Citation for published version (APA): Luijendijk, P. (2014). Aortic coarctation: late complications and treatment strategies

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1 UvA-DARE (Digital Academic Repository) Aortic coarctation: late complications and treatment strategies Luijendijk, P. Link to publication Citation for published version (APA): Luijendijk, P. (2014). Aortic coarctation: late complications and treatment strategies General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 02 Mar 2018

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3 Abstract Aims:Aorticcoarctation(CoA)occursasa simple isolateddisorder,andinamore complex form, combinedwithassociatedcongenitalcardiacabnormalities.longtermoutcomeofallcoapatients may be complicated by dilatation of the thoracic aorta. The aim of this study was to quantify progressiveaorticdilatation,andidentifydeterminantsforprogressiveaorticdilatation. Methods and Results: Cardiovascular Magnetic Resonance Imaging (CMR) and echocardiographic data of 93 CoA patients were analyzed retrospectively on the progression, and determinants, of progressive thoracic aortic dilatation. Outcome of simple versus complex CoA patients were compared.93coapatients(meanage39±12years,male59%)werefollowedwithcmr(followup 5.3±1.8years).Twentyeightpatientswereclassifiedassimpleand68ascomplexCoA.Themean progressionrateofthoracicaorticdilatationwashighestintheascendingaortawith2.2±2.0mm/5 years(range0 7.2mm/5years).HistoryofVSD(=1.77,P=0.004)andanincreasedleftventricular massindex(=0.02,p=0.04)wereassociatedwithprogressiveascendingaorticdilatation.complex CoApatientsshowanincreasedprogressionratecomparedtosimpleCoApatientswith2.4mm/5 yearsversus1.5mm/5yearsrespectively.(p=0.03) Conclusion:Adultpostcoarctectomypatientsshowanincreasedmeanprogressionrateofascending aorticdilatationwith2.2mm/5years.theprogressionrateofascendingaorticdilatationisincreased incomplexcoapatients,ascomparedtosimplecoapatients.thesefindingspointtowardsamore comprehensive genetic subset of patients with an increased risk for progressive ascending aortic dilatation.

4 Introduction Coarctationoftheaorta(CoA)accountsfor5to9%ofallcongenitalcardiacanomalies.Althoughlife expectancy has dramatically improved since the advent of corrective surgical techniques, complications are common and mortality is increased in these patients. 1;2 Aortic aneurysm formation,recoarctation,coexistingbicuspidaorticvalve(bav),infectiveendocarditis,hypertension, premature (coronary) atherosclerosis and cerebrovascular accidents contribute to the increased morbidityandmortality. 37 Aorticaneurysmformation,oneofthemostseverecomplicationsafter coarctationrepair,isfoundin9%ofthesepatients. 8 Itisknownthatintrinsicabnormalitiesofthethoracicaortapredisposeforaorticdilatation, whichcanultimatelyleadtodissectionorrupture,andsubsequentdeath. 9 Aorticdilatationhasbeen describedatvarioussitesofthethoracicaorta,andafteravarietyofsurgicaltechniques;however, which part of the thoracic aorta is most at risk is unknown Moreover, data on the average progressionratesofdilatationofthethoracicaortaisscarce.onlyfewstudieshaveanalyzedpossible predictorsforprogressivedilatation ofthethoracicaortainpostcoarctectomypatients While BAVispresentinmorethanhalfoftheCoApatientsandisknowntopredictaorticdilatationevenin patientswithoutcoa,theinfluenceofotherclinicalparametersonprogressiveaorticdilatationin CoApatientsremainsunknown. 8;14 TheincreasedincidenceofBAVandthepresenceofassociated congenital cardiac abnormalities points towards a subset of CoA patients with a more severe developmental spectrum in these complex CoA patients as compared to simple CoA patients with an isolated coarctation, with or without PDA. 16 Knowledge on progression rates of aortic dilatationincomplexandsimplecoapatientsisimportantforanadequatefollowupandtimingof surgicalintervention.weperformedafollowupstudytoassessandquantifytheprogressionrates ofaorticdilatationthroughoutthethoracicaorticinadultpostcoarctectomypatients.furthermore, we compared outcome in complex and simple CoA, and searched for determinants of progressive aorticdilatationovertime. 17;18 Methods Patients Inthismulticentrestudy93consecutiveadultpostcoarctectomypatients(age39±12years;59% male)fromtwooutpatientclinicswereincludedin2001.theconcordatabase,adutchregistryand DNAbank for adult patients with congenital heart disease, was used to identify adult post coarctectomypatientsinthetwoparticipatingtertiaryreferralcenters. 19;20 Allpatientsparticipated in a previous observational study from our institution in which 111 consecutive patients were evaluated. 21 Outofthese111patients93patientshadsufficientdata,andwerewillingtoparticipate inthepresentstudy.patientswhounderwenttwoserialcardiovascularmagneticresonanceimaging scans(cmr)between2001and2009wereincludedwithaminimumfollowupperiodof1year.all patientsunderwentcmrandechocardiographytwice,regardlessoftheclinicalindication;onceat baseline,andonceafterameanfollowupperiodof5.5years.atbaseline,age,sex,bodysurface area(bsa),ageatintervention,otherassociatedcongenitalcardiacanomalies,andtypeofsurgery were obtained from patients medical records. The presence of hypertension was determined by ambulatorybloodpressuremonitoring(abpm).patientswereconsideredhypertensivewhenmean daytimesystolicbloodpressurewas135mmhgand/ordaymeandiastolicbloodpressurewas85 mmhg,orifonantihypertensivetreatmentonthediscretionofthetreatingphysician. 22 Attheend 6

5 of followup information about reintervention or a history of recoarctation during the follow up periodwasobtainedduringtheiroutpatientvisit. Complex CoApatientsweredefinedaspatients after CoA repair with one, or a combination, of the following associated congenital cardiac anomalies;bav,increasedleftventricular(lv)massindex,historyofventricularseptaldefect(vsd) or the presence of a hypoplastic aortic arch. Simple CoA was defined as aortic coarctation occurring in isolation, with or without a history of patent ductus arteriosus (PDA). 16 The Medical EthicsCommitteeoftwoparticipatingcentresapprovedtheprotocol. MagneticResonanceImaging Image acquisition was performed by cardiovascular magnetic resonance angiography, using a 1.5 Tesla scanner (Siemens Avanto, Erlangen, Germany). To visualize the entire aorta, a three dimensional T1 weighed spoiled gradient echo sequence was used after administration of intravenous Gadolinium. This resulted in a three dimensional representation of the entire aorta. Diametersweredeterminedintheascendingaortaattheleveloftherightpulmonaryartery,distal transverseaorticarch,coarctationsite,descendingaorta,andattheleveloftheaortadiaphragm. The diameter of the ascending aorta at the level of the right pulmonary artery was used as the standard data acquisition point for the ascending aorta. For CMR analyses, two independent observers(rf,pl)usedimpaxclient6.0(leiden,nl).additionally,theaorticarchmorphologywas assessed. 23 Echocardiography Echocardiography was performed with a Vivid 7 (GE, Vingmed Ultrasound, Horton, Norway) ultrasound images system. The echocardiogram performed the closest in time to the concomitant CMRwasanalyzed.Aorticrootdiametersweremeasuredinenddiastoleatthelevelofthesinusof Valsalva. Aortic dimensions were measured using the leading edge to leading edge technique accordingtotherecommendationsoftheamericansocietyofechocardiography. 24;25 Anatomyofthe aortic valve and residual or recurrent gradients across the left ventricular outflow tract as well as ejectionfractionweredetermined.thediagnosisofbavwasmadewhen2aorticcuspswereclearly identifiedintheshortaxis,withpartialorcompletefusionof2aorticvalveleafletsresultingineither partialorcompleteabsenceofafunctionalcommissurebetweenfusedleaflets. 26 Aorticregurgitation andstenosiswasassessedusingmultiplewindows. 27 Aorticregurgitationwasclassifiedasnoneor mild to moderate. Patients were considered to have a significant gradient when we observed a gradientovertheaorticvalveofatleast20mmhg. 28 LeftventricularmasswascalculatedfromM modeechocardiographytracings,usingthedevereuxformula,andindexedforbsa.anincreasedlv masswasdefinedas101g/m²forwomenand117g/m²formen,andwasdeterminedaccordingto thebaselineechocardiographicinvestigation. Statisticalanalysis DataanalysiswasperformedusingtheSPSSstatisticalpackage(16.0forwindows;SPSSInc.,Chicago, Illinois, USA). Data are presented as mean value ± standard deviation, or in case of a skewed distribution as median (range), or as number of patients (percent). Intra and interobserver reproducibilityofthecmranalysisperformedbytwoindependentobserverswasdetermined.the coefficient of variability was calculated as the standard deviation of the difference of the paired

6 measurementsdividedbythemeanoftheaverageofthepairedmeasurements,andexpressedasa percentage.valueswereconsideredstatisticallysignificantatp<0.05. ComparisonsbetweencontinuousvariablesweremadebytwotailedStudentttests.Linear regressionanalysiswasusedtoindentifydeterminantsforprogressiveaorticdilatation.datawere relatively equally interpreted while the followup period was not the same in all patients. The analyseswereperformedwheredatawereweighedforfollowup.univariateregressionanalysiswas performedforallbaselinecharacteristicstodeterminewhetheranassociationwasfoundwiththe progression rate of ascending aortic dilatation. Multivariate stepwise regression analyses were performedusing0.05asthecriterionofsignificanceforentryofthevariablesand0.1forremoval wasusedtoindentifyindependentdeterminantsforprogressiveaorticdilatation. Results Studypopulation Ninetythreeadultpostcoarctectomypatientswereincluded,withameanageof39±12years(range years), mean age at repair 8.6±8.6 years (range years), and mean time after repair 29.9±10.3years(range6 53years).(Table1)Themeanfollowupperiodwas5.4±1.8years(range years),whichyieldedatotalof402patientyears.Twentyeightpatientswereclassifiedas simple CoA patients and 65 as complex CoA patients. Eighteen patients (19%) received surgical correction before the age of one year. In six patients (6%, of which 2 BAV patients) aortic valve replacementhadbeenperformedbecauseofaorticstenosisand/orregurgitationbeforeonsetofthe presentstudy.53patients(57%)werediagnosedwithbav.elevenpatients(12%)werediagnosed with VSD of which 6 had been surgically corrected. Four patients were diagnosed with Turner syndrome and all were complex CoA patients. All patients were considered to be successfully repaired. Successfully repaired was defined as; without residual aortic narrowing requiring intervention,inwhichthethresholdforinterventionwasdefinedaccordingtotheescguidelines. 29 6

7 Table 1. Variable N 55 PDA VSD Crenel

8 dilatation was significantly increased in complex coarctation as compared to simple coarctation patients. The progression rate of ascending aortic dilatation in these complex CoA patients was 2.4±2.0mm/5yearscomparedto1.5±1.9mm/5yearsinthe simple CoApatients.(P<0.03)(Table3) (Figure3) ExcludingpatientswithTurnersyndromegavesimilarresults;2.5±2.0mm/5yearsin complex CoA versus1.5±1.9mm/5yearsin simple CoApatients.Progressionratesofascendingaorticdilatation stratifiedbytheassociatedanomalieshavebeendepictedintable4. Ofpatientswithaprogressionrateof4mmper5years,84%werecomplexCoApatients,and65% had BAV, 5 (26%) patients had VSD, 9 (47%) of the patients were hypertensive, 13 (68%) had in increasedlvmassindex,11(58%)ofthepatientswasoperatedaftertheageof1year(laterepair), 14ofthesepatientsunderwentendtoendanastomosisrepair. Inpatientswithaprogressionrate of4mmper5years67%werecomplexcoapatientsand54%hadbav.themeanprogressionrate oftheaorticdiameterovertime,measuredbyechocardiographywas1.4±2.9mm/5years.(table 2)IndividualgrowthintheaorticrootineachpatientisdepictedinFigure2b.Progressionratesof the other segments of the aorta are depicted in Table 2. Regarding intra and inter observer variability,wefoundameanerrormeasurementof3.9%and2.4%respectively. 6 Table 2. Mean Diameter baseline (mm) Range Mean Diameter FU (mm) Range P Value Mean Progression (mm / 5yrs) Echo data CMR data CoA site SE*

9 25 20 SimpleCoA ComplexCoA 15 N Progressionofascendingaorticdilatation (mm/5years) Figure1:Distributionofprogressionratesofascendingaorticdilatationin5years. 2a 2b Figure2a: Figure2b: Progressionofaorticrootdilatationduringfollowup. Progressionofascendingaorticdilatationduringfollowup.

10 Table 3. Simple CoA n = 28 Range Complex CoA n = 65 Range P Value Table 4. 6 Figure3:Progressionofascendingaorticdilatationin5yearsinsimpleversuscomplexcoarctation(CoA) patients.

11 Determinantsforprogressionofascendingaorticdilatationovertime Atfollowup,univartiateanalysisinall93adultpostcoarctectomypatientsshowedthatahistoryof VSDandanincreasedLVmassindexwereassociatedwithanincreasedprogressionrateofascending aorticdilatation.inmultivariateanalysisahistoryofvsdandanincreasedlvmassindexremained statistically significant as determinants for an increased progression rate of ascending aortic dilatation.(table5)adjustingdiametersfordurationoffollowupgavesimilarresults.furthermore adjusting diameters for BSA did not affect the results. No association was found between an increased LV mass index and hypertension. Aortic arch geometry was not associated with an increased progression rate of ascending aortic dilatation. The arterial pulse pressure was not associatedwithascendingaorticdilatationinourpopulation. Table 5. Variable Beta P Value Univariate Beta VSD LV mass index (g/m²) End to end anastomosis Discussion Thecurrentstudy,forthefirsttimequantitativelydemonstratestheincreasedprogressionrateof ascending aortic dilatation in adult postcoarctectomy patients. Complex CoA patients show an increasedprogressionrateofascendingaorticdilatationcomparedtosimplecoapatients. Previousstudieshaveshownthatadultpostcoarctectomypatientsareatincreasedriskfor dilatation in various segments of the thoracic aorta, particularly in the ascending and descending aorta, or at the coarctation site. 8;1012 In our population we found the progression rate of aortic dilatation to be highest in the ascending aorta, with the diameters of the other segments of the thoracicaortatobeconsistentwithnormalvaluesasdescribedbyhageretal. 30;31 Theprogression rate of ascending aortic dilatation measured by CMR was increased in adult postcoartectomy patientswith2.2mmper5years,comparedtoaprogressionrateof0.5mmper5yearsasdescribed inhealthysubjects. 30 Attheleveloftheaorticroot,wefoundaprogressionrateof1.4mminfive years, measured by echocardiography, which is comparable to previously reported echocardiographic data in patients with BAV. 32 Although the progression rate of ascending aortic dilatationinthesepatientsisincreased,innoneofthepatientsaninterventionwasrequiredduring followup.thesefindingsmightindicatethatthattheriskofaorticruptureisdistinctlydifferentas comparedtopatientswithmarfansyndrome. Previous research has shown already that patients with BAV, with or without CoA are specificallypronetodevelopascendingaorticdilatation.thisassociationisofsignificantimportance

12 in our patient group, as 56% was diagnosed with BAV. 8;11;12;15 The cause of the increased rate of ascending aortic dilatation is likely to be multifactorial. Accelerated degeneration of the aortic media,abnormalitiesofmatrixdisruptionandsmoothmusclecelllosshaveallbeendescribedincoa patientsandinpatientswithisolatedbav.additionallyitisknownthatthepresenceofbavmight causeeccentricflowintheascendingaortawithsignificantlyelevatedaorticwallshearstresswhich mightcauseascendingaorticdilatation. 33 Furthermore,apreviousstudybySehestedetal.revealed alreadystructuralabnormaltissue,withsignificantlymorecollagenandlesssmoothmuscletissuein theprecoarctationalwall,includingtheascendingaorta.itishypothesizedthatthisabnormaltissue influencesbaroreceptoractivityintheuppervascularbed,whichmightexplainthepreoperativeand postoperativehypertension. 34 Voghtetal.demonstratedthattheelasticpropertiesoftheascending aorta are primarily impaired in newborns with an aortic coarctation, and remain unchanged after surgery.thesefindingssupporttheassumptionthatthesemorphologicchangesariseinutero. Whethertheseprocessesarecongenitaloracquiredremainsunclear. 9;3539 However,inour study no significant difference was found between progressive ascending aortic dilatation in CoA patientswithbav(coabav)andwithoutbav.furthermorebavwasnotpredictiveforascending aorticdilatationinourcohortwhichisconflictingwithpreviousstudiesasdescribedabove.however, in a previous study in which the progression rate of ascending aortic dilatation was compared betweenbavpatientsandcoabavpatientsdemonstratedthatcoabavpatientswerelessprone for ascending aortic dilatation. It was hypothesized that CoABAV patients, are protected against ascendingaorticdilatation,whichsuggeststhatthepathophysiologyofascendingaorticdilatationin CoABAV patients may differ from that of isolated BAV patients. The main declaration for the protective effect given in this study is that the surgery performed in the CoABAV patients or the relatedhealingprocessmighthavelimitedfurtherdilatation. 15 Thesefindingsmightdeclarethefact thatnosignificantdifferencewasfoundbetweencoabavpatientsandisolatedcoapatients,and additionallythatbavwasnotpredictivefortheprogressionrateofascendingaorticdilatationinour cohort. No association was found with age and an increased progression rate of ascending aortic dilatation. Previous studies have that advancing age increases the risk of aortic dilatation in BAV patients and in normal human hearts. However, no association was found between age and the progressionrateofascendingaorticdilatationinbav,whichcorrespondswithourfindingsandmight berelatedtopopulationsizeandfollowupduration. 15;40 Additionallyaorticvalvediseasewasnot associatedwithaorticdilatationashasbeenpreviouslydescribedinbavpatients. 41;42 Thismightbe declaredbytherelativelyyoungpopulation,oragainbythefactthatthepathofysiologyincoabav isdistinctlydifferentascomparedtoisolatedbavdisease. In this study we found an increased LV mass and a history of VSD to be independently associatedwithprogressiveascendingaorticdilatation.theincreasedlvmasswhichwefoundtobe independentlyassociatedwiththeincreasedprogressionrateofascendingaorticdilatation,inthis studynotrelatedtohypertension,mighthaveamoredevelopmentalorigin. ThelackofcorrelationbetweenhypertensionandLVmassmightbeduetothefactthatwell treatedandcurrentlynothypertensivepatientsaregroupedintothehypertensivegroup.previous research has shown already that LV hypertrophy occurs in coarctation patients in the absence of restenosis or hypertension even in very young patients which suggest that LV hypertrophy might haveamoredevelopmentalorigin. 21;4345 Thesefindings,combinedwiththehigherincidenceofBAV 6

13 andthepresenceofothercardiaccongenitalabnormalitiesincoapatients,supportstheassumption thataorticcoarctationispartofanextensivedevelopmentalabnormalityoftheproximalsystemic arterialsysteminvolvingtheaorticvalve,proximalaorta,leftventricle,andmyocardialwall. ThesefindingspointtowardsavariableexpressioninCoApatients,withthosepatientswitha moreextensivedevelopmentalabnormalitytobeatincreasedriskforprogressiveascendingaortic dilatation.thesefindingsemphasizetheneedforregularcmrimagingforitisthegoldenstandardin CoA patients, with due regard for the clinical history and the presence of associated congenital cardiacanomalies. Limitations Thisstudywaslimitedduetorelativelysmallpatientnumbers,whichisfrequentlyseeninstudiesin adultpatientswithcongenitalheartdisease,aswellasarelativelyshortfollowupperiod.however, includedpatientscomprisedarepresentativegroup,increasingoverallapplicabilityofthepresented data. Conclusion Adultpostcoarctectomypatientsshowanincreasedprogressionrateofascendingaorticdilatation ascomparedtothehealthypopulation.complexcoarctationpatientswithadditionalcardiovascular abnormalities show an increased progression rate of ascending aortic dilatation as compared to simplecoarctationpatients.thesefindingspointtowardsamorecomprehensivegeneticsubsetof patientswithanapparentincreasedriskofascendingaorticaneurysmformation.

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