Exercise-induced right ventricular dysfunction is associated with ventricular arrhythmias in ...

13 Pages·2015·0.65 MB·English

CLINICAL RESEARCH
EuropeanHeartJournal(2015)36,1998–2010
doi:10.1093/eurheartj/ehv202 Heart failure/cardiomyopathy
Exercise-induced right ventricular dysfunction
is associated with ventricular arrhythmias
in endurance athletes
D
o
w
Andre La Gerche1,2,3*†, Guido Claessen1†, Steven Dymarkowski4, Jens-Uwe Voigt1, nlo
a
d
Frederik De Buck5, Luc Vanhees6, Walter Droogne1, Johan Van Cleemput1, e
d
Piet Claus7, and Hein Heidbuchel8 fro
m
h
1DepartmentofCardiovascularMedicine,UniversityHospitalsLeuven,Leuven,Belgium;2SportsCardiology,BakerIDIHeartandDiabetesInstitute,75CommercialRoad,Melbourne, ttps
VIC3004,Australia;3St.Vincent’sHospitalMelbourne,Fitzroy,Australia;4DepartmentofRadiology,UniversityHospitalsLeuven,Leuven,Belgium;5DepartmentofAnesthesiology, ://a
UniversityHospitalsLeuven,Leuven,Belgium;6DepartmentofRehabilitationSciences,KULeuven,Leuven,Belgium;7DepartmentofCardiovascularImagingandDynamics,KULeuven, c
a
Leuven,Belgium;and8HasseltUniversityandHeartCenter,JessaHospital,Hasselt,Belgium d
e
m
Received9October2014;revised22April2015;accepted1May2015;onlinepublish-ahead-of-print2June2015 ic
.o
u
Seepage1955fortheeditorialcommentonthisarticle(doi:10.1093/eurheartj/ehv199) p
.c
o
m
/e
u
Aims Intenseexerciseplacesdisproportionatestrainontherightventricle(RV)whichmaypromotepro-arrhythmicremod- rhe
a
...............................e.l.l.in..g..i.n..s..o.m...e..a..t.h.l.e.t..e.s....R..V...e.x..e.r.c..is..e..i.m..a..g.i.n.g...m..a.y...e.n..a.b..l.e..e..a.r.l.y..i.d.e..n..t.ifi..c.a..t.io..n...o.f..a..t.h.l.e.t.e..s..a..t.r..is..k..o..f.a..r.r.h..y.t.h..m..i.a.s.............. rtj/a
Methods Exerciseimagingwasperformedin17athleteswithRVventriculararrhythmias(EA-VAs),ofwhicheight(47%)hadan rtic
le
andresults implantablecardiacdefibrillator(ICD),10healthyenduranceathletes(EAs),andsevennon-athletes(NAs).Echocar- -a
b
daniodgrsaypsthoiclicmteriacsuusrpeisdianncnluudlaerdvtehleocRitVye(RnVd-sSy′)s.toCliacrdpiraecssmuaregn–eatricearersaotinoa(nEcSeP(ACRM),RR)Vmferaacstuiroensalcoarmebaicnheadnwgeith(RiVnvFaAsCiv)e, strac
t/3
measurements of pulmonary and systemic artery pressures provided left-ventricular (LV) and RV end-systolic 6
/3
pressure–volumeratios(SP/ESV),biventricularvolumes,andejectionfraction(EF)atrestandduringintenseexercise. 0
/1
Restingmeasuresofcardiacfunctionweresimilarinallgroups,aswasLVfunctionduringexercise.Incontrast,exercise- 99
inducedincreasesinRVFAC,RVS′,andRVESPARwereattenuatedinEA-VAsduringexercisewhencomparedwithEAs 8/2
3
andNAs(P,0.0001forinteractiongroup×workload).Duringexercise-CMR,decreasesinRVESVandaugmentation 9
8
1
ofbothRVEFandRVSP/ESVweresignificantlylessinEA-VAsrelativetoEAsandNAs(P,0.01fortherespective 7
0
interactions).Receiver-operatorcharacteristiccurvesdemonstratedthatRVexercisemeasurescouldaccuratelydiffer- b
y
entiateEA-VAsfromsubjectswithoutarrhythmias[AUCforDRVESPAR¼0.96(0.89–1.00),P,0.0001]. gu
..................................................................................................................................................................................... e
s
Conclusion Amongathleteswithnormalcardiacfunctionatrest,exercisetestingrevealsRVcontractiledysfunctionamongathletes t o
n
withRVarrhythmias.RVstresstestingshowspromiseasanon-invasivemeansofrisk-stratifyingathletes. 2
----------------------------------------------------------------------------------------------------------------------------------------------------------- 1 N
Keywords Athletes † Rightventricle † Arrhythmias † Sportscardiology † Cardiacmagneticresonanceimaging † Exercise ov
e
† ArrhythmogenicRightventricularcardiomyopathy † Echocardiography m
b
e
r 2
0
1
8
Introduction abnormalities.2–4Theaccurateidentificationofthosefewathletes
withapotentialforlifethreateningarrhythmiasremainsamajor
Amongenduranceathletes,ventriculararrhythmiasmostfrequently clinicalchallenge.
arisefromtheRV.WhiletheseventriculararrhythmiasofRVorigin Wehavedevelopedevidencesupportingahypothesisthatthe
aremostoftenbenign,1asignificantincidenceofmajorarrhythmic RVmaybean‘Achilles’heel’oftheenduranceathlete’sheart.While
andfataleventshavebeendescribedinsomecohortsofathletes the LVremains relatively unaffected, the RV hastowithstand a
in association with structural, functional, and electrical RV disproportionate haemodynamic load during intense exercise5
*Correspondingauthor.Tel:[phone],Fax:[phone],Email:[email protected]
†Contributedequallyasfirstauthors.
PublishedonbehalfoftheEuropeanSocietyofCardiology.Allrightsreserved.&TheAuthor2015.Forpermissionspleaseemail:[email protected].
ArrhythmiasandexerciseRVdysfunction 1999
resultingintransientexercise-inducedRVdysfunctionandchronic Study design
RVremodelling.5–11Inapre-clinicalmodel,thisexercise-induced
Cardiopulmonaryexercisetestingwasperformedonanuprightcycle
RV remodelling has been associated with a propensity to RV ergometer (ER900 and Oxycon Alpha, Jaeger, Germany). Breath-
arrhythmias.12 by-breathanalysisprovidedmeasuresofoxygenconsumptionatpeak
Using novel exercise echocardiographyand real-time cardiac exercise(VO peak),ventilatoryequivalentforcarbondioxide(VE/
2
magneticresonance(CMR)measurestoassessRVfunctionduring VCO2ratio),andmaximalpoweroutputinWatts(Pmax).Inthosesub-
exercise,wehypothesizedthatexercisecouldpromoteRVdysfunc- jectswithanICD,thedevicewasre-programmedsuchthatallpacing
tioninenduranceathleteswithventriculararrhythmias(EA-VAs). andshocksweresuspendedduringtheexercisetestingandnoneof
theathleteswithanICDwerepaced.Havingpreviouslydemonstrated
WecomparedEA-VAswithhealthyenduranceathletes(EAs)and
that66%ofP correspondedtothemaximalsustainableexercise
non-athleticcontrols(NAs)withtheaimof(i)validatingthepatho- max
intensityinasupineposition,14weprescribedsubsequentexercise
physiologicalconceptofexercise-inducedpro-arrhythmicremodel- D
effortsas:25%(‘lowintensity’),50%(‘moderateintensity’),and66% o
ling in humans and (ii) developing a non-invasive clinical tool w
fordifferentiatinghealthyathletesfromthosewithapropensityto (‘peakintensity’)ofPmax. nlo
Afteratleast3hrest,echocardiographywasperformedatrestand a
d
seriousarrhythmias. duringlow-,moderate-,andpeak-intensityexerciseusingaprogram- ed
mablesemi-supineergometerwithleftlateraltilt(Easystress,Ecogito fro
m
Methods Medicalsprl,Liege,Belgium). h
Thefollowingday,allsubjects(excepttheeightEA-VAswithanICD) ttp
s
Subjects underwentexerciseCMRwithsimultaneousinvasivepressuremeasure- ://a
ments.Priortoexercise,a6Frpulmonaryarterycatheterwasinserted c
a
Enduranceathleteswithventriculararrhythmiaswererecruitedfroman underfluoroscopicguidanceanda20-gaugearterialcatheterwasplaced de
existingcohortatourinstitutioninadditiontonewcasespresenting intheradialartery.Pressuretracingswerecontinuouslyacquiredviaa m
ic
over36months.Thefollowinginclusioncriteriahadtobefulfilled:(i) CMRcompatiblehaemodynamicmonitor(MaglifeSerenity,Schiller .o
u
ceuxrerrecnisteotrrapinreinvgioruesgipmaert(icaitplaetaiostn3in×c2omhppeetritwiveeeskp)o;(riti)aRnVdaarnrhinyttehnmsiivaes AG,Baar,Switzerland). p.co
m
excludingidiopathicRVOT-VT,requiredtohaveamonomorphicleft Echocardiography /e
u
bfourn≥dl3ebberaantschatbalorcaktemoofr≥p1h2o0lobg.yp.(ma).,sourst(aci)nferdeqouren(bt)isnoolante-sdusptraeinmead- Restingandreal-timeexerciseimageswereacquiredusingaVividE9 rhea
ta‘auptrpheeleavtreeen’dstrhmiceuoalrraptr’h,boweloahtgiscich≥alwl2y0ans0o0cr/odmnaasyli.doAertrhehldaedtteoaspiwpnecealruredanienccmelusildcdeodsntsrifiusttchetenutrhawelaiotrhrt uaAdnliSatars)la.tyosRsoleeiucdsntmoidnyfgflsoyimcnsaetereadumsisauil(nrGevgesEE,lociVnchciiontliugePdmsA,ineCagdn(daUvteLrltirVarslaEiosaFonnwud1ne1vdre2enA;atGScri,qEcHuuViloraiernrdtgdemainmn,edeNdnaoUsniraolwtlnryaassys,e)odeuaaarnnclddy- rtj/article-a
functionalabnormalitiesoftheRVgiventhatsuchchangeshaveprevi- b
ouslybeendescribedinhealthyenduranceathletes.5,7,11Manyofthe cordingtocontemporaryguidelines.15,16Right-ventricularoutflowtract stra
dimension (RVOTd) was measured in a parasternal short-axis view c
a‘gtehnleet-eeslucsoivueld’4beardrehsyctrhibmeodgbeynitcherisgyhntd-vroemnteric‘euxlearrcicsea-ridnidoumceydo’p2,a3thoyr fsrioonm(tRhVeIRTVd)frweeawsmalletaosuthreedaoarttitchveallveevealnnoufltuhseantrdictuhsepRidVvinafllvoewfrdoimmeann- t/36/30
(ARVC),wherebythereis:(i)mildstructuralandfunctionalabnormal- apicalacquisition.16Two-dimensionalglobalpeak-systolicstrainand /19
itiessufficienttomeetTaskForceCriteriaforaclinicaldiagnosisof 9
strainrate(SRs)werequantifiedfortheLVandRVonapicalgrey-scale 8
ARVC,13(ii)aprotractedhistoryofintenseenduranceexercisetraining, /2
images(60–90frames/s)asdescribedpreviously.17 3
and(iii)noevidenceofinheriteddisease.Thus,allathletesunderwent 9
Duringexercise,thefollowingmeasureswereobtained:(i)LVEFand 81
comprehensiveevaluationandwereexcludedfromparticipationifa 7
RVFACfromasingle-planefour-chamberviewasdescribedprevious- 0
mutationorvariantofuncertainsignificancewasidentifiedinanyof ly,17(ii)RVfreewallpeak-systolicvelocity(S′)bytissueDopplerimaging by
the five desmosomal genes associated with ARVC, or if therewas g
(framerate,120–160frames/s),and(iii)systolicpulmonaryarterypres- u
clinicalevidenceofdiseaseinheritance.3Athleteswithmoderateor e
severe RVabnormalitieswere excluded asthis isnottypical of an sure(PASP)fromthemaximaltrans-tricuspidregurgitantvelocities st o
withoutadditionofrightatrialpressureestimates.Enhancementof n
exercise-induced syndrome. Between 2011 and 2014, 25 athletes 2
theDopplersignalwithagitatedcolloidenhancementwasusedinall 1
fulfilledthestudyinclusioncriteriaand17acceptedtoparticipate.Of N
subjectsasdescribedpreviously.17AsasurrogateofRVcontractility, o
these,eightathleteshadanimplantabledefibrillator(ICD).Fifteenof v
17EA-VAsweretreatedwithbeta-blockersornon-dihydropyridine theRVend-systolicpressure–arearelationship(RVESPAR)wascalcu- em
latedasPASPdividedbyRVend-systolicarea.17 b
calcium-channelblockersaloneorincombinationwithanti-arrhythmic er 2
medications.Thesemedicationswerewithheldforatleast24hpriorto 0
Cardiac magnetic resonance equipment, 1
exercisetesting.Alleligiblevolunteersweremaleandthereforeonly 8
image acquisition, and analysis
malesubjectswererecruitedascontrolsubjects.
Thefirst10EAsrespondingtoadvertisementsatlocaltriathlonand Biventricularvolumesweremeasuredduringsupinecyclingexercise
cyclingclubswhowerecompetinginendurancesportsandperforming usingareal-timeCMRmethodwhichwehavepreviouslyvalidated
regularcyclingand/orrunningtrainingof.6h/weekwereenrolled.Se- againstinvasivestandards.14Inbrief,subjectsperformedsupineexercise
vennon-athletes(NAs)whowereparticipatinginrecreationalactivity withintheCMRboreusingacycleergometerwithadjustableelectronic
only (mild-to-moderate non-competitive exercise for ,3h/week) resistance(Lode,Groningen,TheNetherlands).Imageswereacquired
wereincluded.Nosubjectsmetexclusioncriteriaofknowncardiovas- withaPhilipsAchieva1.5TCMRwithafive-elementphased-arraycoil
culardiseaseorabnormalitiesonECGorechocardiogram. (PhilipsMedicalSystems,Best,TheNetherlands).Steady-statefreepre-
ThestudyprotocolconformedtotheDeclarationofHelsinkiand cessioncineimagingwasperformedwithoutcardiacgating.Astackof
wasapprovedbythelocalEthicsCommittee.Allsubjectsprovided 13–18contiguous8mmimagesliceswasacquiredintheshort-axis
informedconsent. planeandsubsequentlyinthehorizontallong-axisplane.
2000 A.LaGercheetal.
Table1 Clinicalcharacteristics
Endurance Non-athletes Enduranceathleteswithventricular ANOVA
athletes (n57) arrhythmias(n517) P-value
.................................................
(n510)
NoICD(n59) ICD(n58)
...............................................................................................................................................................................
Clinical
Age(years) 35+6 34+16 39+8 40+9 0.57
BMI(kg/m2) 22.9+1.5 23.2+1.7 26.1+3.0* 26.0+1.9* 0.004
Yearsofendurancesports 9(6–17) 0(0–0) 21(12–34)§ 17(8–20)§ 0.002
Hoursperweek 11(6–15)§ 0.6(0–2) 11(7–14)§ 15(14–21)§ <0.0001 D
............................................................................................................................................................................... ow
ARVCtaskforcecriteria nlo
a
Definite(2major,1majorand 3 8 0.009 d
e
2minor,or4minor) d
Borderline(1majorand 0 0 1.0 fro
m
1minoror3minor) h
Possible(1or2minor) 6 0 0.002 ttp
s
RVOTectopicsonly‡ 0 0 1.0 ://a
............................................................................................................................................................................... c
a
d
Medications e
m
Beta-blockers – – 6 5 ic
.o
Calciumantagonists – – 2 0 u
p
Flecainide – – 0 2 .c
o
m
Amiodarone – – 1 2 /e
Sotalol – – 0 2 urh
e
Cibenzoline – – 0 1 a
............................................................................................................................................................................... rtj/a
Biochemistry rtic
NT-proBNP(pg/mL) 32(12–43) 24(5–37) 83(21–294) 132(68–218)*§ 0.002 le
............................................................................................................................................................................... -a
b
Cardiopulmonarytesting stra
VO peak(mL/min/kg) 54.0+9.7 40.3+3.7* 38.8+9.1* 37.3+6.3* <0.0001 c
2 t/3
Peakpower(Watts) 365+68 261+48* 328+57 291+42 0.004 6
/3
PeakHR(b.p.m.) 181+7 178+16 174+25 156+14* 0.017 0
/1
VE/VCO (L/min) 0.026+0.003 0.024+0.004 0.027+0.003 0.027+0.004 0.2 9
2 9
8
/2
3
Datapresentedasmean+SDormedian(25and75%percentile);P-valuesfromANOVAusingBonferronipost-hoctestformultiplecomparisons. 9
8
*P,0.05fordifferencevs.EAs. 1
7
§P,0.05vs.controls. 0
‡Intheabsenceofanyotherarrhythmiasorstructuralabnormalities. by
Boldtexthighlightssignificantcomparisons(P,0.05). g
u
e
s
t o
n
2
Statistical analysis 1
Simultaneous with the image acquisition, ECG and respiratory N
timingwereretrospectivelysynchronizedusinganin-housedeveloped DatawereanalysedusingIBMSPSSstatistics22software.Gaussiandis- ov
e
softwareprogram(RightVol,Leuven,Belgium)suchthatcontouring tributionofallcontinuousvariableswasconfirmedusingaKolmogorov– m
b
couldbeperformedatthesamepointoftherespiratorycycleforall Smirnov test and values are reported as mean+SD oras median e
slices. (25and75%percentile)asappropriate.Forclinicalcharacteristics,com- r 20
1
Biventricularvolumeswerecalculatedfromendocardialcontours parisonsbetweengroupsforcontinuousvariableswereperformedby 8
traced on the short-axis (SAX) image with simultaneous reference one-wayANOVA,whereastheFisher’sExactorx2testwasusedfor
tothehorizontallong-axis(HLA)planethusenablingtheanalysers categoricalvariables.AMixedLinearModelwithcompoundsymmetric
(GC and ALG) to confirm the position of the atrio-ventricular covariancematrixandtheBonferronipost-hoctestformultiplecompar-
plane.Totalpulmonaryresistance(tPVR)wascalculatedastheratio isonswasperformedtoevaluatetheLVandRVvolumechangesduring
of mean pulmonary artery pressure (mPAP) to CO and total exercisewithinandbetweengroups.Theinteractionbetweengroup
systemicvascularresistance(tSVR)astheratioofmeansystemicar- and workload was included to assess differences between groups.
terial pressure (mSAP) to CO. The end-systolic pressure–volume Receiver-operatingcharacteristic(ROC)curveswereconstructedand
ratio (SP/ESV) was calculated as mPAP/RVESV for the RV and as areaundertheROCcurvescalculated20toidentifythebestechocardio-
(0.9×systolic blood pressure)/LVESV for the LV, as previously graphicandexerciseCMRmethodsfordistinguishingathleteswithVA
described.18,19 NT-proBNP was analysed from venous blood fromhealthysubjects(expressedasareaand95%confidenceintervals).
samples. Resting,peak-exercise,anddelta(D:changefromresttopeak)values
ArrhythmiasandexerciseRVdysfunction 2001
Table2 ARVCtaskforcecriteriaandectopyobservedduringexercisetesting
EAs(n510) NAs(n57) EA-VAs(n517)
............................................
NoICD(n59) ICD(n58)
...............................................................................................................................................................................
ARVCtaskforcecriteriadetails P-value*
Globalorregionaldysfunction Major 0 0 1 4 0.13
andstructuralRValterations Minor 0 0 1 0 1.0
Repolarizationabnormality Major 0 0 3 4 0.64
Minor 2 0 2 3 0.49
Depolarizationabnormality Major 0 0 0 0 1.0 D
Minor NA NA 2 5 0.15 ow
n
Arrhythmias Major 0 0 3 7 0.049 lo
a
Minor 0 0 6 1 0.049 d
e
Familyhistory MMianjoorr 00 00 00 00 11..00 d fro
m
DelayedenhancementonCMR NAa 1 0 1 2 1.0 h
............................................................................................................................................................................... ttp
s
Ectopyobservedduringexercisetesting P-value‡ ://a
Anyectopics 5 1 8 6 0.016 ca
d
Non-RVOTmorphology 3 1 3 4 0.41 em
Multiplemorphologies 0 0 1 0 0.41 ic
.o
Frequentectopy(.50ectopics) 0 0 4 0 0.006 up
Non-sustainedVT 0 0 3 0 0.027 .co
m
/e
u
EAs,enduranceathletes;NAs,non-athletes;EA-VAs,enduranceathleteswithventriculararrhythmias;NA,notavailable:signalaveragedECGswerenotperformedincontrol rh
subjects. ea
*a‡DPP--evvlaaallyuueeedcceaalnlcchuuallanattceeeddmffeoonrrtccooonmmCppaaMrriiRssooinsnnbboeetttwwaeereeenncoaEglAlng-izrVeoAdusptwsa.sikthfoarncdewcritihteoruiotnICfoDrsA. RVC. rtj/artic
le
Boldtexthighlightssignificantcomparisons(P,0.05). -a
b
s
tra
c
wereassessed.Thesignificanceofdifferencesinareaunderthecurveof have on clinical decision making. The prevalence of other task t/36
thecorrelatedrestandpeakexerciseROCcurveswastestedusingthe force criteria abnormalities was similar between EA-VAs with /30
methodologydescribedbyDelongetal.21 andwithoutICDs.Theputativeriskfactorofdelayedenhance- /19
9
Intra-andinterobservervariabilityofechocardiographicmeasures mentonCMR(whichisnotalistedtaskforcecriterion)wasob- 8/2
wereassessedatrestandduringthethreeexercisestagesin15subjects. 3
servedinone ostensiblyhealthyEA and nomore frequentlyin 9
Themeanvalueofthetwoobservations(x)andtheabsolutevalue EA-VAs.Ventricularectopyduringcardiopulmonaryexercisetest- 817
ofthedifferencebetweenobservations(e)+SDweredetermined. 0
ingwaslessfrequentlyobservedinNAsbutwassimilarinEAsand b
ReproducibilitywasassessedbythecoefficientofvariationCV¼(e/x) y
EA-VAs.Non-RVOTandvariablemorphologyectopicsweresimi- g
100%,theintra-classcorrelationcoefficient(two-waymixedandabsolute u
e
asiggrneifiecmanetn.tquoted).AP-valueof ,0.05wasconsideredstatistically lsaursltyaionbedseVrvTedweinreaollbgserorvuepds,inwEhAile-VAfrseqwuiethnotuetcatnopICyDanbdutnonont- st on
2
inthosewithanICD(Table2). 1
N
Results Echocardiography at rest and during ove
m
exercise b
Thedemographic,clinical,andexerciseechocardiographiccharac- e
r 2
teristicsofthefourstudygroupsarepresentedinTable1.Athletes Therewerefewdifferencesbetweenthegroupsinrestingcardiac 0
1
ineachgroupwereofsimilaragebutathleteswitharrhythmiashad measures(Table3).Aswouldbeexpected,cardiacvolumesanddi- 8
competedinsportsforlongerandhadhigherBMIsatthetimeof mensionsweregreaterintheathletes,consistentwithtypicalathlet-
thestudy.HealthyEAshadahigherVO peakcomparedwiththe ic cardiac remodelling. However, there were no significant
2
othergroups,consistentwiththefactthattheEA-VAshadbeen differencesinfunctionalmeasuresofLV,RV,orhaemodynamicmea-
advisedtode-train.Sixty-fivepercentoftheEA-VAsfulfilledthe sures(LVEF,RVFAC,RVS′,andPASP)withtheexceptionofRV
diagnosticTaskForceCriteriaforARVCbutnonehadevidence strain ratewhich was reduced in EA-VAs when compared with
offamilialdiseaseorRVabnormalitiesthatwereconsideredmod- healthyEAsandNAs(P¼0.002)andRVESPARwhichwasreduced
erateorsevere.AsdetailedinTable2,theEA-VAswhometmajor in EA-VAs when compared with NAs (P¼0.011). EA-VAs had
arrhythmiacriteriaforARVCweremorelikelytohavebeentrea- larger RV outflow tract dimensions than healthy EAs and NAs
tedwithanimplantableICD(P,0.05)reflectingthelikelyinflu- whileRV inflowdimensionsandatrialareasweresimilaramong
encethatsustainedventriculararrhythmiasofnon-RVOTorigin theathletegroupsbutlargerthanNAs.
2002 A.LaGercheetal.
Table3 Echocardiographicmeasuresatrestandduringexercise
Endurance Non-athletes Enduranceathletes ANOVA
athletes (n57) withventricular P-value
(n510) arrhythmias(n517)
...............................................................................................................................................................................
Rest
HR(b.p.m.) 52+8 62+12 55+9 0.220
LVIVSd(mm) 9.7+3.4 9.7+0.7 10.6+1.1 0.184
LVEDV(mL) 142+17 110+9* 131+24§ 0.012
LVESV(mL) 55+10 47+5 55+17 0.333
D
LVEF(%) 61.0+4.5 57.4+5.9 58.6+7.0 0.460 o
w
LVstrain(%) 19.7+2.6 17.7+2.3 18.1+2.8 0.200 nlo
a
LVsystolicstrainrate(-/s) 1.14+0.20 1.13+0.07 1.0+0.12 0.050 d
e
LRVVsd′ia(cstmo/lisc)area(cm2) 287..21++31..44 228..12++21..13* 307..51++61..19§ 00..018052 d from
RVsystolicarea(cm2) 14.7+1.6 11.6+1.5 18.1+5.1*§ 0.002 http
RVFAC,(%) 45.2+6.2 47.5+6.1 41.1+6.9 0.080 s
RVstrain(%) 26.0+2.5 27.8+2.0 23.8+4.6 0.050 ://ac
a
RVsystolicstrainrate(-/s) 1.51+0.22 1.61+0.19 1.28+0.22*§ 0.002 d
e
RVs′(cm/s) 11.5+2.4 11.5+1.6 10.0+2.1 0.150 mic
TAPSE(mm) 30+5 25+4 26+4 0.070 .ou
p
PASP(mmHg) 25+5 21+3 23+4 0.340 .c
o
RVESPAR(mmHg/cm2) 1.7+0.4 1.9+0.4 1.4+0.4§ 0.011 m
/e
RVOTd(mm) 33+4 32+6 39+8*§ 0.003 u
rh
RVITd(mm) 46+6 41+6 51+4§ 0.001 e
a
Leftatrialarea(cm2) 21.1+3.6 15.8+2.5* 20.3+2.7§ 0.002 rtj/a
Rightatrialarea(cm2) 21.1+4.9 16.7+4.0 22.5+3.3§ 0.010 rtic
............................................................................................................................................................................... le
Peakexercise -ab
s
HR(b.p.m.) 138+10 129+8 123+20 0.059 tra
c
LVEDV(mL) 127+22 102+13 122+22 0.050 t/3
LVESV(mL) 31+16 30+3 27+22 0.836 6/3
0
LVEF(%) 74.2+5.9 70.9+2.3 69.3+8.5 0.290 /1
LVs′(cm/s) 13.5+1.3 13.6+2.4 10.9+3.2 0.185 99
8
LVe′(cm/s) 16.9+2.8 15.6+2.8 13.6+3.7 0.363 /2
3
RVdiastolicarea(cm2) 25.8+2.2 20.9+1.9 30.5+6.2*§ 0.001 98
1
RVsystolicarea(cm2) 11.1+1.6 8.9+1.0 17.4+6.4*§ 0.001 70
RVFAC,(%) 57.1+5.2 57.0+5.2 44.1+10.6*§ 0.001 by
RVs′(cm/s) 18.9+1.2 20.6+2.9 14.6+3.4*§ <0.0001 gu
e
s
PASP(mmHg) 61+7 49+10* 48+9* 0.010 t o
RVESPAR(mmHg/cm2) 5.7+1.1 5.6+1.5 3.0+1.2*§ <0.0001 n 2
1
N
P-valuesfromANOVAusingBonferronipost-hoctestformultiplecomparisons. ov
*P,0.05fordifferencevs.EAs. em
§P,0.05vs.NAs. b
e
Boldtexthighlightssignificantcomparisons(P,0.05). r 2
0
1
8
Echocardiographicmeasureswerenotobtainableinallsubjectsat between within-subject changes during exercise vs. between-
peakexercise.Dopplermyocardialvelocitieswereobtainedinall subjectgroups¼0.84, Figure 1A). Incontrast, exercise-induced
34subjects,LVEFandRVFACin32subjects(94%),andRVESPAR increasesofRVFAC,RVS′,andRVESPARwereimpairedinEA-VAs
in24subjects(71%).Despitethis,peakexercisemeasuresdemon- relativetoEAsandNAs(P,0.0001forinteractionexercise×
stratedsignificantimpairmentinRVreserveinEA-VAs,whileLV group;Figure1B–D).WithinthegroupofEA-VAs,thosewithan
measuresweresimilarinallgroups(Table3).Right-ventricularareas ICDhadlowerRVFAC(36.0+8.1vs.52.1+5.3%;P,0.0001)
weregreaterwhileRVFACandRVS′werereducedinEA-VAsrela- andRVS′(12.6+2.6vs.16.7+2.9cm/s;P,0.0001)atpeakexer-
tivetobothEAsandNAs.Thesedifferencesaremorerigorously cisethanthosewithoutICD(P,0.0001).Anexampleofexercise
definedusingrepeatedexercisemeasures(Figure1).Duringexer- echocardiographycomparingRVfunctioninanEAandEA-VAis
cise,LVEFaugmentationwassimilarbetweenallgroups(interaction providedinFigure2andSupplementarymaterialonline,VideoS1.
ArrhythmiasandexerciseRVdysfunction 2003
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Figure1 Echocardiographicmeasuresdemonstratingreducedright-ventricular(RV)reserveinathleteswitharrhythmias.Changesin(A)left- -a
b
ventricularejectionfraction(LVEF),(B)RVfractionalareachange(RVFAC),(C)RVpeaksystolictricuspidannularvelocity(RVS′),and(D)RV stra
end-systolicpressure–arearelationship(RVESPAR)fromresttopeakexercise.P-valuesareshownfortheinteractionbetweengroupand ct/3
exerciseintensity.Ateachexerciseintensity,*P,0.05forthedifferencebetweenenduranceathleteswithventriculararrhythmias(EA-VAs) 6
andEAsand§P,0.05forthedifferencebetweenEA-VAsandnon-athletes(NAs).Errorbarsdepictthestandarderrorofthemean. /30
/1
9
9
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/2
3
NTproBNPdidnotcorrelatewithrestingLVstrain(r¼20.31; volumes in both groups were larger than NAs (P¼0.01 and 98
1
P¼0.09),restingLVEF(r¼20.086,P¼0.6),orpeakexercise P¼0.04,respectively).Allrestinghaemodynamicmeasureswere 7
0
LVEF(r¼20.026,P¼0.9).Incontrast,NTproBNP correlated similarbetweengroups(Table4). b
y
modestly with resting RVFAC (r¼20.42; P¼0.016), RV S′ Duringexercise,CMRmeasureswereacquiredinallsubjects gu
e
(r¼20.44;P¼0.012),andRVstrain(r¼20.57,P,0.01)buta withoutICDs.Atpeakexercise,RVEDVandRVESVweresignifi- st o
muchstrongercorrelation was found betweenNTproBNPand cantly largerand RVEF was reduced in EA-VAs relative to EAs n
peakexerciseRVFACandRVS′(r¼20.78and20.71respectively; andNAs(Table4).Whenrepeatedexercisemeasureswereas- 21
N
P,0.0001;seeSupplementarymaterialonline,FigureS1). sessed,therewasacleardifferencebetweentheeffectofexercise o
v
e
EchocardiographicmeasuresofRVfunction,pulmonaryartery onRVandLVmeasuresinEA-VAs(Figure3).WhileLVfunction m
b
pressures,andcardiacoutputdemonstratedexcellentreproducibil- was similar between groups (Figure 3A, C, and E), RV function e
r 2
ity. Intra-class correlation coefficients ranged between 0.93 wasreduced duringexercise. Relative toEAsand NAs,the RV 0
1
and0.997forintraobservervariabilityandbetween0.82and0.98 acutelydilatedandfailedtocontractadequately,asdemonstrated 8
forinterobservervariability(seeSupplementarymaterialonline, byarelativeincreaseinRVEDV(interactionP¼0.013,Figure3B)
TableS1). and an attenuated decrease in RVESV (interaction P,0.0001,
Figure3D).Asaresult,RVEFaugmentationwasimpairedinEA-VAs
compared with healthy EAs and NAs (interaction P,0.001;
Cardiac magnetic resonance-derived
Figure3F).AnexampleofexerciseCMRcomparingRVfunction
cardiac volumes and invasive
in an EA and EA-VA is provided in Figure 4 and Supplementary
haemodynamics during exercise
materialonline,VideoS2.
TherewerenodifferencesinrestingcardiacvolumesbetweenEAs IncreasesinSV,HR,mPAP,andSBPweresimilarbetweenthedif-
andEA-VAsreflectingthefactthatabnormalitiesinRVstructureand ferentgroups(Table4).ThemPAP/COslopewassimilarinEAs,NAs,
functionintheEA-VAgroupwere,atmost,mild.Asexpected,RV andEA-VAs(0.92+0.42vs.1.11+0.46vs.1.23+1.1mmHg/L/min;
2004 A.LaGercheetal.
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Figure2 Reducedexerciseright-ventricular(RV)functioninanathletewitharrhythmiaswhencomparedwithnormalexerciseRVfunctionina t/3
6
healthyenduranceathlete.End-systolicimagesoftheRVaredepictedatrestandatpeakexerciseinahealthyenduranceathlete(EA)andan /3
0
athletewithventriculararrhythmias(EA-VA).ThereisaclearreductioninRVend-systolicareafromresttopeakexerciseinEAresultingin /1
9
9
anappropriateincreaseinRVfractionalareachange(RVFAC),whereastheRVareadoesnotdecreaseinEA-VAandtheRVFACdoesnotincrease. 8
ThedifferenceinRVaugmentationisevenbetterappreciatedinvideoformat(seeSupplementarymaterialonline,VideoS1). /23
9
8
1
7
0
P¼0.64;Figure5).Ontheotherhand,theaugmentationofRVSP/ AUC for RVESPAR (P¼0.02) and a trend for improvement in b
y
ESV was reduced in EA-VAs compared with EAs and NAs (P¼ RVFAC(P¼0.052)andRVS′(P¼0.054).Inthecohortundergoing g
u
e
0.002forinteraction),againincontrasttothechangeinLVSP/ESV ex-CMRwhichexcludedEA-VAswithanICD,restingCMRmea- s
fromresttopeakexercisethatwassimilarbetweengroups. sures did not differentiate athletes with arrhythmias [AUC for t on
AsillustratedinSupplementarymaterialonline,FigureS2,therewas RVESV¼0.59(0.33–0.85),RVEF¼0.55(0.28–0.83),andRVSP/ 21
N
astrongcorrelationbetweenechocardiography-derivedRVESPAR ESV¼0.47(0.15–0.67),respectively,Figure6C],whereaspeakex- o
v
andCMR-derivedRVSP/ESV(r¼0.84;P,0.0001). ercisemeasuresdid[AUC¼0.86(0.70–1.00),0.78(0.55–1.00), em
b
and0.88(0.74–1.00)respectively,Figure6D].Thisrepresentedasig- e
Impaired right-ventricular contractile ntiivfiecatontriemstp(rPov,em0.e0n5t)i.nAAnUinCcrfeoarsaellinCMRVREmSPeAasRur,es3a.t0e9xmermciHseg/rcemla2- r 2018
reserve as a means of identifying
fromresttopeakexercisehadasensitivity¼83%andspecificity¼
arrhythmic risk 100%, while an increase in RV SP/ESV,0.25mmHg/mL had a
Receiveroperatingcharacteristiccurvesdemonstratedthattheabil- sensitivity¼83% and specificity¼88% for identifying athletes
ityofRVmeasurestoaccuratelydifferentiateEA-VAsfromhealthy withRVarrhythmias.
subjects(EAsandNAs)wasrelativelymodestatrestusingechocar-
diography[AUCforRVESPAR¼0.78(0.61–0.95),RVFAC¼0.72 Discussion
(0.54–0.90), and RV S′¼0.71 (0.53–0.90), Figure 6A] but was
impressive at peak exercise [AUC¼0.96 (0.89–1.00), 0.89 Consistentwithourhypothesisthatpro-arrhythmicremodelling
(0.78–1.00),and0.90(0.79–1.00),respectively,Figure6B].When predominantlyaffectstheRV,wedemonstratedthatathleteswith
comparedwithrest,thisrepresentedasignificantimprovementin ventriculararrhythmiasdevelopRVdysfunctionduringexercise
ArrhythmiasandexerciseRVdysfunction 2005
Table4 Cardiacmagneticresonancemeasuresatrestandduringexercise
Endurance Non-athletes Enduranceathletes ANOVA
athletes (n57) withventricular P-value
(n510) arrhythmias(n59)
...............................................................................................................................................................................
Rest
HR(b.p.m.) 59+8 67+7 61+12 0.23
CO(L/min) 8.1+1.0 7.4+1.5 7.7+1.7 0.63
LVEDV(mL) 225+18 196+23* 229+24§ 0.01
LVESV(mL) 86+10 85+17 100+32 0.3
D
LVSV(mL) 139+14 111+17* 129+22 0.012 o
w
LVEF(%) 61.8+3.3 56.6+5.9 56.8+10.2 0.22 nlo
a
RVEDV(mL) 237+28 200+22 233+34 0.04 d
e
RVESV(mL) 99+13 90+14 108+31 0.3 d fro
RVSV(mL) 138+19 110+13* 125+21 0.02 m
RVEF(%) 58.0+2.9 55.1+3.7 54.1+8.1 0.29 http
mSAP(mmHg) 96+7 89+7 93+6 0.11 s
mPAP(mmHg) 14+4 11+2 15+4 0.09 ://ac
a
tSVR 964+152 984+181 1009+248 0.88 d
e
m
tPVR 136+38 118+27 168+78 0.18 ic
............................................................................................................................................................................... .o
u
Peakexercise p
.c
HR(b.p.m) 161+12 151+9 149+25 0.30 o
m
CO(L/min) 24.0+2.6 19.5+3.6 21.5+5.1 0.077 /e
u
LVEDV(mL) 218+14 186+25* 224+19§ 0.001 rh
e
LLLVVVESEVFSV((%m(m)L)L) 71065.513+++611.766 61952.759+++311.809 61574.925+++122018.0 000...30045956 artj/article
RVEDV(mL) 214+28 179+22* 237+27§ 0.001 -ab
s
RVESV(mL) 67+19 52+10 95+30*§ 0.002 tra
c
RVSV(mL) 147+22 127+17 142+24 0.19 t/3
RVEF(%) 68.7+6.9 70.9+4.1 60.3+10.4§ 0.025 6/3
0
mSAP(mmHg) 129+10 116+10 126+12 0.074 /1
9
mPAP(mmHg) 28+7 23+6 30+10 0.303 9
8
tSVR 435+67 489+89 492+136 0.40 /2
3
9
tPVR 94+31 98+29 121+74 0.48 8
1
7
0
P-valuesfromANOVAusingBonferronipost-hoctestformultiplecomparisons. by
*P,0.05fordifferencevs.EAs. g
u
§P,0.05vs.NAs. e
s
Boldtexthighlightssignificantcomparisons(P,0.05). t o
n
2
1
N
whilehealthysubjectsdonot.Importantly,thiswasevidentdespite thatthismayserveasasubstrateforcomplexRVarrhythmias.22 o
v
e
therebeingfewabnormalitiesatrest.Thisisofconsiderableclinical GiventhatthehaemodynamicloadontheRVisminimalatrest m
b
significancegiventhatroutineclinicalassessmentofathleteswith andincreasesdisproportionatelywithexerciseintensity,5,23itstands e
r 2
suspected arrhythmias comprises cardiac imaging at rest, often toreasonthatexerciseoffersanopportunitytoidentifyearlyorsubtle 0
1
withafocusontheLV.Ouralternativestrategyoffocusingonthe RVdysfunction.Consistentwiththispremise,therewerefewdif- 8
RVduringexerciseprovedfarmoreaccurateinidentifyingathletes ferencesbetweenEA-VAsandEAsusingconventionalechocardio-
withpotentiallyseriousarrhythmiasandoffersconsiderableprom- graphic and CMR measures performed at rest. Right-ventricular
iseasanon-invasiveriskstratificationtool. outflowtractdimensionswereslightlygreaterwhileRVsystolicstrain
rateandRVESPARwereslightlylowerinEA-VAswhencompared
withEAsbutthesemeasureswereofrelativelypoorpredictivevalue
Understandingthecontextofarrhythmias
onROCanalysis.Ontheotherhand,everymeasureofRVfunction
in athletes; the association with
wasreducedinEA-VAsduringexerciseandthiswasconsistentlyde-
right-ventricular dysfunction
monstratedusingbothechocardiographyandCMR.Exerciseimaging
Intenseenduranceexercisehasbeenassociatedwithdisproportion- alsoprovedmoreusefulthanrhythmanalysisgiventhatventricular
ate RV wall stress and RV injury,5,7 and we have hypothesized ectopics were observed in healthy athletes and those with a
2006 A.LaGercheetal.
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Figure3 Magneticresonance-derivedbiventricularvolumechangesduringexercise.ChangesinEDV,end-diastolicvolume;ESV,end-systolic gu
e
volume;andEF,ejectionfractionduringincrementalexerciseareshownforenduranceathleteswithventriculararrhythmias(EA-VAs)(red),EAs s
(green),andnon-athletes(NAs)(blue).P-valuesareshownfortheinteractionbetweengroupandexercise-intensity.Ateachexerciseintensity, t on
*P,0.05forthedifferencebetweenEA-VAsandEAsand§P,0.05forthedifferencebetweenEA-VAsandNAs.Errorbarsdepictthestandard 21
errorofthemean. N
o
v
e
m
b
e
r 2
predispositiontoarrhythmiaswithequalfrequency.Paradoxically, attenuatedinEA-VAsrelativetoEAsandNAs.Thus,itcanbecon- 0
1
frequentectopicsandnon-sustainedVToccurredinthoseathletes cludedthattheRVisdisproportionatelyaffectedbyexerciseand 8
whohadbeenconsideredatlowerriskofsustainedarrhythmiasand ourvalidationofthisconceptinhumansagreeswithpre-clinicalro-
hadnotbeentreatedwithanICD. dentmodelsinwhichenduranceexercisepromotespro-arrhythmic
Real-timeCMRperformedduringfreebreathingandstrenuous remodellingoftheRV,whilesparingtheLV.12
exercisehasbeenrigorouslyvalidated14andhastheadvantageof Consistent with previous studies, we observed a near-linear
providingsimultaneouscomparisonsbetweenLVandRVfunction. relationship between pulmonary artery pressures and cardiac
Thus,confidencecanbeplacedinthedivergenceofventricular output (the so-called ‘P/Q relationship’).5,23 This current data
functionobservedinEA-VAsduringexercise.IntheLV,augmenta- representsthelargestpublisheddescriptionofinvasivelydeter-
tionofsystolicfunction(reductionsinLVESVandincreasesinLVEF) mined P/Q ratios in young healthy subjects and confirms that
wassimilarbetweenEA-VAs,EAs,andNAs(Figure3).Incontrast, mean pulmonaryartery pressures frequentlyexceed 25mmHg
thereductioninRVESVandtheincreaseinRVEFweresignificantly atpeakexercise(Figure5).Thisrepresentsatwo-tothree-fold
ArrhythmiasandexerciseRVdysfunction 2007
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Figure4 Reducedexerciseright-ventricular(RV)functioninanathletewitharrhythmiaswhencomparedwithnormalexerciseRVfunctionina rh
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hveenalttrhicyuelanrdaurrrahnyctehmatihasle(tEeA.E-VnAd-)s.yInstEoAlic,tihmeargeeissaauregmdeenpticatteiodnaotfrbeostthanLdVaatndpeRaVk-feuxnecrtcioisnewinithaehxeealrtchiyseeannddutrhaencReVaethjelectteio(nEfAra)catinodnainncartehalseetsefwroitmh artj/a
56to74%.RestingRVfunctionissimilarinEAandEA-VA,butRVfunctionfailstoaugmentinEA-VA.ThedifferenceinRVaugmentationiseven rtic
le
betterappreciatedinvideoformat(seeSupplementarymaterialonline,VideoS2). -a
b
s
tra
c
Exercise echocardiography or cardiac t/3
6
magnetic resonance? /3
0
/1
Exercise-inducedRVdysfunctioninEA-VAswasconsistentlyob- 99
8
servedacrossimagingmodalities.Furthermore,therewasastrong /2
3
inversecorrelationbetweenmeasuresofRVfunctionatpeakexer- 98
1
ciseandNT-proBNP(seeSupplementarymaterialonline,FigureS1) 7
0
andalsoastrongcorrelationbetweenRVcontractilityasdeter- b
y
minedbyechocardiographyandex-CMR(seeSupplementaryma- gu
e
terial online, Figure S2). Thus, the question arises as to which st o
imagingtechniqueisbetter.Despiteexpectationsofmoreaccurate n
2
quantificationofRVfunctionwithexerciseCMR,itdidnotprove 1
N
betterthanechocardiographyatidentifyingathleteswithsubtle o
v
e
RVdysfunctionandarrhythmias(Figure6).Giventhewidespread m
b
availabilityandcost-effectivenessofechocardiography,thisisanim- e
r 2
portantfinding.WhileafocusonRVmeasuresisnotcommonly 0
1
practiced,themeasuresemployedinthisstudyarerelativelysimple 8
andcouldeasilybeincludedinclinicalroutine.Duringexercise,
Figure5 Relationshipbetweenmeanpulmonaryarterypressure RVFACandRVS′ wereobtainedinthemajorityofsubjectsand
andcardiacoutput.TherelationshipbetweenmPAPandCOissimi-
couldaccuratelyidentifyathleteswitharrhythmias(Figure6B).The
larforEAs,NAs,andEA-VAsasindicatedbythefactthatthereisno
strongestechocardiographicmeasurewasRVESPARbutitsclinical
significantinteractionbetweengroupsandthemPAP/COrelation-
utilitymaybelimitedbythefactthatitwasmeasurableinonly71%
ship.Errorbarsdepictthestandarderrorofthemean.
of subjects. In contrast, high-quality images can be acquired by
Ex-CMRinvirtuallyallsubjectsbutthetechniqueremainsexpensive
increase in systolic load during exercise which is a far greater and confined to few specialized centres. Although the areas
proportionalincreasethanfortheLVandcouldexplainwhythe undertheex-CMRROCcurvesseemedinferiortothoseofecho-
RVismostsusceptibletoexercise-induceddysfunction. cardiography,directcomparisonislimitedbythefactthatathletes