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, 12 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: 23 Dec 2018

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3 Abstract Background: Postcoarctectomy (CoA) patients have enhanced pulse wave reflection, which is thoughttocontributetocardiovasculardiseaseinthispatientgroup.wecomparedwavereflection in relatively healthy group of CoA patients without hypertension or recoarctation and matched controlsandcomparedwavereflectionresponsestopharmacologicalvasodilation. Methods: In step 1 we measured augmentation index (AIx), a measure of wave reflection, using applanationtonometryin thirtypostcoarctectomy patientswithouthypertensionorrecoarctation (age32±yrs,18males,bloodpressure127±/69±9mmhg)andcontrolsubjects(age33±9yrs, 18males,bloodpressure122±11/69±8mmHg).Instep2weassessedAIxresponsetosalbutamol andntgin7postcoarctectomypatientsandcontrols(bothgroupsage33±9yrs,5males). Results:Step1:AIxwashigherinCoApatientscomparedtocontrols(17±14vs.9±14%,p<0.01).Step 2:themeandecreaseinAIxfrombaselineinresponsetosalbutamolwas5±12vs.3±3%(p=0.54)for CoApatientsversuscontrolsubjectsand24±7%vs.14±7%inresponsetoNTG(p=0.04). Conclusion: In conclusion, CoA patients without hypertension or recoarctation have higher AIx compared to matched controls.the decrease in AIx was similar after salbutamol, but was greater after NTG in CoA patients compared to controls. Although wave reflection is increased in CoA patients,itcanbedecreasedpharmacologically.

4 Introduction Aorticcoarctationisarelativelycommoncongenitalheartdefectcharacterizedbyastenosisinthe aortic arch. Despite successful surgical repair, adult postcoarctectomy (CoA) patients have an increased risk of cardiovascular disease and decreased life expectancy compared to the general population. 14 Intraarterial measurements have shown that blood pressure waves are altered in patientswithaorticcoarctationandthatthechangeinpressurewaveformmaybeexplainedbyearly and thus increased reflection of the pressure waves on the stenosis. 5 In population studies the augmentationindex(aix),ameasureofwavereflection,isapredictorofcardiovasculareventsand mortalityindependentofbloodpressure. 6 CoApatientshaveenhancedwavereflectionevenafter surgical repair and it has been hypothesized that this might contribute to the development of cardiovascular disease in CoA patients. 7 Two recent noninvasive studies assessing AIx using applanationtonometrygaveconflictingresults.inlinewithinvasivedata,szczepaniakandcolleagues foundhigheraixincoapatients, 8 whileswanandcolleaguesfoundnodifference. 9 InCoApatients, enhanced wave reflection is thought to arise from early reflection of pressure waves on the reconstructedandscarredaorta. 7 Thereconstructedprestenoticaortahasindeedbeenshownto have reduced elastic properties, ;11 even when the coarctation is repaired in early childhood. 12 Furthermore the type of surgical intervention and anatomy of the aortic arch may influence local arterial stiffness and increase wave reflection Differences between CoA patients and controls maybecausedbydifferencesinageandbloodpressure,whichcouldactaspossibleconfounders. Moreover,thequestionremainswhetherenhancedpulsewavereflectioninCoApatientsisrelated toanatomicorfunctionalchangesintheproximalaortaandwhetherdifferencesinwavereflection can be influenced by vasoactive substances. In normotensive and hypertensive subjects with a normal structure of the aorta, angiotensin II or noradrenalin induced vasoconstriction causes an increase in AIx, 15 whereas vasodilators, such as nitroprusside and calcium channel blockers lower AIx. 16 Since in CoA patients increased wave reflection might be caused by disturbances in the anatomyandfunctionalpropertiesoftheproximalaorta,itisnotknownwhethervasodilatingdrugs decreasewavereflectiontothesameextentasinpersonswithanormalanatomyoftheaorta. WehypothesizedthatAixisincreasedinCoApatientscomparedtohealthycontrolsandthat pharmacologically induced vasodilation differs between CoA patients and healthy controls. We therefore set out to examine AIx in a relatively healthy subgroup of CoA patients without hypertension or evidence of restenosis and compared to healthy controls. In a subgroup of CoA patientsandcontrolsweexaminedtheeffectofsalbutamolandnitroglycerine(ntg)asameasureof endotheliumdependentandendotheliumindependentvasodilationonaix. Methods Thestudyconsistedoftwoparts.ToassessdifferencesinhemodynamicsbetweenCoApatientsand controls we noninvasively assessed peripheral and central hemodynamics (step 1). We then examineddifferencesinresponsetoendotheliumdependentandindependentvasodilationincoa patients and controls by determining wave reflection and central hemodynamics before and after salbutamol and nitroglycerine (step 2). The study protocols were approved by the medical ethics committeeoftheamsterdammedicalcenterandallparticipantsgaveinformedconsent.

5 Studypopulationanddesign WeusedtheCONgenitalCORvitia(CONCOR)database,theDutchnationalregistryofpatientswith congenital heart disease, to recruit CoA patients from the Academic Medical Center and two participatingtertiaryreferralcenters.controlsubjectswererecruitedviaadvertisementandamong hospital staff. All measurements were conducted in a quiet, temperaturecontrolled room. Participants were asked to visit the research facility after an overnight fast. Measurements were performedinsupinepositioninthemorningaftera15minuterest.allhemodynamicmeasurements wereperformedbyasingleinvestigator(bvdb). Step1In30CoApatientswithouthypertensionandwithoutevidenceofrecoarctation,which wasruledoutbycardiacmagneticresonanceimaging,andin30controlsubjectsmatchedforage and gender, peripheral and central hemodynamics and arterial stiffness were measured. Brachial systolicanddiastolicbloodpressure(sbp,dbp)weremeasured3timesat1minuteintervalsusinga validatedoscillometricdevice(omron5it)withanappropriatelysizedcuff.weusedtheaverage of the last two readings for the calibration of central hemodynamic measurements and further analyses.centralhemodynamicsandpulsewavevelocity(pwv),asameasureofarterialstiffness, wereperformedusingthesphygmocorsystem(atcormedicalptyltd,westryde,australia). 17 By usingapplanationtonometrywithahighfidelitymicromanometer(millarinstruments,texas,usa) peripheral pressure waveforms were recorded from the radial artery of the right arm. Using the brachialbloodpressureforcalibrationandwiththeuseofavalidatedgeneralizedtransferfunctiona corresponding central (aortic) waveform was generated. Central DBP, SBP, mean arterial pressure (MAP),pulsepressure,reflectiontime(Tr)andAIxwerecalculatedbyfurtheranalysisofthecentral waveform.theaixisthedifferencebetweenthesecondandfirstsystolicpeaksdividedbythepulse pressure,andisreportedasapercentageandwascorrectedforheartrateof75beatsperminute. First we tested the validity of the radial to aortic transfer function in CoA patients by measuring radial and carotid artery waveforms in a group of 37 CoA patients with and without hypertension (data not shown). The aortic AIx derived from waveforms at the right radial artery correlated significantly with right carotid artery AIx (r=0.72, p=<0.001). This is similar to previous findingsbysegersandcolleaguesreportingacorrelationof0.75betweenaorticaixderivedfromthe radialarteryandcarotidaixinmiddleagednormotensiveandmildlyhypertensivesubjectsfreefrom cardiovascular disease. 18 Because radial measurements are easier to perform and are more reproducible we decided to calculate aortic waveforms from radial artery measurements. Carotid femoral PWV was assessed using the foottofoot method. Measurements were done in duplicate andmeanswereusedforanalysis. Step 2 In 7 CoA patients and 7 age and gender matched control subjects, wave reflection response to endothelium dependent vasodilation and endothelium independent vasodilation with salbutamolandntgwasdeterminedbyapplanationtonometryoftherightradialarteryasdescribed previously. 19 After calibration with brachial blood pressure, baseline applanation tonometry measurements were performed. Thereafter, 400gsalbutamol (Pharmachemie BV, Haarlem, the Netherlands) was inhaled by the participant under supervision of the investigator. Applanation tonometrymeasurementswererepeatedafter5,,15and20minutes.afteraminuteinterval the next baseline measurement was taken and immediately followed by administration of 400g sublingual nitroglycerine spray (Sandoz BV, Almere, the Netherlands). After 3, 5,, 15 and 20 minutes measurements were repeated. We calculated AIx at baseline and at time of maximum

6 responsetosalbutamolorntg.tofurtherexaminetheeffectofsalbutamolandntgonperipheral andcentralpressurewavesweusedamodelofthearterialsystemtocalculatecentralpressureand flowfromtheperipheralpressurewavesallowingseparationintobackwardandforwardwavesby waveformanalysisasdescribedpreviously. 20;21 Statisticalanalysis Data are presented as mean±standard deviation (SD) for continuous variables and n (%) for categoricalvariables.comparisonsofvariablesbetweengroupsweremadebyunpairedstudent st tests for continuous variables in the step 1 analysis; in the step 2 analysis because of the limited sample size we conservatively used the nonparametric MannWhitney test. Categorical variables were compared by2test. A p value less than 0.05 was considered statistically significant. All statisticalanalyseswereperformedusingspsssoftware(version16.0,chicago,illinois,usa). Results Step1Table1showsbaselineandhemodynamicparametersofCoApatientsandcontrols.Patients andcontrolswerewellmatchedforage,genderandbodymassindex.peripheralsbpanddbpwere not significantly different between CoA patients and controls, although PP tended to be higher in CoA patients, 58±12 vs. 53±9 mm Hg, (p=0.06). AIx was increased in CoA patients compared to controls, 17±14 vs. 9±14 % (p<0.01). There was a trend towards a higher central SBP (±12 vs. 4±11mmHg,p=0.06),whilecentralDBPwassimilar.ThecentralPPwassignificantlyhigherinCoA patients, 40±8 vs. 34±6 mm Hg (p<0.01). PWV did not differ between the two groups, 5.9±0.8 vs. 6.1±1.1m/sforCoApatientscomparedtocontrols(p=0.24). Table 1. Parameter CoA Controls P Value n ± 33 ± 9 Male, n (%) 2 24 ± 3 23 ± ± 122 ± 11 ± 12 4 ± 11 ± 9 ± 9 AIx, % 17 ± 14 9 ± ± 20

7 Step 2 Mean age was 33±9 years for both the CoA patients and controls subjects, both groups consistedof2malesand5females.onesubjectineachgroupusedantihypertensivemedication.at baseline,coapatientshadhighersbpandsimilardbpcomparedtocontrols(125±7/71±4vs.116±6 /68±5mmHg,p=0.02/p=0.33).BaselineAIxvaluesforCoApatientswerehigherbeforesalbutamol (22±16 vs. 2±6 %, p=0.01) and NTG administration (25±13 vs. 2±11 %, p=0.11). The absolute decreaseinaixfrombaselineforsalbutamolwassimilarforcoapatientsandcontrols(5±12vs.3±3 %,p=0.54),whileincoapatientstheabsolutedecreaseinresponsetontgwaslargercomparedto controls(24±7%vs.14±7%,p=0.04).figure1showstheresponseoftheperipheralpressurewaves tosalbutamolandntgadministrationincoapatientsandcontrols.figure2showstheresponseof the central aortic pressure waves. After NTG the decrease in central systolic peak significantly differed between CoA patients and controls with a central SBP decrease of 7.4 mm Hg in CoA patientsand3.0mmhgincontrols(p=0.01),whileperipheralsbpwassimilarbetweencoapatients andcontrolsinresponsetosalbutamolandntg.whenseparatedinforwardandbackwardwaves, thelatesystolicpartoftheforwardwaveandtoalesserdegreethebackwardwavedecreasedafter NTGcomparedtobaselineinbothgroups,butthiseffectwasmoreevidentintheCoAgroupthanin controls.becauseofthecombineddecreaseinforwardandbackwardpressurewaves,theresultant reductioninaix,centralsbpandppwasthereforesignificantlylargerincoapatientscomparedto thanincontrols.

8 A Salbutamol CoA patients B Salbutamol Controls C NTG CoA patients D NTG Controls Figure1.Wavesareameanofthegroup.Radialpulsewavesatbaseline(solidlines)andafteradministration (dottedlines)ofsalbutamol(panelaandb)andntg(panelcandd)incoapatientsandcontrols.

9 A Salbutamol CoA patients B Salbutamol Controls C NTG CoA patients D NTG Controls Figure2.Wavesareameanofthegroup.Aorticpulsewavesatbaseline(solidlines)andafteradministration (dottedlines)ofsalbutamol(panelaandb)andntg(panelcandd)incoapatientsandcontrols.

10 A Forward wave Salbutamol CoA patients Backward wave B Forward wave Salbutamol Controls Backward wave C Forward wave NTG CoA patients Backward wave D Forward wave NTG Controls Backward wave 0 Figure3.Wavesareameanofthegroup.Aorticpulsewavesseparatedinforwardandbackwardwavesat baseline(solidlines)andafteradministration(dottedlines)ofsalbutamol(panelaandb)andntg(panelcand D)inCoApatientsandcontrols.

11 Discussion This study shows that CoA patients without hypertension or recoarctation have an increased AIx comparedtoageandgendermatchedhealthycontrols.coapatientscomparedtocontrolsubjects hadsimilaraixresponsetoendotheliumdependentvasodilationwithsalbutamol,whileendothelium independentvasodilationwithntgcausedagreaterdecreaseinaixandcentralsystolicpressurein CoApatients. Foralongtimeithasbeenrecognizedthatincaseofacoarctationoftheaortathedecrease indiameterandelasticityoftheproximalaortareducesthecushioningfunctionresultinginachange of the pressure wave because of early reflection on the coarctation site. 5 This is supported by a report showing a decrease, but not a complete normalisation, of the AIx after successful balloon dilatation of the aortic stenosis. 22 Previous invasive measurements in CoA patients have demonstrated that wave reflection remains enhanced after successful surgical repair. 7 Important determinants of AIx are age and blood pressure, but even in normotensive CoA patients AIx was higher compared to age matched controls. 8 In comparison with the report by Murakami and colleagues 7, we found a smaller difference in wave reflection between CoA patients and controls despite a higher average age of our study population. However, our patients exhibited no sign of clinicallyrelevantrecoarctationandwerefreeofhypertension,whereasmurakami sstudyconsisted of a more heterogeneous group of CoA patients, two of whom had a pressure gradient over the coarctation site. Also, we used healthy normotensive controls free of cardiovascular disease that were individually matched for age and gender with CoA patients, whereas the control group of Murakami sstudyconsistedofsubjectswhohadcatheterizationforvariouscardiacoraorticdiseases andwereassumedtobenormalcontrols.ourdataofincreasedaixincoapatientsareinlinewith previousintraarterialstudiesandalsowithonenoninvasivestudyusingapplanationtonometry. 8 A second study using applanation tonometry, however, found no difference in AIx between normotensivecoapatientsandcontrolswithsimilarageasinourstudy, 9 butasinourstudytheydid findincreasedcentralpp.furthermore,inthestudyofszczepaniakandcolleaguesaixwasincreased incoapatientswithandwithoutresidualstenosisoftheaorta,suggestingthatthefunctionofthe proximalaortaisimpairedirrespectiveofresidualstenosisoftheaorta. 8 Pressurewavesgeneratedbycontractionoftheleftventricle(forwardwaves)traveldown theaortawithacertainspeed(pulsewavevelocity),wheretheyreflectatpointswherethereisa discontinuity (reflection points) and travel back to the heart (backward waves). Pressure waves measured anywhere in the arterial system are the result of the interaction between forward and backward waves. It has been hypothesized that the increased wave reflection observed in CoA patients is caused by reflection of the forward pressure wave on the reconstructed aorta. 7 Our findingsofanincreasedaixandashorterreflectiontimesupporttheseobservations.ingeneralthe AIxisprincipallydeterminedbyheartrate,aorticstiffnessandreflectionsite. 23;24 Heartratedidnot differbetweencoapatientsandcontrols,andcorrectionforheartratedidnotchangetheobserved differencesbetweenthetwogroups.wefoundnodifferencesincarotidfemoralpwv,amarkerof theglobalaorticstiffness,betweencoapatientsandcontrols.however,thismaynotexcludelocal differencesinaorticdistensibility.previousultrasoundandmagneticresonancestudieshaveshown thattheproximalaortaislessdistensibleevenaftercorrectionofthecoarctation. 25;26 Itisknownthat the pressure wave (and thus PP) arises from the interaction of left ventricular ejection and complianceofthearterialsystem,whichismainlydeterminedbytheaorta. 27 Indeedweandothers

12 haveshownincreasedcentralaorticppincoapatients. 79 BecausetheincreaseinAIxcouldnotbe explainedbydifferencesinheartrateorglobalaorticstiffnessinourstudy,thelossofelasticityin thereconstructedaortaandsubsequentchangesinreflectionsiteisthemostlikelyexplanationfor theobserveddifferencesinwavereflection. In order to assess whether wave reflection can be pharmacologically modified in CoA patientsweusedsalbutamolandntg,whicharethoughttoaffectpulsewaveformsbydecreasing themagnitudeofwavereflectionfromperipheralsitesthroughvasodilation. 19 TheAIxisforalarge partdeterminedbybackwardwavesarisingfromthelowerbody,sothechangeinaixinresponseto salbutamol and NTG would mainly result from dilatation of the postcoarctation vascular bed. At baselineandafterendotheliumdependent(salbutamol)andendotheliumindependentvasodilation (NTG),AIxremainedhigherinCoApatients.Meaningthatthereisanadditionalfactorthatincreases wavereflectionincoapatients.althoughithasbeenshownthatprestenoticarterieshaveabnormal vasodilation,poststenoticarteriesindeedhadnormalvascularresponsetoglyceryltrinitrate. 28 We thereforeconcludethatitislikelythattheincreasedwavereflectionseenincoapatientsispartially caused by factors which cannot be influenced by pharmacologically induced vasodilation, such as anatomicalorfunctionalpropertiesoftheaorticarch. Themeandecreaseinwavereflectionforsalbutamolwascomparablebetweenthegroups. However,NTGreducedwavereflectiontoalargerdegreeinCoApatientsthanincontrolpatients. Our wave separation analysis model showed that not only the backward but also the forward contributes to this. This suggests that in CoA patients reducing preload would effectively reduce wavereflection. Limitations Ourstudywascrosssectionalandhasalltheinherentlimitations.Sincewedidnotmeasureaortic lengthinpatientsorcontrolswecannotexcludethatdifferencesinaorticpathlengthcontributeto the earlywavereflection.because height wassimilarincoapatientsand controls,we considerit unlikely that the small surgically resected part of the aorta could explain the increased wave reflection.furthermoretherewasnoassociationbetweenheightandaixincoapatients(datanot shown),suggestingthatdifferencesinaorticpathlengththatresultfromdifferencesinheightare notanimportantdeterminantofwavereflection.thenumberofcoapatientsandcontrolsinthe salbutamolandntgstudywassmall.wemaythereforehavemissedsmalldifferencesinresponseto vasodilationbetweengroups.thedecreaseinaixforcoapatientsandcontrolsaftersalbutamoland NTGwas,however,comparabletonormotensivehealthycontrolsinapreviousstudy 19. Conclusion WavereflectionisincreasedinnormotensiveCoApatientswithoutrecoarctationcomparedtoage and gender matched controls. The increased AIx observed in CoA patients before and after pharmacologicallyinducedvasodilationgivesfurthersupporttopersistentanatomicalandfunctional disturbances in the aorta as a cause of early wave reflection. We show, however, that wave reflection can be modified pharmacologically by vasodilating drugs and that the effect of NTG on wavereflectionandcentralsystolicpressurewaslargerincoapatientsthanincontrols.

13 Perspectives Increased AIx and central pressures are independent predictors of cardiovascular disease in the population.antihypertensivedrugs,preferablythosewithvasodilatingcapacitiesshouldbeassessed fortheirabilitytoloweraixandcentralpressureincoapatients.ithasnotbeendeterminedthough whether AIx and central pressures longitudinally predict cardiovascular events in CoA patients. Prospectivefollowupstudieswouldneedtobedesignedtoanswerthisquestion.Inthemeantimea firststepwouldbetoassesswhethertheaixorcentralpressuresareassociatedwithorgandamage inthisspecificpatientgroup.

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