Original
article
Diastolic
Function
Is
Impaired
in
Patients
With
Prehypertension:
Data
From
the
EPIPorto
Study
Ricardo
Ladeiras-Lopes,
a,b,c,^,*
Ricardo
Fontes-Carvalho,
a,b,c,^Eduardo
M.
Vilela,
bPaulo
Bettencourt,
c,dAdelino
Leite-Moreira,
a,c,eand
Ana
Azevedo
a,f,gaDepartamentodeCirurgiaeFisiologia,FaculdadedeMedicina,UniversidadedoPorto,Porto,Portugal b
DepartamentodeCardiologia,CentroHospitalardeGaia/Espinho,VilaNovadeGaia,Portugal
c
UnidadedeInvestigac¸a˜oCardiovascular,UniversidadedoPorto,Porto,Portugal
d
DepartamentodeMedicina,FaculdadedeMedicina,UniversidadedoPorto,Porto,Portugal
e
DepartamentodeCirurgiaCardiotora´cica,CentroHospitalarSa˜oJoa˜o,Porto,Portugal
f
DepartamentodeEpidemiologiaClı´nica,MedicinaPreditivaeSau´dePublica,FaculdadedeMedicina,UniversidadedoPorto,Porto,Portugal
gEpidemiologyResearchUnit(EPIUnit)–InstitutodeSau´dePu´blica,UniversidadedoPorto,Porto,Portugal
* Correspondingauthor:DepartamentodeCardiologia,CentroHospitalardeGaia/Espinho,RuaConceicaoFernandes,4434-502VilaNovadeGaia,Portugal. E-mailaddress:ricardoladeiraslopes@gmail.com(R.Ladeiras-Lopes).
^ Bothauthorsequallycontributedtothiswork.
Articlehistory: Received7June2017 Accepted2November2017 Keywords: Prehypertension Hypertension Diastolicfunction ABSTRACT
Introductionandobjectives: Hypertensioncausessubclinicalchangesinleftventricularstructure and function, namely diastolicdysfunction. Diastolic dysfunction is apredictor ofheart failure, being involvedintheassociationbetweenhypertensionandheartfailurewithpreservedejectionfraction.We aimedtodeterminewhetherpatientswithprehypertensionhaveearlychangesindiastolicfunctionina largecommunity-basedcohortofasymptomaticadults.
Methods: A cross-sectional evaluation was performedof a community-based cohort consisting of 925adults,aged45yearsorolder,withoutknowncardiovasculardisease.Allparticipantsunderwent detailedclinicalandechocardiographicexamination.Theparticipantswerecategorizedaccordingtothe Europeanguidelinesfortheclassificationofofficebloodpressure(BP)levelsasoptimal,prehypertensive (normal and high-normal categories), and hypertensive. Diastolic function was evaluated by echocardiography using e’ velocities and E/e’ ratio. Diastolic dysfunction was defined using the 2016ASE/EACVIJointRecommendationsanda2017clinically-orientedalgorithm.
Results: In this cohort (61.5 10.5 years; 37% men), prehypertension was present in 30.4% and hypertensionin51.0%.UsingoptimalBPasthereference,therewasaprogressivedecreaseofe’velocityin prehypertensiveandhypertensiveindividuals(12.23.5vs11.33.1vs9.62.9cm/s,respectively;Pfor trend<.001).Aftermultivariableadjustment,bothBPcategorieswereindependentpredictorsofalowere’ velocity(b=-0.56,P=.035forprehypertensionandb=–1.08,P<.001forhypertension).
Conclusions: In this large community-based cohort, adults with prehypertension already showed impairedcardiacrelaxationbeforetheonsetofhypertension.
C 2017SociedadEspan˜oladeCardiologı´a.PublishedbyElsevierEspan˜a,S.L.U.Allrightsreserved.
La
funcio´n
diasto´lica
se
altera
en
pacientes
con
prehipertensio´n:
datos
del
estudio
EPIPorto
Palabrasclave: Prehipertensio´n Hipertensio´n Funcio´ndiasto´lica RESUMENIntroduccio´nyobjetivos:La hipertensio´ncausacambiossubclı´nicos enlaestructuraylafuncio´ndel ventrı´culo izquierdo, es decir, disfuncio´n diasto´lica. La disfuncio´n diasto´lica es un predictor de insuficienciacardiaca,puesparticipaenlaasociacio´nentrehipertensio´neinsuficienciacardiacacon fraccio´ndeeyeccio´nconservada.Elobjetivoesevaluarenunagrancohortepoblacionaldeadultos asintoma´ticossilospacientesconprehipertensio´ntienencambiosprecocesenlafuncio´ndiasto´lica.
Me´todos: Seevaluo´ de manera transversaluna cohorte poblacionalconsistenteen925adultosde 45an˜ osoma´ssinenfermedadcardiovascularconocida.Todoslosparticipantessesometieronaun examenclı´nicoyecocardiogra´ficodetallado.Seclasifico´ alosparticipantes,segu´nlasguı´aseuropeas paralaclasificacio´ndelapresio´narterial(PA)enlaconsulta,comoo´ptima,prehipertensio´n(normaly normal-alta) ehipertensio´n. La funcio´n diasto´lica se evaluo´ mediante ecocardiografı´a usando las velocidadesde e’ylarazo´nE/e’.Ladisfuncio´ndiasto´licasedefinio´ utilizandolasrecomendaciones conjuntasdeASE/EACVIde2016yunalgoritmodeorientacio´nclı´nicade2017.
http://dx.doi.org/10.1016/j.rec.2017.11.015
INTRODUCTION
Arterialhypertensionisanimportantindependentriskfactor for cardiovasculardisease and thesingle largestcontributor to global mortality.1 In hypertension, subclinical organ damage
representsanintermediatestageinthecardiovascularcontinuum, beingassociated withcardiovascularevents.2 Therefore,current
European guidelines recommend a holistic approach to the hypertensive patient, which includes the assessment of organ damage(cardiac,vascular,renal,andophthalmic)aspartof the diagnosticworkupofthesepatients.3Regardingcardiac involve-ment, hypertension can cause changes in both structure and function,4particularlyleftventricularhypertrophyandimpaired
diastolicfunction.5 Bothhave beenshown tobeindependently
associatedwithmortalityandcardiovascularevents.6
Diastolic dysfunction (DD) is prevalent among the general population,affecting 20%to 30%of individuals7,8and isstrongly
associatedwithaging,9obesity,8insulinresistance,10and
hyperten-sion.11Althoughusuallysubclinical,11DDisanimportantpredictor
ofheartfailure,especiallyofheartfailurewithpreservedejection fraction,12andoflong-termmortality.13Thesefindingssupportthe roleofDDasanintermediatestepbetweenhypertensionandblood pressure(BP).11Theimportanceofassessingdiastolicfunctionin
hypertensionisacknowledgedinrecentrecommendations,which statethatevaluationofdiastolicparametersshouldbeanintegral partoftheechocardiogramofthehypertensivepatient.14However,
therecentlyupdated2016JointGuidelineoftheAmericanSocietyof EchocardiographyandtheEuropeanAssociationofCardiovascular Imaging(‘‘50%rule’’)15has beencriticized duetotheabsenceof
validationdatatosupportitsuseandthepotentialfor underdiag-nosingDD,andnewdiagnosticalgorithmshavebeenproposed.16
Observationalstudieshaveshownthattheriskof cardiovas-culareventsisdirectlyrelatedtosystolicBP (SBP)anddiastolic BP(DBP)values,withaprogressivelyhigherriskforBPlevelsover 115mmHg of SBP and 75mmHg of DBP.17 However, although
hypertension is clearly associated with DD, few studies have assessed whether ‘‘prehypertensive patients’’ (BP 120-139/ 80-89mmHg) already have subclinical impaired diastolic func-tion.18Moreover,fewstudieshaveassessedtheimpactofdifferent
BPparametersondiastolicfunction.19
Inthisstudyweaimedtoassess:a)whetherindividualsinthe prehypertensiverangealreadyhavechangesindiastolicfunction;
andb)theassociationbetweendiastolicfunctionanddifferentBP parameters,suchasSBP,DBP,andpulsepressure(PP).
METHODS
StudySample
This was a cross-sectional study including participants selectedwithinthefirstfollow-upofacohortrepresentativeat baselineoftheadultpopulationofPorto,Portugal—theEPIPorto cohortstudy.From1999to2003thecohortassemblywasmade byrandom-digitdialingusinghouseholdsasthesamplingframe, followedbyrandomselectionof1personaged18yearsorolder ineachhousehold.Refusalswerenotsubstitutedwithinthesame household.Theproportionofparticipationwas70%.Atbaseline, 2485participantswererecruited.BetweenOctober2006andJuly 2008, participants aged 45 years or over were eligible for a systematic evaluation of parameters of cardiac structure and function, which included a cardiovascular clinical history, physical examination,detailed anthropometricevaluation, col-lectionofa fastingbloodsample,anda transthoracic echocar-diogram(Figure1).Among2048cohortmembersintheeligible agerangeat thistime,134(6.5%)haddied,198(9.7%)refused to be re-evaluated, and 580 (28.3%) were lost to follow-up (unreachablebytelephoneorpost).Ofthe1136participantswho underwentcardiacevaluation,weexcludedfromthisstudythose with previous myocardialinfarction, percutaneous or surgical revascularization, priorcardiac surgery or moderate tosevere valvularheartdisease,atrialfibrillation,abnormalleftventricle ejection fraction and symptoms of angina, or heart failure (Figure1).Writteninformedconsentwasobtainedfromallthe individuals and the study was approved by the local ethics committee.
ClinicalVariableDefinitions
Participantswereinstructedtotaketheirusualmedicationand abstain from alcohol, tea, coffee, smoking, and exercise in the 30minutesbeforethemedicalevaluationandBP measurement. SystolicBPwasidentifiedbyphaseIKorotkoffsoundandDBPby phaseV.TwomeasurementsofBPseparatedbyatleast5minutes weretaken,onasingleoccasion,inthesittingposition,withan ERKA 300 sphygmomanometerafter a 10-minute rest,withno tightclothes,ontherightupperarm,andatheartlevel.Themean wasconsideredandwhenthedifferencewaslargerthan5mmHg forsystolicorDBPathirdmeasurementwastakenandthemean ofthe2closestvalues wasregistered.According tothecurrent guidelines,3 participantsweredivided into groups accordingto
their BP levels: ‘‘optimal BP’’ (SBP < 120mmHg and DBP < 80mmHg); ‘‘prehypertension’’ (SBP 120-139mmHg or DBP 80-89mmHg); ‘‘hypertension’’ (SBP 140mmHg or DBP 90mmHgoruseofantihypertensivemedication).
Abbreviations
BP:bloodpressure
DBP:diastolicbloodpressure DD:diastolicdysfunction PP:pulsepressure
SBP:systolicbloodpressure
Resultados: En esta cohorte (61,5 10,5 an˜os; el 37% varones), tenı´a prehipertensio´n el 30,4% e hipertensio´nel51,0%.Seutilizo´ laPAo´ptimacomoreferencia,yseobservo´ unadisminucio´nprogresivadela velocidade’enlosindividuosprehipertensosehipertensos(12,23,5frentea11,33,1frentea9,6 2,9cm/srespectivamente;pdetendencia<0,001).Despue´sdelajustemultivariable,ambascategorı´asdePA fueronpredictorasindependientes deunamenorvelocidad e’(prehipertensio´n,b=–0,56; p=0,035; hipertensio´n,b=–1,08;p<0,001).
Conclusiones: Enestacohortepoblacional,losadultosconprehipertensio´nmostraronunarelajacio´n cardiacaalteradaantesdeliniciodelahipertensio´n.
Diabeteswasdefinedasfastingbloodglucose126mg/dLor thepatient’s self-reportedhistoryofdiabetesoruseofdiabetes medications.
AnalyticalandAnthropometricEvaluation
Afastingvenousbloodsamplewasobtainedin themorning for measurement of glucose, total cholesterol, LDL, HDL, and triglycerides.
Anthropometric measurements were performed after an overnight fast, withthe participant wearing light clothing and no footwear. Bodyweight was measured to thenearest 0.1kg using a digital scale, and height was measured to the nearest centimeterinthestandingpositionusingawallstadiometer.Body mass index was calculated as weight (kg) divided by squared height(m2).Overweightwasdefinedasbodymassindex
25and below30kg/m2,andobesityasbodymassindex30kg/m2.
EchocardiographyData
Allechocardiographic studieswereacquired usingthesame equipment(Hewlett-PackardSonos5500)andimmediatelyafter assessmentofBP.Imageswerestoredonvideotapeforsubsequent offlineanalysisby2experiencedcardiologists,blindedtoclinical data.Cardiacchamber dimensions,volumesandleftventricular massweremeasuredfollowingthestandardrecommendations20
andindexedtobodysurfacearea.Systolicfunctionwasevaluated by ejection fraction calculation using the modified biplane Simpson’srule.Diastolicfunctionwasassessedaccordingtothe 2016 Joint Guidelines on Diastolic Function Evaluation15 with measurement of mitral inflowvelocities (E-wave, A-wave, E/A ratio)andE-wavedecelerationtimeandisovolumetricrelaxation time usingpulsed-wave Dopplerin theapical4-chamberview.
Velocities were recorded at end-expiration and averaged over 3consecutivecardiaccycles.Pulsed-wavetissueDopplervelocities wereacquiredatend-expiration,intheapical4-chamberview,at thelateralsideofthemitralannulus,measuringearlydiastolic(e0)
and late diastolic (a0) velocities and estimating the E/e0 ratio
accordingly.
The main definition of DD used in the study followed the recommendationsinthe2016consensusdocument,15whereDD
wasdefinedifmorethan2ofthefollowingwerepresent:lateral E/e’ratio>13,laterale’velocity<10cm/s,leftatrialmaximum volume index > 34mL/m2, and peak tricuspid regurgitation
velocity>2.8m/s.Diastolicfunctionwasclassifiedasnormalif lessthan2werepresentandindeterminateif2ofthe4conditions werepresent(Figure2).Inaddition,consideringthelimitationsof the2016recommendations,wealsoincludeddatausing2 addi-tional DD definitions: the previous European Association of Cardiovascular Imaging/American Society of Echocardiography (EACVI/ASE) consensus from 200921 and a recently published
clinically-orientedalgorithmtoassessDDandleftventriclefilling pressure(seeFigure2foradetaileddescriptionofthealgorithm).16
StatisticalAnalysis
Continuousvariablesarereportedasmeanstandarddeviation or median [interquartile range]. Discrete variables are given in frequencyandpercentage.ANOVAorthechi-squaredtestwereused totestforsignificantdifferencesbetweendemographicandclinical variablesacrossBPgroups(optimal,prehypertension,hypertension). The Spearman rank correlation was used to assess the relationshipbetweenSBP,DBP,andPPanddiastolicindices.The ‘‘nptrend’’commandinStatawasusedtoperformanonparametric testoftrendfortheranksacrossorderedgroups.
ToassesswhetherthecategoriesofBP wereassociatedwith lateralE’andE/E’ratio,weusedmultivariablelinearregression
analysisincludingage,sex,bodymassindex,presenceofdiabetes, andBPcategoryinthemodel,thelatterasacategoricalvariable with‘‘optimalBP’’asthereferencecategory.Forevaluationofthe association between DD and BP variables, we used Firth-type penalized likelihood logistic regression analysis, to correct for small-sample bias in beta coefficient estimation. McFadden’s R-squared was used to assess the goodness-of-fit of the final regression models. Cases of indeterminate diastolic function (n=134)wereexcludedfromthisanalysis.
Considering the mean e’ velocities in thegroups of interest (optimal BP, prehypertension, and hypertension), assuming a within-groupvarianceof12andthenumberofindividualsineach groupofinterest,wehadapowerofapproximately100%todetect a significant difference in e’ velocities with a type I error probabilitybelow5%.
AllstatisticalanalyseswereconductedusingStata14.0forMac (StataCorp,CollegeStation,Texas,UnitedStates).
RESULTS
Thefinalanalysisincluded925participantswithameanage of 61.5 10.5 years (37%men). The prevalenceof hypertension was 51.0% (472 individuals) and 30.4% (281 individuals) were prehypertensive(normalorhigh-normalBPcategories).Theclinical, anthropometric,analyticalandechocardiographiccharacteristicsof thestudysampleareshowninTable1.Individualswith prehyper-tensionandhypertensionshowedanincreasedleftventricularmass indexandthelatterwasanindependentpredictorofe’velocityand E/e’ratio.Regardingantihypertensivetherapy,22.2%weretakinga renin-angiotensinaxismodifier,5.5%acalciumchannelantagonist and10.4%wereondiuretics.
According to the 2016 ASE/EACVI Joint Recommendations, diastolic function was considered normal in 783 individuals (84.7%),abnormalin8(0.9%)andindeterminatein134(14.5%). However,whenthe2017clinically-orientedalgorithmwasused, theprevalenceofDDwas49.2%:16.2%hadgradeIDD,5.2%had gradeII,and0.3%gradeIIIDD.In254individuals,DDwasgraded asindeterminate.
AssociationBetweenDifferentBloodPressureParameters andDiastolicFunction
SystolicBPvalues correlatedwithdiastolicfunction parame-ters,showinganegativecorrelationwithe’velocity(Spearman’s
r
= –0.3; P < .001) and a positive correlation with E/e’ ratio (Spearman’s
r
= 0.2; P < .001), as detailed in Figure 3. After adjustingforage,sex,bodymassindex,anddiabetes,weobserved that for each 10mmHg increase in SBP there was a 0.2cm/s decreaseine’velocityanda0.1increaseintheE/e’ratio,asdetailed inTable2.SystolicBPwasnotassociatedwithDDusingthemore stringent2016criteria.However,each10mmHgincreaseinSBP wasassociatedwitha20%increaseintheadjustedoddsforDD accordingtothe2017clinically-orientedalgorithm.Asshown in Figure3,there wasalsoan inversecorrelation betweenDBPande’velocity(Spearman’s
r
=–0.1;P=.01),butnot withE/e’ratio(Spearman’sr
=–0.1;P=.23).Inthemultivariable analysis,foreach10mmHgincreaseinDBPweobserveda0.3cm/s decreaseine’velocity,anda30%increaseintheadjustedoddsfor DDaccordingtothe2017algorithm(nosignificantassociationwas foundwhenusingthe2016jointcriteria).PPwasinverselycorrelatedwiththee’velocity(Spearman’s
r
= –0.4; P < .001) and positively correlated with the E/E’ ratio (Spearman’sr
=0.3;P<.001),asdetailedinFigure3.Inthe multi-variableregressionanalyses,PPwassignificantlyassociatedwithE/e’ ratio(each10mmHgincreaseinPPwasassociatedwitha0.2increase intheE/e’ratio)butnotwithe’velocity.PPwasassociatedwithan increasedoddsofDDwhenweusedboththe2016criteria(oddsratio [OR],1.07;P<.001)and2017algorithm(OR,1.01;P=.013).HigherSBPandPPwereassociatedwithanincreaseinleftatrial volumeindexintheunivariateanalyses,butnotDBP.However, afteradjustmentforage,sex,bodymassindexanddiabetes,only PPremainedasignificantpredictorofleftatrialvolumeindex. DiastolicFunctionParametersinDifferentCategoriesofBlood Pressure
WhencomparedwithindividualswithoptimalBP, prehyper-tensive and hypertensive participants showed a progressive
Figure2.Aclassificationschemeforcharacterizationofdiastolicfunctionaccordingtothe2016ASE/EACVIJointRecommendationsand2017clinically-oriented algorithm.ASE/EACVI,AmericanSocietyofEchocardiography/EuropeanAssociationofCardiovascularImaging;LA,leftatrial;LV,leftventricle;TR,tricuspid regurgitation.
deteriorationindiastolicfunctionparameters(Pfortrend<.001). Prehypertension was associated withlower E’ velocity (11.3 3.1cm/svs12.23.5cm/sinindividualswithoptimalBP;P=.003), whichwasevenlowerinthosewithhypertension(9.62.9cm/svs
12.23.5cm/s;P<.001),asdepictedinFigure4.Inthemultivariable analysis,bothprehypertension(
b
=–0.56;P=.035)andhypertension (b
=–1.08;P<.001)wereassociatedwithasignificantdecreaseinthe E’velocity,asdetailedinTable3.Table1
StudyParticipantCharacteristics,AccordingtoBloodPressureLevels
Total (n=925) OptimalBP (n=172) Prehypertension (n=281) Hypertension (n=472) P Age,y 61.510.5 56.510.0 58.79.8 65.09.8 <.001 Malesex 346(37) 41(24) 132(47) 173(37) <.001
Cardiovascularriskfactors
Diabetes 99(11) 6(3) 17(6) 76(16) <.001 Totalcholesterol,mg/dL 220.653.1 222.372.2 220.758.9 220.039.7 .881 LDL-C,mg/dL 134.853.3 139.274.7 136.361.2 132.335.9 .305 HDL-C,mg/dL 61.945.9 67.772.7 62.257.9 59.613.7 .141 Triglycerides,mg/dL 152.8468.1 164.9757.9 166.0601.0 140.678.6 .724 BMI,kg/m2 27.34.6 25.64.3 26.94.6 28.24.5 <.001 SBP,mmHg 132.519.4 109.36.5 127.47.5 144.118.5 <.001 DBP,mmHg 78.411.2 67.16.2 78.38.0 82.611.4 <.001 Pulsepressure,mmHg 52.116.7 41.710.0 47.212.8 58.817.8 <.001 Echocardiographicdata Septum,mm 8.61.4 7.91.1 8.41.2 9.01.5 <.001 Posteriorwall,mm 7.91.2 7.21.0 7.71.1 8.21.3 <.001 LVmassindex,g/m2 78.318.8 70.313.8 75.217.1 83.219.9 <.001 LAvolumeindex,mL/m2 28.2 9.5 26.99.2 27.78.6 29.010.0 .023 LVEDvolumeindex,mL/m2
65.615.9 64.916.0 65.814.8 65.816.5 .800 LVESvolumeindex,mL/m2
26.48.8 26.18.5 26.58.8 26.58.8 .835 Ejectionfraction,% 60.76.1 60.95.7 60.96.3 60.56.0 .594 E-wave,cm/s 71.615.3 73.315.6 71.114.9 71.215.4 .274 A-wave,cm/s 78.219.9 68.919.5 72.516.8 85.019.3 <.001 E/Aratio 0.960.30 1.120.33 1.030.31 0.870.26 <.001 Decelerationtime,ms 236.354.1 226.651.1 228.747.7 244.457.6 <.001 IVRT,ms 91.315.8 87.912.3 91.115.2 92.717.0 .003 BMI,bodymassindex;BP,bloodpressure;DBP,diastolicbloodpressure;HDL-C,high-densitylipoproteincholesterol;IVRT,isovolumicrelaxationtime;LDL-C,low-density lipoproteincholesterol;LA,leftatria;LV,leftventricle;LVED,leftventricleend-diastolic;LVES,leftventricleend-systolic;SBP,systolicbloodpressure.
DataarepresentedasmeanstandarddeviationforcontinuousvariablesandNo.(%)forcategoricalvariables;PvalueforANOVAorchi-squaredtestforsignificantdifferences betweenBPgroups.
Therewasasignificanttrendtowardaprogressiveincreasein theE/e’ratioasBPlevelsincreased(6.42.1foroptimalBP,6.7 2.1forprehypertensionand8.02.9forhypertensiveindividuals; Pfortrend<.001).However,afteradjustmentforage,sex,bodymass index,anddiabetes,onlyhypertensionwassignificantlyassociated withthelateralE/e’ratio(Table3).
Accordingtothe2016JointRecommendations,DDwaspresent in 0.8% of prehypertensive and 1.3% of hypertensive patients (Table 4). Using theless stringent2017algorithm, there wasa progressiveandsignificantincreaseintheprevalenceofDDacross BPcategories, from28% inindividualswithoptimalBP, 39% in prehypertensionand63%inhypertension(Table4).Furthermore, wefoundanincreasingprevalenceoflikelyelevatedleftventricle
fillingpressures(1%,5%,and11%intheoptimal,prehypertensive andhypertensivegroups,respectively).
WefoundnosignificantassociationbetweenBPcategoriesandDD usingthe2016criteria(8casesofDD).Prehypertensionwas signifi-cantlyassociatedwithincreasedoddsofDDintheunivariateanalysis, usingthe2017algorithm(OR,1.68;P=.013),althoughthePvalue wasslightlyhigherthan.05inthemultivariableanalysis(Table3).
DISCUSSION
Inthiscross-sectionalstudyusingacommunity-basedcohortof asymptomaticindividualswithoutknowncardiovasculardisease,
Table2
RegressionAnalysesEvaluatingtheAssociationBetweenSBP,DBPandPPandEchocardiographicDiastolicIndexes(E’Velocity,E/E’Ratio,andPresenceofDiastolic Dysfunction)
Univariableanalysis Multivariableanalysis*
bcoefficient SE P bcoefficient SE P E’velocity SBP(permmHg) –0.049 0.005 <.001 –0.015 0.005 .003 DBP(permmHg) –0.030 0.010 .001 –0.031 0.008 <.001 PP(permmHg) –0.065 0.006 <.001 –0.010 0.006 .126 E/E’ratio SBP(permmHg) 0.032 0.004 <.001 0.013 0.004 .004 DBP(permmHg) 0.009 0.008 .238 0.009 0.007 .225 PP(permmHg) 0.051 0.005 <.001 0.020 0.005 <.001 LAvolumeindex SBP(permmHg) 0.061 0.016 <.001 0.032 0.018 .065 DBP(permmHg) –0.016 0.028 .567 –0.017 0.029 .559 PP(permmHg) 0.124 0.018 <.001 0.094 0.022 <.001
Oddsratio SE P Oddsratio SE P
Diastolicdysfunction
2016jointASE/EACVIrecommendations
SBP(permmHg) 1.05 0.016 .002 1.03 0.017 .108 DBP(permmHg) 0.98 0.032 .447 0.99 0.032 .658 PP(permmHg) 1.08 0.017 <.001 1.07 0.018 <.001 2017clinically-orientedalgorithm SBP(permmHg) 1.03 0.004 <.001 1.02 0.004 <.001 DBP(permmHg) 1.02 0.006 <.001 1.03 0.007 <.001 PP(permmHg) 1.04 0.005 <.001 1.01 0.005 .013
ASE/EACVI,AmericanSocietyofEchocardiography/EuropeanAssociationofCardiovascularImaging;DBP,diastolicbloodpressure;PP,pulsepressure;SBP,systolicblood pressure;SE,standarderror.
Fortheunivariableanalyses,eachbloodpressurevariable(SBP,DBPandPP)isincludedindividuallyinthemodelforpredictionofeachofthediastolicindexes(linear regression)anddiastolicdysfunction(logisticregression).
*Inthemultivariableanalyses,age,sex,bodymassindex,andthepresenceofdiabeteswereincludedinthemodel,inadditiontothebloodpressurevariableassessedin
eachregressionequation.AllmultivariablemodelsshowedMcFadden’sR-squaredbetween0.2and0.4,thereforeprovidinggood-fitmodels.
wefoundacontinuousassociationbetweenthedeteriorationof diastolicfunctionandBPlevels,includingSBP,DBP,andPP.More importantly, we observed that although diastolic function im-pairmentis morepronouncedin hypertensiveindividuals, these changes were already present in prehypertensive individuals, reflectingsubclinicalorgandamageinthispopulation.
ImpairmentofDiastolicFunctioninPrehypertensive Individuals
Thereiscurrentlystrongevidencesupportingacontinuumof cardiovascularriskinfunctionofBPvalues,notexclusivetothe hypertensiverange.11,12,17Thisrelationshipwashighlightedina
meta-analysisof61prospectivestudies,whichshowedastrong rel-ationshipbetweencardiovascularmortalityandBPvalues,downto BPvaluesof115/75mmHg.17Also,previousstudieshaveshown
thatprehypertensiveindividualshavemoretarget-organdamage thannormotensiveindividuals,namelyvasculardamage.22,23
In our study we showed a continuous relationship between increasingdegreesofBP(especiallySBPandDBP)andadeterioration inE’velocity,suggestingimpairedcardiacrelaxation.Thisobservation supportsthenotionthatthesechangesmayreflectthecumulative effectofhypertensiononthemyocardium.6Moreover,weobserved
thatprehypertensiveindividualshadsignificantlylowerE’velocities comparedwithpatientswith‘‘optimalBP’’,showingthatchangesin diastolicfunctionarealreadypresentintheprehypertensivestage. Theseresultsareinagreement witha previouslypublishedstudy basedonananalysisfromtheARICcohort18comprisingasampleof
4871olderindividuals(meanage75years),showingaprogressive impairmentofdiastolicfunctionparametersthroughoutdifferentBP thresholds(fromoptimalBPtohypertension).Althoughtherewere significant differences between the groups in terms of diastolic function parameters(e’ lateral,E/e’lateral) andprevalenceofDD, therewerenodifferencesinsystolicfunctionparameters.
Inourstudy,PPwasassociatedwithahigherE/e’ratioandleft atrial volume index (denoting increased left ventricle filling pressure),andwithincreasedoddsofDD.PPisanindirectindex ofarterialstiffnessandanindependentpredictorofcardiovascular mortality.24 Data from the Framingham Heart Study provide
supportthatinmiddle-agedandelderlyindividuals,PPhasmore prognosticpowerforcardiovasculareventsthanSBPorDBP,25and
identifiesthehighest-riskpatientsfordevelopingheartfailure.26
Increasedarterialstiffnessmightincreaseleftventricle hypertro-phyduetocardiacpressureoverload,thereforecontributingtothe morphologicalandfunctionalchangesinvolvedinthe pathophysi-ologyofDDandelicitsubclinicalcardiacdamage.
Table3
AssociationBetweenBloodPressureCategoriesandDiastolicFunctionParameters
Univariableanalysis Multivariableanalysis*
bcoefficient SE P bcoefficient SE P
E’velocity
Optimal Reference Reference
Prehypertension –0.94 0.30 .002 –0.56 0.27 .035
Hypertension –2.58 0.27 <.001 –1.08 0.26 <.001
E/E’ratio
Optimal Reference Reference
Prehypertension 0.31 0.24 .206 0.24 0.23 .289
Hypertension 1.61 0.22 <.001 0.78 0.23 .001
Oddsratio SE P Oddsratio SE P
Diastolicdysfunction
2016jointASE/EACVIrecommendations
Optimal Reference Reference
Prehypertension 3.25 5.05 .448 2.47 3.88 .566
Hypertension 5.90 8.68 .227 2.42 3.68 .561
2017clinically-orientedalgorithm
Optimal Reference Reference
Prehypertension 1.68 0.35 .013 1.48 0.33 .080
Hypertension 4.31 0.84 <.001 2.47 0.53 <.001
ASE/EACVI,AmericanSocietyofEchocardiography/EuropeanAssociationofCardiovascularImaging;SE,standarderror.
*
Inthemultivariableanalyses,age,sex,bodymassindex,andthepresenceofdiabeteswereincludedinthemodel,inadditiontothebloodpressurecategoriesassessedin eachregressionequation.AllmultivariablemodelsshowedMcFadden’sR-squaredbetween0.2-0.4,thereforeprovidinggood-fitmodels.
Table4
PrevalenceandGradeofDiastolicDysfunctionAcrossBloodPressureCategoriesUsingthe2016JointRecommendationsandthe2017Clinically-orientedAlgorithm
2016ASE/EACVIJointRecommendations 2017Clinically-OrientedAlgorithm Diastolicfunction LVfillingpressures
Normal DD Indeterminate Normal DD Likelynormal Indeterminate Likelyelevated BPcategory
Optimal 165(95.9) 0(0.0) 7(4.1) 124(72.1) 48(27.9) 57(71.2) 22(27.5) 1(1.2) Prehypertension 254(90.4) 2(0.8) 25(8.9) 170(60.5) 111(39.5) 118(70.2) 42(25.0) 8(4.8) Hypertension 364(77.1) 6(1.3) 102(21.6) 176(37.3) 296(62.7) 169(49.6) 132(38.7) 40(11.7) ASE/EACVI,AmericanSocietyofEchocardiography/EuropeanAssociationofCardiovascularImaging;BP,bloodpressure;DD,diastolicdysfunction;LV,leftventricle. DataareexpressedasNo.(%).
Our data corroborate the sensitivity of diastolic function parametersasmarkersofmyocardialsubclinicalorgandamagein thisclinicalsetting.Froma pathophysiologicalstandpoint,several mechanisms might account for the progressive deterioration of cardiacrelaxationandincreased myocardialstiffness27: increased fibrosis,hypophosphorylationoftitin,alteredmyocardial metabo-lism,decreasednitricoxideavailabilityandaproinflammatorymilieu. TheRoleofDiastolicFunctionasaTargetOrgan
inCardiovascularRiskAssessment
The presenceofDD,evenwhensubclinical,is consideredan independentpredictorofcardiovasculareventsandmortality.7For example,in hypertensiveindividualsfromtheASCOTsubstudy, the E/e’ ratio was an independent predictor of cardiovascular events.6Curiously,mostE/e’ratiovalueswerewithinthenormal
range,reflectingthatthisisindeedasensitiveparameter.Evenin hypertensivepatientswithleftventricularhypertrophy,whichis anestablished marker of target organdamage,3 impairment of
diastolicfunctionparametersaddsprognosticinformation, allow-ingabetterassessmentofriskinthispopulation.28
Inourstudy,wedecidedtoinclude2differentcriteriatodefine DD:the2016ASE/EACVIJointRecommendations15andarecently publishedclinically-orientedalgorithm.16Theformerreplacedthe
previousrecommendations for echocardiographic assessment of diastolicfunction.21However,ithasbeenstronglycriticizedbecause itwasnotvalidatedandbecauseits‘‘50%rule’’isverystringent, resulting in a large proportion of patients being included as ‘‘indeterminate’’group(14.5%inourstudy).Indeed,accordingto the2016JointRecommendations,wefoundaprevalenceofDDof 0.9%,markedlydifferentfromthe49.2%usingthe2017algorithm and22.0%usingthepreviousrecommendationsfrom2009(Tableof thesupplementarymaterial).ThisprevalenceofDDisinlinewitha recentlypublishedstudyusingdatafrom1485participantsofthe community-basedSTANISLAScohort(1.3%).29Thesmallnumberof
casesof DD usingthe 2016criteria might account for the lack ofsignificantassociationin themultivariableanalysis bothwith prehypertensionand hypertension.Onthe otherhand,usingthe 2017clinically-orientedalgorithm,hypertensivepatientshada2.47 increasedoddsofDDandprehypertensionwasassociatedwitha 1.48increasedoddsofDD(P=.080).GiventheimportanceofDDin theinterfacebetweenhypertensionandthedevelopmentofBP,4,30
ourfindingsofferapossibleexplanationfortheincreased cardio-vascularriskinprehypertensiveindividuals.31
StrengthsandLimitations
Thestrengthsofthisstudyincludetheassessmentofarelatively largesampleofthegeneralpopulation,withoutothercardiac dis-eases,using contemporary echocardiographic techniques for the assessmentofdiastolicfunction.21Inthisstudy,whichcomprised
individuals45yearsorolder,theprevalenceofhypertensionwas 53.6%,whichis similartothat reported inEuropean individuals aged between 35 and 64 years (44.2%),32 and for Portuguese
individualsbetween35and64years(46.9%).33Diastolicfunction
wasevaluatedaccordingtotherecommendationsoftheconsensus documentoftheEuropeanAssociationofEchocardiographyandthe AmericanSocietyofEchocardiography,21whichrecommendthe
eval-uationofE’velocitiesandE/E’ratiofromtissueDoppler.Inthisstudy, weobservedastrongerassociationbetweenBPparametersandE’ velocity,whichisconsideredanearlyandpreload-independentindex of left ventricular relaxation,28 whereasthe E/E’ ratio is used to
estimateincreasedleftventriclefillingpressures.34
Inthisstudy,mostpatientswerefemale(63%)andweadopted across-sectionaldesign,whichpartiallylimitscommentson caus-ality. Furthermore, among the 2048 cohort memberswithin the
eligible age range, 580 individuals (28%) were unreachable by telephoneorpost.Althoughweexcludedpatientswithclinicalsigns ofcoronaryarterydisease,wedidnotperformanystressteststo excludemyocardialischemia,whichisalsoadeterminantofDD.In theassessmentofdiastolicfunction,wedidnotevaluate intraob-serverorinterobservervariability.However,all4cardiologistshad extensive experience in echocardiography and worked in the sameinstitutionandadetailedprocedureprotocolwasdiscussed betweentheteam,priortothestartofthestudy,toharmonizethe methodologyandthemeasurements.Regardingthelogistic regres-sionmodels,duetothesmallnumberofpositivecasesofDDusing someofthedefinitions,maximumlikelihoodestimationof conven-tionallogisticmodelmaysufferfromsmall-samplebias.Toaddress thisproblem,aswellastheriskofover-adjustmentafterforcing 4variablesinthemultivariablemodel(age,sex,bodymassindex,and diabetes),weusedFirth-typepenalizedlikelihoodlogisticregression analysis.Finally,inthisstudy,allBPmeasurementswereobtained usingofficeBP,andnotwithambulatoryBPmonitoring,whichis currentlythegold-standardmethodrecommendedinhypertension guidelinesandprovidesamoreaccurateapproachtotherelationship between cardiovascular morbidity and mortality thanoffice BP.3
TheuseofambulatoryBPmonitoringwouldpotentiallyresultinthe reclassificationofsomeindividualsinalowerBPcategory.35
CONCLUSIONS
In this large sample of the general population, there wasa continuous relationshipbetween BP levels and deterioration of diastolicfunctionparameters.Changesindiastolicfunctionwere alreadypresentinprehypertensiveindividuals,reflecting myocar-dial subclinical organ damage in this population. Given the prognosticimpactofDDinhypertensivepatients,these observa-tionsreinforcetheimportanceofassessingdiastolicfunctioninthe workupofbothhypertensiveandprehypertensivepatients.
CONFLICTSOFINTEREST
Nonedeclared.
WHATISKNOWNABOUTTHETOPIC?
– Hypertensionisamajorcardiovascularriskfactorthatis associated withstructural andfunctional deleterious cardiac changes, contributing to impaired diastolic function and heart failure with preserved ejection fraction. Few studies have specifically evaluated the associationbetweenprehypertensionandDD, especial-lyconsideringtherecent2016updated recommenda-tionsfortheevaluationofdiastole.
WHATDOESTHISSTUDYADD?
– Usingacommunity-basedcohortfreeofknown cardio-vascular disease, we found a continuous relationship betweenBPlevelsanddeteriorationofdiastolicfunction parameters. Furthermore, prehypertensive individuals seemedtohaveanincreasedoddsofDDusingboththe 2016ASE/EACVIJointRecommendationsanda2017 clin-ically-oriented algorithm. Ourfindingsemphasize the importanceofassessingdiastolicfunctionintheworkup ofbothhypertensiveandprehypertensivepatients
APPENDIXA.SUPPLEMENTARYMATERIAL
Supplementarymaterialassociatedwiththisarticlecan befoundintheonlineversionavailableat:http://dx.doi. org/10.1016/j.rec.2017.11.015.
REFERENCES
1.PoulterNR,PrabhakaranD,CaulfieldM.Hypertension.Lancet.2015;386:801–812.
2.SehestedtT,JeppesenJ,HansenTW,etal.Riskpredictionisimprovedbyadding markersofsubclinicalorgandamagetoSCORE.EurHeartJ.2010;31:883–891.
3.ManciaG,FagardR,NarkiewiczK,etal.2013ESH/ESCPracticeGuidelinesforthe ManagementofArterialHypertension.BloodPress.2014;23:3–16.
4.LipGY,FelmedenDC,Li-Saw-HeeFL,BeeversDG.Hypertensiveheartdisease.A com-plexsyndromeorahypertensive’cardiomyopathy’?EurHeartJ.2000;21:1653–1665.
5.BountioukosM,SchinkelAF,BaxJJ,LampropoulosS,PoldermansD.Theimpactof hypertensiononsystolicanddiastolicleftventricularfunction.AtissueDoppler echocardiographicstudy.AmHeartJ.2006;151:1323.e7-e12.
6.SharpAS,TappRJ,ThomSA,etal.TissueDopplerE/E’ratioisapowerfulpredictorof primarycardiaceventsinahypertensivepopulation:anASCOTsubstudy.EurHeart J.2010;31:747–752.
7.RedfieldMM,JacobsenSJ,BurnettJrJC,MahoneyDW,BaileyKR,RodehefferRJ. Burdenofsystolicanddiastolicventriculardysfunctioninthecommunity: appre-ciatingthescopeoftheheartfailureepidemic.JAMA.2003;289:194–202.
8.Fontes-CarvalhoR,GoncalvesA,SeveroM,etal.Direct,inflammation-mediated andblood-pressure-mediatedeffectsoftotalandabdominaladiposityondiastolic function:EPIPortostudy.IntJCardiol.2015;191:64–70.
9.YousafF,CollertonJ,KingstonA,etal.Prevalenceofleftventriculardysfunctionina UK communitysampleofvery oldpeople: theNewcastle 85+ study.Heart. 2012;98:1418–1423.
10.Fontes-CarvalhoR,Ladeiras-LopesR,BettencourtP,Leite-MoreiraA,AzevedoA. Diastolicdysfunctioninthediabeticcontinuum:associationwithinsulin resis-tance,metabolicsyndromeandtype2diabetes.CardiovascDiabetol.2015;14:4.
11.WanSH,VogelMW,ChenHH.Pre-clinicaldiastolicdysfunction.JAmCollCardiol. 2014;63:407–416.
12.KaneGC,KaronBL,MahoneyDW,etal.Progressionofleftventriculardiastolic dysfunctionandriskofheartfailure.JAMA.2011;306:856–863.
13.MogelvangR,SogaardP,PedersenSA, etal.Cardiacdysfunctionassessedby echocardiographictissueDopplerimagingisanindependentpredictorofmortality inthegeneralpopulation.Circulation.2009;119:2679–2685.
14.MarwickTH,GillebertTC,AurigemmaG,etal.Recommendationsontheuseof echocardiographyinadulthypertension:areportfromtheEuropeanAssociation ofCardiovascularImaging(EACVI)andtheAmericanSocietyofEchocardiography (ASE).EurHeartJCardiovascImaging.2015;16:577–605.
15.NaguehSF,SmisethOA,AppletonCP,etal.RecommendationsfortheEvaluationof LeftVentricularDiastolic FunctionbyEchocardiography:AnUpdatefromthe AmericanSocietyofEchocardiographyandtheEuropeanAssociationof Cardio-vascularImaging.EurHeartJCardiovascImaging.2016;17:1321–1360.
16.MitterSS,ShahSJ,ThomasJD.ATestinContext:E/AandE/e’toAssessDiastolic DysfunctionandLVFillingPressure.JAmCollCardiol.2017;69:1451–1464.
17.LewingtonS,ClarkeR,QizilbashN,PetoR,CollinsR;ProspectiveStudies Collabo-ration.Age-specific relevance ofusualbloodpressureto vascularmortality: ameta-analysisofindividualdataforonemillionadultsin61prospectivestudies. Lancet.2002;360:1903–1913.
18.SantosAB,GuptaDK,BelloNA,etal.PrehypertensionIsAssociatedWith Abnor-malitiesofCardiacStructureandFunctionintheAtherosclerosisRiskin Commu-nitiesStudy.AmJHypertens.2016;29:568–574.
19.PerkiomakiJS, MottonenM,Lumme J,KesaniemiYA,UkkolaO,HuikuriHV. PredictorsofDevelopmentofEchocardiographicLeftVentricularDiastolic Dys-functionintheSubjectsAged40to59Years(fromtheOuluProjectElucidatingRisk ofAtherosclerosisStudy).AmJCardiol.2015;116:1374–1378.
20.LangRM,BadanoLP,Mor-AviV,etal.Recommendationsforcardiacchamber quantification byechocardiographyinadults:anupdatefrom the American SocietyofEchocardiography andthe EuropeanAssociation ofCardiovascular Imaging.EurHeartJCardiovascImaging.2015;16:233–270.
21.NaguehSF,AppletonCP,GillebertTC,etal.Recommendationsfortheevaluationof left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10:165–193.
22.IkramMK,WittemanJC,VingerlingJR,BretelerMM,HofmanA,DeJongPT.Retinal vesseldiametersandriskofhypertension:theRotterdamStudy.Hypertension. 2006;47:189–194.
23.TenekeciogluE,YilmazM,YontarOC,etal.Microalbuminuriainuntreated pre-hypertensionandhypertensionwithoutdiabetes.IntJClinExpMed.2014;7:3420– 3429.
24.Benetos A, RudnichiA, Safar M, GuizeL. Pulse pressureand cardiovascular mortality innormotensiveand hypertensivesubjects. Hypertension. 1998;32: 560–564.
25.FranklinSS,KhanSA,WongND,LarsonMG,LevyD.Ispulsepressureuseful inpredicting riskfor coronary heartDisease? TheFraminghamheart study. Circulation.1999;100:354–360.
26.HaiderAW,LarsonMG,FranklinSS,LevyD,FraminghamHeartS.Systolicblood pressure,diastolicbloodpressure,andpulsepressureaspredictorsofriskfor congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003;138:10–16.
27.MesserliFH,RimoldiSF,BangaloreS.TheTransitionFromHypertensiontoHeart Failure:ContemporaryUpdate.JACCHeartFail.2017;5:543–551.
28.WangM,YipGW,WangAY,etal.TissueDopplerimagingprovidesincremental prognosticvalueinpatientswith systemichypertensionand leftventricular hypertrophy.JHypertens.2005;23:183–191.
29.HuttinO,FraserAG,CoiroS,etal.ImpactofChangesinConsensusDiagnostic RecommendationsontheEchocardiographicPrevalenceofDiastolicDysfunction.J AmCollCardiol.2017;69:3119–3121.
30.VermaA,SolomonSD.Diastolicdysfunctionasalinkbetweenhypertensionand heartfailure.MedClinNorthAm.2009;93:647–664.
31.GuoX,ZhangX,GuoL,etal.Associationbetweenpre-hypertensionand cardio-vascularoutcomes:asystematicreviewandmeta-analysisofprospectivestudies. CurrHypertensRep.2013;15:703–716.
32.Wolf-MaierK,CooperRS,BanegasJR,etal.Hypertensionprevalenceandblood pressurelevelsin6Europeancountries,Canada,andtheUnitedStates.JAMA. 2003;289:2363–2369.
33.PoloniaJ,MartinsL,PintoF,NazareJ.Prevalence,awareness,treatmentandcontrol ofhypertensionandsaltintakeinPortugal:changesoveradecade.ThePHYSA study.JHypertens.2014;32:1211–1221.
34.OmmenSR,NishimuraRA,AppletonCP,etal.ClinicalutilityofDoppler echocar-diographyandtissueDopplerimagingintheestimationofleftventricularfilling pressures:AcomparativesimultaneousDoppler-catheterizationstudy.Circulation. 2000;102:1788–1794.
35.GorostidiM,SobrinoJ,SeguraJ,etal.Ambulatorybloodpressuremonitoringin hypertensivepatientswithhighcardiovascularrisk:across-sectionalanalysisofa 20,000-patientdatabaseinSpain.JHypertens.2007;25:977–984.
