansla sclérodermiesystémique,demeurentmalconnus.

Objectif.—Étudiersilestadedelacapillaroscopiedigitale(CD)etl’échocardiographied’effort peuventprédirel’HTAPSuivi.

Méthodes.—Quarantepatientsavecsclérodermiesystémiqueontétéinclus(âge54±13ans ;68 %femme).Tousbénéﬁciaientd’uneéchocardiographied’effort,etd’uneCD.L’HTAPde reposétaitdéﬁnieparunepressionartériellepulmonairesystolique(PAPs)>35mmHg,l’HTAP d’effort(HTAPeffort)parunePAPsd’effort>50mmHg.

Résultats.—Dix-septpatients(43 %)développaientuneHTAPeffort.Pendantlesuivi(25±15 mois),11 patientssansd’HTAPàl’inclusion,développaientuneHTAPsuivi(28 %),tousavaient uneHTAPEffort.Les patientsavec uneHTAPsuiviétaient plusâgés(60±14 vs50±12ans ;

p=0,04)avaientunePAPsdereposetd’effortplushautes(respectivement,30±4 vs22±5 and60±12 vs40±11mmHg;p<0,0001),unE/e’d’effortplusélevé(9,4±0,7 vs5,8±0,4;

p=0,0003)etprésentaientplusfréquemmentunstadeCD>2(90 %vs35 %;p=0,0009).Après ajustementàl’âge,lesPAPsdereposetd’effortainsiquelestadeCD>2étaientassociéesàla PAPsmaximalederepospendantlesuivietàl’apparitiond’HTPSuivi(p<0,05).Lespatientsavec uneHTAPEffortetunstadeCD>2 avaientuneincidenced’HTPsuivitrèsélevée(82 %).Après ajustementàl’âge,l’associationdecesparamètresétaientfortementassociéeàl’HTPsuivi (HR11,6,IC2,4—55,3 ;p=0,002).

Conclusion.— Danslasclérodermiesystémique,l’échocardiographied’effortetlaCDsontutiles pouridentiﬁerungroupedepatientsàrisquededévelopperuneHTAPSuivi.

Background

Systemicsclerosisisarareandcomplexautoimmunedisease characterized by widespread vascular lesions and ﬁbrosis leadingtomultiple organimpairmentfor themostsevere presentationofthedisease[1].Lung,pulmonarycirculation andmyocardiumimpairmentcan leadtothedevelopment ofpulmonaryarterialhypertension(PH)causedby precapil-laryand/orpost-capillarymechanisms.Earlydetectionand treatmentofPHiscrucialinsystemicsclerosis,asitisamain causeofdeathandpooroutcome[2].Insystemicsclerosis, nailfoldvideocapillaroscopy(NVC)isaninterestingtoolfor identifyingmicrovascularimpairment.Althoughsome stud-ies have shown the association of NVCwith severe organ involvement[3],ithasnotbeenshowntobelinkedtothe newonsetofrestingPHduringfollow-up(FUPH). Exercise-inducedPH(EIPH)hasrecentlybeensuggestedasapotential highlysensitive toolfortheearlyidentiﬁcationofpatients

withsystemicsclerosiswhoareatriskofdevelopingresting

PH [4,5]. However, probablydue to lack of speciﬁcity, it

seemsthattheincidenceofEIPHmayoverestimatethe per-centageofFUPH[6].Althoughanexaminationofthe haemo-dynamicsofpulmonarycirculationisofvalue[6,7],exercise echocardiography was not included in the last European SocietyofCardiologyrecommendations[8],becauseofthe ongoingdebateaboutitsusefulnessindaily-lifepractice.

The presentstudy soughttoevaluate theusefulnessof exerciseechocardiography,B-typenatriureticpeptide(BNP) blood concentration and NVC in an integrated screening approachforpatientsatriskofFUPHinsystemicsclerosis.

Methods

FromJanuary2008toNovember2012weprospectively stud-ied 68 consecutive patients with a diagnosis of systemic

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Figure1. Studyﬂow chart. EIPH:exercise-inducedpulmonary hypertension;FUPH:onsetofpulmonary arterialhypertension during follow-up;PH:pulmonaryhypertension;TRV:tricuspidregurgitationvelocity.

sclerosisfollowedintherheumatologycentreofCHU Sart-TilmaninLiège.Fivepatientsrefusedtoparticipateinthe study.Exclusioncriteriawereinabilitytoprovideinformed consent; previous ischaemic heart or valvular heart dis-ease;inabilitytoperformanexercisetest;baselineresting PH;andunquantifiablesystolicpulmonaryarterialpressure (sPAP).Fifteenpatientswereexcludedfromthepopulation (n=63) because of unquantifiable sPAP (24% of the popu-lation), one for ≥moderate mitral regurgitation, two for coronaryarterydiseaseandthreeforbaselinerestingPH(7% ofpatientswithregistrabletricuspidregurgitation).Finally, twopatientswerelostduringfollow-up,sothefinal analy-sisincluded 40patients(Fig.1).Therelevantinstitutional reviewboardapprovedtheprotocol,andallpatientsgave writteninformedconsent.

Echocardiographic

examination

All patients underwent comprehensive resting echocardi-ography, using a conventional method, with a Vivid 9

ultrasoundsystem(GeneralElectricHealthcare,Little Chal-font,UK),atbaselineandduringfollow-up(twiceayear), blindedforNVCresultsatbaseline.Ofﬂineanalysiswas per-formedretrospectivelyusingacustomizedsoftwarepackage (EchoPac). Left ventricular (LV) stroke volume was cal-culated as the difference between LV end-diastolic and end-systolicvolumesassessedbythebiapicalSimpson’sdisc method, and LV ejection fraction was derived from the stroke volume/LV end-diastolicvolumeratio.Cardiac out-putwasobtainedbymultiplyingLV,strokevolumeandheart rate.PeakEwaveandAwavevelocitiesofthemitralinﬂow were measured with pulsed-waveDoppler. Tissue Doppler imagingwasappliedforthemeasurementofe’waveatthe lateralmitralannulusaspect.BothmeasurementsofEandA wavesandtissueDopplerimagingatthemitralannuluslevel wereperformedduringexercise,justbeforefusionofEand Awaves.Rightventricularfractionalareachange,tricuspid annularplanesystolicexcursionandmaximalsystolic veloc-ityofthetricuspidannulus(s’)wereassessedinallpatients. Thesystolicpulmonaryarterialpressure(sPAP)wasderived

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fromthemaximalvelocityofthetricuspidregurgitantjet, according to the simpliﬁed Bernoulli equation, with the additionofrightatrialpressure,estimatedfromthe dimen-sionandcollapsibilityoftheinferiorvenacava[9].Apeak value>35mmHg wasconsidered todeﬁne resting PH [10]

atbaselineandFUPH. Atpeakexercise,sPAPwasderived fromthe tricuspidregurgitantjetvelocity,withthe addi-tionof10mmHgfor theestimationofrightatrial pressure

[11]. EIPH wasdefinedas sPAP>50mmHg [12]. mPAPwas estimatedusingtheChemlaformula:mPAP=0.61×sPAP+2. TheslopeofthemPAP/LVCOrelationshipwasestimatedas theratiobetweenchanges(peak—restvalue)inmPAPand changes in LVCO [13,14]. All echocardiographic variables were acquired at peak exercise, except for mitral inflow velocitiesandtissueDopplerimagingatthemitralannulus. Asymptom-limitedgradedbicycleexercisetestwas per-formedinasemisupinepositiononatiltedtable.Afteran initialworkloadof25Wmaintainedfor2minutes,the work-load was gradually increased by 25W every 2minutes. A 12-leadelectrocardiogramwasmonitoredcontinuously,and blood pressurewasmeasured atrest andat each levelof exercise.Allpatientspresentednormaltests,definedasthe absenceof the occurrenceof: angina; ≥2mm ST-segment depressioncomparedwithbaselinelevel;or complex ven-triculararrhythmias.

NVC

and

lung

function

assessment

Using an optical probe videocapillaroscope, the nailfold of the second, third, fourth and fifth fingers was exam-inedbilaterallyineachpatientasdescribedpreviously[3]. NVC grades were qualitatively assessed as normal (grade 1:normalcapillarymorphology,regulardistributionandno capillary loss), early (grade 2: few capillary microhaem-orrhages and giant capillaries, no loss of capillaries and preserveddistribution),active(grade3:frequentcapillary microhaemorrhagesandgiantcapillaries,moderatelossof capillaries,milddisorganizationofthemicrovascular archi-tecture and absent or mild ramified capillaries) and late (grade4:irregularenlargementofcapillaries,feworabsent giant capillaries and microhaemorrhages, severe loss of capillariesandlargeavascularareas,disorganizationof cap-illaryandramifiedcapillary).

All patients underwent standard pulmonary function tests,withassessmentoftotallungcapacity,vitalcapacity, forcedvitalcapacity,forcedexpiratoryvolumein1second, ratioofforcedexpiratoryvolumein1secondtovital capac-ityanddiffusingcapacityofthelungforcarbonmonoxide.

BNP

blood

concentration

assessment

BNPbloodconcentrationwasassessedatrest, justbefore echocardiographyexamination,inasubset of30 patients. Venousbloodsamplesweredrawnbeforeechocardiography, after 10minutes of supine rest. Chilled ethylenediamine-tetraacetic acid tubes were centrifuged immediately at 4000rpm(4—8◦C)for15minutes.

Statistical

analysis

Continuous variables are expressed as means±standard deviations; categorical variables are presented as

numbers and percentages. Data comparisons were per-formedaccordingtothepresenceorabsenceofFUPHusing Student’sunpairedandpairedttests,the␹2_test_or_Fisher’s

exacttest,asappropriate.Therelationshipsbetween max-imalsPAPduringfollow-up andother continuousvariables (i.e.demographicdata,resting andexercise echocardiog-raphic data) were evaluated by simple linear regression. PredictorsofhighestsPAPduringfollow-upwereidentiﬁed withtheuseofunivariateandmultivariablelinear regres-sions.Univariate and multivariable logisticregression and Coxproportional-hazardsmodelsanalyseswereperformed todeﬁnepredictorsofFUPH.Inallmultivariableanalyses, because of the sample size and the limited number of outcomedata,adjustmentswereperformed withonlytwo variablesin ordertolimitstatistical power reductionand to avoid type II error. The value of ␹2 _for _each _variable

definedits prognosticvalue. Sequential Cox modelswere performedtodeterminetheincrementalprognosticbenefit of different variables over age. A statistically significant increaseinthegloballog-likelihood␹2_of_the_model_defined

incremental prognostic value. Probabilities of FUPH-free survivalwereobtainedbyKaplan-Meierestimates,andthen comparedusingatwo-sidedlog-ranktest.ValuesofP<0.05 were considered statistically signiﬁcant. All statistical analyseswereperformedwithSPSSsoftware,version16.0.

Results

Population

characteristics

The mean age of the population was 54±13 years; 68% werewomen. sPAP increased significantly during exercise (from24±6to46±14mmHg;P<0.0001).Seventeen(43%) patientsdevelopedEIPH.Afterameanfollow-upof25±15 months(median28months),11patients(28%)hadFUPH,all intheEIPHgroup.PatientswithEIPHandFUPHwere signifi-cantlyolder(62±12vs48±11yearsand60±14vs50±12 years,respectively;P<0.05inbothcases).Femalesexwas morefrequentintheEIPHgroup(90%vs62%;P=0.03),but notin the FUPH group (64% vs 69%; P=0.69. There were nosignificantdifferencesbetweenthetwogroupsregarding medicationandlungfunctiontestvariables(Table1).There werenosignificantdifferencesbetweenthetwogroupsin termsofRaynaud’sphenomenon(82%vs87%;P=1.00orthe presenceofScl-70antibodies(36%vs31%;P=0.70.Patients withFUPHhadahigherBNPbloodconcentration(79±86vs 23±21pg/mL;P=0.01).

NVC

grades

NVCgrade 1wasfound in8% ofpatients, grade2 in38%, grade3in28%andgrade4in20%(eightpatients).Therewas asignificantrelationshipbetweenthedifferentNVCgrades and the onset of PH during follow-up (P=0.01) (Fig. 2). PatientswithFUPHpresented more frequentlyNVCgrade 4 (45% vs 11%; P=0.03) and less frequently NVC grade 2 (54%vs9%;P=0.006).Therewerenosignificantdifferences betweentheFUPHandnoFUPHgroupsregardingNVCgrade 1(0vs12%;P=0.13)andgrade3(45vs23%;P=0.18).There wasasignificantlyhigherproportionofNVC>grade2inthe FUPHgroup(90%vs35%;P=0.0009).

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Table1 Demographic,clinicalandexercisedata.

Variables Wholecohort

(n=40) NoFUPH (n=29,72%) FUPH (n=11,28%) P Demographic,clinicalandbiologicaldata

Age(years) 54±13 50±12 60±14 0.04

Femalesex 27(68) 20(69) 7(64) 0.69

Bodymassindex(kg/m2₎ ₂₄_±₅ ₂₄_±₅ ₂₅_±₆ _0.72

Heartrate(bpm) 74±14 73±13 74±16 0.72

Systolicarterialpressure(mmHg) 128±19 126±19 134±16 0.36

Diastolicarterialpressure(mmHg) 73±9 73±10 74±7 0.90

Raynaud’sphenomenon 34(85) 25(87) 9(82) 1.00

DelaybetweendiagnosisandTTE(months) 36±36 37±39 31±28 0.62

NYHAclass>II 3(8) 3(10) 0(0) 0.26 PresenceofScl-70antibodies 13(33) 9(31) 4(36) 0.70 BNP(pg/mL) 41±61 23±21 79±86 0.01 Riskfactors Systemichypertension 4(10) 2(7) 2(11) 0.33 Hypercholesterolaemia 9(23) 7(25) 2(18) 0.64 Smoker 10(24) 9(31) 1(9) 0.08

FamilyhistoryofCVdisease 2(5) 2(7) 0(0) 0.24

Pulmonaryfunction

Totallungcapacity(%predicted) 93±21 95±21 82±16 0.15

Vitalcapacity(%predicted) 104±24 105±26 96±17 0.32

Forcevitalcapacity(%predicted) 101±25 102±21 93±17 0.30

FEV1(%predicted) 95±20 96±20 87±22 0.27

FEV1/vitalcapacity(%predicted) 99±12 100±12 96±13 0.38

DLCO(%predicted) 65±14 66±15 60±12 0.33 Medication ACEinhibitors 2(5) 1(4) 1(10) 0.51 Beta-blockers 3(8) 1(4) 2(9) 0.15 Diuretics 2(5) 1(4) 1(10) 0.51 Calciuminhibitors 20(50) 13(52) 7(70) 0.32 Corticoids 9(23) 5(20) 4(40) 0.23 Immunosuppressors 6(16) 4(16) 2(20) 0.77 Exercisedata Workload(W) 75±31 81±30 65±36 0.22

Durationofexercise(minutes) 4.9±1.3 4.7±1.3 5.1±1.6 0.55

Heartrate(bpm) 119±17 119±16 122±21 0.65

Systolicarterialpressure(mmHg) 168±23 163±23 176±21 0.19

Diastolicarterialpressure(mmHg) 82±12 81±11 84±13 0.55

Dataareexpressedasmean±standarddeviationornumber(%).ACE:angiotensin-convertingenzyme;BNP:B-typenatriureticpeptide; bpm:beats per minute; CV: cardiovascular; DLCO: diffusing capacity of the lung for carbon monoxide; FEV1: forced expiratory volumein1second;FUPH:onsetofpulmonaryhypertensionduringfollow-up;NYHA:NewYorkHeartAssociation;TTE:transthoracic echocardiography.

Resting

and

exercise

echocardiography

Patients with FUPH had higher baseline sPAP (30±4 vs 22±5mmHg; P< 0.0001, baseline mPAP (20±2 vs 15±3mmHg;P<0.0001),indexedleftatrialarea(10±3vs 8±1cm2_;_P₌_0.01),_exercise_sPAP₍₆₀_±₁₂_vs₄₀_±₁₁_mmHg; P<0.0001; Fig.3), exercisemPAP(38±7 vs26±7mmHg;

P<0.0001)andexercise-inducedchangesinsPAP(+25±10 vs+14±9mmHg;P=0.001)(Tables2and3).Patientswith EIPHhadahigherexerciseE/e’ratio(9.1±1.2vs5.7±1.4;

P=0.0002). During exercise (Table 3), LV ejection frac-tion (67±5 vs 71±5%; P=0.001) and its rate of change (+4±3vs+8±4%;P=0.008)werelowerintheFUPHgroup.

Conversely, the E/e’ ratio, resulting from lower e’ wave velocity,washigherintheFUPHgroup(9.4±0.7vs5.8±0.4 [P=0.0003]and17±0.1vs12±0.2cm/s[P=0.03], respec-tively).TheslopeofthemPAP-LVCOrelationship(6.7±2.7 vs3.4±2.1mmHg/L/min;P=0.003)washigherintheFUPH group.

Finally,40%ofpatientspresentedneitherEIPHnorNVC grade>2,32% presentedeither EIPH or NVCgrade>2 and 18%hadbothEIPHandNVCgrade>2.Therewasasigniﬁcant differenceintheincidenceofFUPHbetweenpatientswith noEIPH and NVCgrade<2 andpatients withEIPH or NVC grade>2,andthosewhohad bothEIPH andNVCgrade>2 (0%vs17%vs82%,respectively;P<0.0001).

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Figure 2. Comparison of theincidence of nailfold videocapil-laroscopy(NVC)gradesaccordingtothetwogroups.FUPH:onset ofpulmonaryarterialhypertensionduringfollow-up.

Figure3. Comparisonofrestingandexercisesystolicpulmonary arterialpressure(sPAP)accordingtothetwogroups.FUPH:onset ofpulmonaryarterialhypertensionduringfollow-up.

Determinants

of

the

maximal

value

of

sPAP

during

follow-up

Asigniﬁcant correlationwasfoundbetween maximalsPAP duringfollow-upandexerciseleftatrialpressure(r2₌_0.43; P<0.004), as well as resting indexed left atrial area (r2₌_0.43; _P_<_0.0001), _resting _sPAP _(r2₌_0.36; _P_<_0.0001),

exercisesPAP(r2₌_0.36;_P_<_0.0001),_the_slope_of_the

mPAP-LVCOrelationship(r2₌_0.22;_P₌_0.01)_and_exercise_indexed

right atrial area (r2₌_0.31; _P₌_0.002). _A _correlation _was

found with age (r2₌_0.18; _P₌_0.009) _and _{exercise-induced}

changesinLVejectionfraction(r2₌_0.15;_P₌_0.01).

After adjustment for age, resting sPAP and exercise sPAP remained independently associated with maximal resting sPAP during follow-up (␤=0.9±0.3 [P=0.02] and ␤=0.4±0.1 [P=0.02], respectively), asdid NVCgrade>2 (␤=9.1±2.9;P=0.004).

Inthe subgroupof 30patients withBNPblood concen-tration measurements available, BNP was related to the maximal value of sPAP during follow-up (r2₌_0.41; P<0.001)andremainedassociatedafteradjustmentforage (␤=0.1±0.03;P=0.001).

Determinants

of

FUPH

Logistic

regression

analyses

Age was associated with the onset of PH during follow-up (odds ratio [OR] 1.06; 95% conﬁdence interval [CI] 1.01—1.13;P=0.047),aswererestingsPAPandexercisesPAP (OR1.71,95%CI1.19—2.45[P=0.003]andOR1.18,95%CI 1.06—1.32[P=0.003],respectively).Similarly,NVCgrade>2 wasrelatedtoFUPH(hazardratio[HR]18.9,95%CI2.1—172;

P=0.009).

After adjustment for age, resting sPAP and exercise sPAPremainedassociatedwithFUPH(oddsratio1.68,95% CI 1.17—2.4 [P=0.005] and OR 1.17, 95% CI 1.05—1.32 [P=0.006],respectively),asdidNVCgrade>2(OR16.9,95% CI1.7—168;P=0.02).

Beyondage (␹2₌_4.5%),_there_was_an_incremental_value

for NVC grade>2 (␹2₌_14.1%; _P_<_0.0001), _resting _sPAP

(␹2₌_22.1%)_and_EIPH_(␹2₌_25.2%;_P_<_0.0001)_to_predict_FUPH

(Fig.4).

In thesubgroup of 30 patients withBNPconcentration measurementsavailable,BNPwasnotassociatedwithFUPH (OR1.04,95%CI0.99—1.08;P=0.054).

Time-dependency

statistical

analyses

Afterafollow-upof24months,patientswithNVCgrade>2 andEIPHhadlowerFUPH-freesurvivalrates(61.8±11.4%vs 100%[P<0.05]and55.4±12.8%vs100%[P<0.05], respec-tively).Inaddition,patientswithnoEIPHandNVCgrade<2 had a greater FUPH-free survival rate than patients with either EIPH or NVC grade>2 and patients with both EIPH and NVC grade>2 (100% vs 75.8±15.6% vs 41.6±15.6%, respectively;P=0.0001).

InCoxregressionanalyses,agewasassociatedwithFUPH (HR1.06,95%CI1.02—1.11;P=0.007),aswererestingsPAP andexercisesPAP(HR1.41,95% CI1.18—1.69[P=0.0001] andHR1.16, 95%CI1.08—1.25[P=0.0001],respectively). NVCgrade>2 wasassociatedwith theonsetof PH during follow-up(HR8.9,95%CI1.13—69.4;P=0.04).Finally,the combinationofEIPHandNVCgrade>2wasrelatedtoFUPH (HR15.1,95%CI3.2—70.3;P=0.001).

Afteradjustmentforage,restingsPAPandexercisesPAP were associated with FUPH (HR 1.41, 95% CI 1.08—1.70 [P=0.0001] and HR 1.2, 95% CI 1.08—1.25 [P=0.0001], respectively),aswasNVCgrade>2(HR9.1,95%CI1.1—74.8;

P=0.04).Finally,EIPHandNVCgrade>2alsoremained asso-ciatedwithFUPH(HR11.6,95%CI2.4—55.3;P=0.002).

Beyondage (␹2₌_7.7%),_there_was_an_incremental_value

for NVC grade>2 (␹2₌_11.8%; _P_<_0.0001), _resting _sPAP

(␹2₌_16.1%; _P_<_0.0001), _EIPH _(␹2₌_21.3%; _P_<_0.0001) _and

the combination of EIPH and NVC grade>2 (␹2₌_23.8%; P<0.0001)topredictFUPH(Fig.4).

Inthesubsetof30patientswithBNPconcentration mea-surements available, BNP was associated with FUPH (HR 1.02, 95% CI 1.01—1.03; P=0.004), and this association

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Table2 Restingechocardiographicdata.

(n=40) NoFUPH (n=29,72%) FUPH (n=11,28%) P RestingLVechocardiographicdata

LVindexedend-diastolicvolume(mL) 45±11 47±13 42±7 0.30

LVindexedend-systolicvolume(mL) 16±5 17±7 15±3 0.48

LVindexedstrokevolume(mL) 29±6 30±7 28±5 0.40

Simpson’sLVEF(%) 63±4 64±4 62±5 0.41

Cardiacoutput(L/min) 3.7±0.9 3.7±0.2 3.5±0.3 0.65

E(cm/s) 6.9±1.3 6.9±0.2 7.1±0.5 0.75 Edecelerationtime(ms) 179±37 179±7 172±13 0.75 A(cm/s) 6.7±1.8 6.7±0.3 7.2±0.6 0.63 E/Aratio 1.1±0.5 1.1±0.1 1.2±0.2 0.59 e’(cm/s) 1.1±0.5 1.3±0.1 1.1±0.1 0.10 E/e’ratio 5.9±1.7 5.6±0.3 6.8±0.6 0.08

RestingRVechocardiographicdata

RV/LVratio 0.75±0.1 0.7±0.1 0.8±0.1 0.30 RVend-diastolicarea(cm2₎ _13.9_±_3.7 _14.1_±_4.2 _13.3_±_2.4 _0.53 RVend-systolicarea(cm2₎ _7.2_±_2.3 _7.5_±_2.4 _7.0_±_2.1 _0.59 RVFAC(%) 47.8±8.8 47.3±7.7 47.4±10.2 0.98 TAPSE(mm) 23±5 23±4 24±6 0.77 s’(cm/s) 12.3±2.7 12.5±2.6 12.6±2 0.89 ICVmax(cm/s) 12±4 12±4 13±3 0.33 IVRT(ms) 46±23 49±22 41±29 0.39 MPI 0.36±0.14 0.35±0.12 0.38±0.19 0.63

Pulmonaryaccelerationtime(ms) 138±35 144±35 119±31 0.06

sPAP(mmHg) 24±6 22±5 30±4 <0.0001

mPAP(mmHg) 16±4 15±3 20±2 <0.0001

Restingatrialarea

LAindexedarea(cm2₎ ₈_±₂ ₈_±₁ ₁₀_±₃ _0.01

RAindexedarea(cm2₎ ₇_±₃ ₇_±₁ ₉_±₄ _0.03

Dataareexpressedasmean±standarddeviation.FUPH:onsetofpulmonaryhypertensionduringfollow-up;ICV:isovolumiccontraction velocity;IRVT:isovolumicrelaxation time;LA:left atrial;LV:leftventricular;LVEF: leftventricularejectionfraction;mPAP: mean pulmonary arterial pressure; MPI: myocardial performance index; RA: right atrial; RV: right ventricular; RVFAC: right ventricular fractionalareachange;sPAP:systolicpulmonaryarterialpressure;TAPSE:tricuspidannularplanesystolicexcursion.

remainedsigniﬁcantafteradjustmentforage(HR1.02,95% CI1.01—1.03;P=0.01).

Discussion

The present study shows that: the developmentof PH at follow-upisnotarareconditionin patientswithsystemic sclerosis(28%);NVCgrade>2isapowerfulpredictorofthe onsetofFUPHinpatientswithsystemicsclerosis;and exer-cisesPAP canpredict the evolutionof resting sPAPduring FU.Ourdataalsosuggestthatanintegratedapproachbased upon both comprehensive exercise echocardiography and NVCcouldbe useful in identifyinga subgroup of patients withsystemicsclerosisathigherriskofdevelopingPH.

NVC

grade

and

onset

of

resting

PH

NVCis aninterestingtoolinsystemicsclerosisfor investi-gatingtheunderlyingdiseaselesion.However,ithasbeen poorlyexplored,anditspotential roleinpredicting FUPH

has, to the best of our knowledge, hardly been studied. A few studies have reported a correlation between wors-ening NVC grade and severe organ involvement. Smith etal.[3]showedthepotentialclinicalsignificanceofNVC in 66 patients with systemic sclerosis; the authors clas-sified microvascular lesions within four different stages, dependingonthepresenceandimportanceofgiant capillar-ies, microhaemorrhages and loss of capillaries (i.e. from ‘‘normal’’to‘‘late’’ NVCgrade).Patientswere followed-upclinicallyat18—24months,andsevereorganinvolvement ofthenineorgansystemswasstudied.Theauthors demon-stratedacloserelationship betweenworseningNVCgrade andfuturesevereperipheralvascularinvolvement,aswell as future severe lung involvement. Similarly, we demon-strated a close relationship between NVC grade>2 and FUPH, strengthening the potential clinical value of NVC in risk stratification of patients with systemic sclerosis. Theseresultssuggestthatlocalmicrovascularstatus prob-ably represents global microvascular impairment, and is linkedto myocardialand pulmonary microvascular status, assuggestedbyrestingandexerciseechocardiographydata

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Table3 Exerciseechocardiographicdata.

(n=40) NoFUPH (n=29,72%) FUPH (n=11,28%) P ExerciseLVechocardiographicdata

LVindexedend-diastolicvolume(mL) 50±11 51±13 47±6 0.36

LVindexedend-systolicvolume(mL) 15±5 15±5 16±3 0.79

LVindexedstrokevolume(mL) 35±8 36±9 31±3 0.15

Simpson’sLVEF(%) 0±5 71±5 67±5 0.001

Cardiacoutput(L/min) 7.2±2.1 7.6±0.4 6.2±0.8 0.15

E(cm/s) 9.8±1.9 9.6±1.9 10.0±2.2 0.21 Edecelerationtime(ms) 118±37 114±8 118±19 0.86 A(cm/s) 9.4±1.7 9.2±0.3 10.1±0.8 0.34 E/Aratio 1.1±0.2 1.1±0.1 1.0±0.1 0.76 e’(cm/s) 1.6±0.4 1.7±0.1 1.2±0.2 0.03 E/e’ratio 6.5±1.4 5.8±0.4 9.4±0.7 0.0003

ExerciseRVechocardiographicdata

RVend-diastolicarea(cm2₎ _12.1_±_2.9 _12.0_±_3.0 _12.5_±_3.3 _0.71 RVend-systolicarea(cm2₎ _5.7_±_1.6 _5.8_±_1.8 _5.5_±_1.1 _0.67 RVFAC(%) 52.6±10 51.9±9.6 54.2±11.8 0.59 LVend-diastolicdiameter,(mm) 39.6±4.8 40.6±4.9 36.6±4.1 0.05 RV/LVratio 71.0±12 69.3±12.2 79.4±10.7 0.04 TAPSE(mm) 27.1±5.4 26.5±3.5 29.3±8.4 0.15 s’(cm/s) 16.3±3.7 16.9±3.8 14.7±3.3 0.18 ICVmax(cm/s) 15.7±4.8 15.5±5.4 15.7±2.4 0.95 IVRT(ms) 37.4±15.7 35±12 44±26 0.32 sPAP(mmHg) 46±14 40±11 60±12 <0.0001 mPAP(mmHg) 29±8 26±7 38±7 <0.0001

SlopeofmPAPa_(mmHg/L/min) _4.2_±_2.7 _3.4_±_2.1 _6.7_±_2.7 _0.003

EIPH 17(43) 6(21) 11(100) <0.0001

Exerciseatrialarea

LAindexedarea(cm2₎ ₉_±₃ ₈_±₂ ₁₀_±₅ _0.09

RAindexedarea(cm2₎ ₈_±₃ ₇_±₁ ₁₀_±₅ _0.03

Dataare expressed as mean_±standarddeviation or number(%). EIPH: exercise-inducedpulmonary hypertension;FUPH: onsetof pulmonaryhypertensionduringfollow-up;ICV:isovolumiccontractionvelocity;IRVT:isovolumicrelaxationtime;LA:leftatrial;LV:left ventricular;LVEF:leftventricularejectionfraction;mPAP:meanpulmonaryarterialpressure;RA:rightatrial;RV:rightventricular; RVFAC:right ventricularfractional areachange;sPAP: systolicpulmonary arterialpressure;TAPSE: tricuspidannular planesystolic excursion.

a _Slope_of_mPAP_indicates_the_ratio_between_changes_in_mPAP_and_changes_in_LVCO.

(i.e. higher exercise E/e’ and lower exercise-induced changeinthesevariablesintheFUPHgroup).

Exercise

echocardiography

and

evolution

of

sPAP

The accuracy of exercise echocardiography in detecting the development of PH during exercise in systemic scle-rosis has been reported by several authors. Steen et al.

[5] reported an EIPH incidence of 44% (defined by a post-exercise≥20mmHg increase in sPAP) in 54 patients. Using right heart catheterization, the authors confirmed the involvement of a precapillary mechanism in the vast majorityofcasesand,lessfrequently,apost-capillary aeti-ology. Ofnote, fourpatients hadresting PH notdetected by echocardiography, and only one patient had normal catheterization.Thepotentialclinical significanceofEIPH wasdemonstratedbyAlkotobetal.[4]in65patients;they foundasimilarrateofEIPH(46%),withaslightlydifferent

definitionof EIPH (exercisesPAP>40mmHg). Finally, they showedarelationshipbetweenEIPHanddecreasedexercise capacity,withaweakinverserelationshipbetweenexercise sPAPandmaximalworkload achieved(r=—0.34;P=0.006) or exercise duration (r=—0.31; P=0.01). Nevertheless, despitethesefindings,thepotentialroleofEIPHand exer-ciseechocardiographyfortheriskstratificationofpatients withPHwaslittlehighlighted inthelastEuropean recom-mendations[8]. Infact, onlyone recentstudy reporteda significantrelationshipbetweenexercisesPAPandFUPHin systemicsclerosis[15].Usingexerciseechocardiographyina cohortof170patientswithsystemicsclerosis,Codulloetal.

[15]foundthatpatientswhodevelopedPHduringfollow-up (3.5±0.2 years) had markedly significant higher exercise sPAP, exercise-induced change in sPAP and change in PAP indexedtochangeincardiacoutput.Inamultivariable anal-ysis,theoccurrenceofFUPH(definedasmPAP≥25mmHgin rightheartcatheterization)wasbestpredictedby exercise-induced changes in sPAP. Although the definitions of EIPH

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Figure 4. Incremental value over age of nailfold videocapil-laroscopy(NVC)grade,restingsystolicpulmonaryarterialpressure (sPAP),exercise-induced pulmonary hypertension (EIPH) and the combinationofEIPHandNVCgrade.

(exercisesPAP>50mmHg)andFUPH(restingPH>35mmHg on echocardiography) were different from previous stud-ies, our data confirmed that EIPH assessed by exercise echocardiographycanpredict the evolutionof future res-tingsPAP.Resting sPAPaswellasexercisesPAParestrong predictors of FUPH. In addition, exercise sPAP provides incrementalvalueinpredictingtheonsetofFUPH,and exer-ciseechocardiographybringsvaluableinformationaboutthe pathophysiologyofthedisease.Exerciseechocardiography showstheconsequencesforthemyocardiumandpulmonary microvascularfunction.Thus,increasedrestingandexercise pulmonaryvascularresistanceintheFUPHgroupmay sug-gestapulmonaryvascularimpairment.Reducedmyocardial microvascularfunctionissuggestedbyincreasedestimated exercise LV filling pressure and lower exercise-induced changeinLVejectionfraction,whichprobablycorresponds tomicrovascularischaemiaduringexercise.Thishypothesis issupportedbypreviousstudieswithsinglephotonemission computedtomographyassessmentofmyocardialperfusion, whichshowedischaemia insystemicsclerosiswithout any coronaryarterylesions[16].Myocardialscintigraphy demon-strated evidence of reversible ischaemia together with irreversible lesions, and showed inducibility of coronary vasospasm by cold pressor provocation, suggesting both myocardialischaemiaandfibrosis[17].Vignauxetal.[18]

showedan increase in LVfunction andin myocardial per-fusion after administration of nifedipine in patients with systemicsclerosis,suggestingalinkbetweenmicrovascular dynamicreserveandLVfunction.

Study

limitations

The main limitation of our study was the low incidence ofright heartcatheterizationtoconﬁrm restingPH inthe FUPH group. Two patients had conﬁrmed resting PH dur-ingfollow-up(mPAP26mmHgandmPAP33mmHg),andone hadresting mPAPduringfollow-upin thegreyzone (mPAP 21mmHg).However,thisdidnotaffect themainresultof ourstudy, which was that exercise echocardiographyand NVCcanscreenpatientsatriskofdevelopingFUPH.Inthis

group, patientshad ahigherincrease in restingsPAP dur-ingfollow-up(3±4.5vs0.4±0.7mmHg/month;P=0.005), suggestingadynamicandrapidincreaseinsPAPovertime, correspondingtoahighriskofdevelopingrestingPH.

Thesecondlimitationofourstudywastherelativesmall sizeofthepopulation,butthisreﬂectsthelowincidenceof systemicsclerosis.Consequently, regardingthesizeofthe populationandthenumberofeventsduringFU,itwasnot possibletoperformcomplexmultivariableanalyses (includ-ingmorethantwovariables).Asageisawell-knownvariable inﬂuencing the level of sPAP, we decided to perform an adjustmentforageinthemultivariableanalysis.

Inaddition,thetimingoffollow-upwasdetermined arbi-trarily, and could be modiﬁed depending on the clinical statusofthepatients.Therefore,therealtimeofonsetof FUPHwasnotknownprecisely(itoccurredbetweenthetime of diagnosis of FUPH and the previous echocardiographic control)andconstitutesabiasfortime-dependency analy-ses.Thus,CoxregressionandKaplan-Meieranalysesshould be interpreted withcaution, and either linear or logistic regression may be more informative in the present case. However,evenwiththislimitation,theresultsoflinearand logistic regression were quite similarto time-dependency analysisresults.

ThesmallLVvolumesreportedcouldberelatedto fore-shortening views, and may also explain the low cardiac output reported. However, this underestimation affected thewholepopulationand,consequently,didnotinfluence thereliabilityofthemainresultofthisstudy,whichwasthe demonstrationthatexercisesPAPandNVCgradeare inde-pendentdeterminantsofFUPH.Becauseofthehighresting heart ratein some patientsand theearly fusion ofE and Awaves, the E/e’ratio wasonly available in50% ofboth groups ofpatients.Although useful,E/e’ratioassessment duringexerciseseemsmoderatelyfeasibleandapplicablein routineassessmentinthisparticularpopulation.Itisknown that pulmonary function status influences sPAP; however, therewerenosignificantdifferencesbetweenpatientswith andwithoutPHduringfollow-upforeachofthelung func-tion variables. This could be a consequence of the small population and a type II error. Patients with FUPH were significantly older, andsPAP increaseswith age.However, afteradjustmentforageandrestingsPAP,bothexercisesPAP andNVCgrade>2remainedsignificantlyassociatedwiththe occurrenceofPHduringFU,suggestingthatthesetwo varia-blesareindependentofageandthebaselinevalueofresting sPAP.

Finally, 15/63 (24%) patients had unquantiﬁable sPAP due to the absenceof registrable tricuspidregurgitation, whichcouldbealimitationtothelargeapplicationof exer-cise echocardiographytotherisk stratiﬁcationof patients with systemicsclerosis. However,contrast echocardiogra-phy couldbe performed in thesepatients toincrease the feasibilityoftheregistrationofthetricuspidregurgitation, andfurtherstudiesshouldassessthispoint.

Conclusion

Exerciseechocardiographyand NVCcanhelp usto under-standthepathophysiologicalmechanismsleadingtoresting PH in patients withsystemic sclerosis,andcould beused

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for individual risk stratiﬁcation and decisionmaking. NVC revealstheprimarylesionofthedisease(i.e.microvascular impairment) and echocardiographyallows the assessment of the consequences of this lesion for myocardial and pulmonary vascular function. Patients with no abnormal increase in sPAP during exercise and presenting an NVC grade<2 are at very low risk of FUPH, contrasting with patientswithbothEIPHandNVCgrade>2,inwhomtherisk ofdevelopingPHduringfollow-upisparticularlyhigh(82%).

Funding

DamienVoilliot is supported bya researchgrantfromthe EuropeanAssociationofCardiovascularImaging.

Acknowledgements

WeespeciallythankCarmineCelentanoforhisvaluable sup-portandhelpwiththeinvestigationsinthisstudy.

Disclosure

of

interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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