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9788375993011TableofContentsTreatmentofhypertensioninpatientswithtype2diabetesmellitus
PeterM.Nilsson,RenataCfkov,SverreE.
Kjeldsen.....................................................................................................1Hypertensioninpregnancy:
recommendationsfordiagnosisandtreatmentRenata
Cfkov..............................................................................................................................................................
3HowwellishypertensioncontrolledinEurope?Serap
Erdine..................................................................................................................................................................
5HypertensioninchronicrenalfailureJoseL.Rodicio,JoseM.
Alcazar.....................................................................................................................................7Howto
handlerenovascularhypertension?JoseM.Alcazar,JoseL.
Rodicio.....................................................................................................................................9Isolated
systolichypertension:cardiovascularriskandtreatmentbenefitsCsabaFarsang,Peter
Sleight.......................................................................................................................................11Patient
adherenceandpharmacologicaltreatmentofarterialhypertensionMennoPruijm,MariePauleSchneider,
MichelBurnier................................................................................................13Cyclosporininduced
hypertensionRenataCfkov,Hermann
Haller..................................................................................................................................15Hypertension
andleftventricularhypertrophyEnricoAgabitiRosei,MariaLorenza
Muiesan..............................................................................................................17Assessmentofpreclinical
targetorgandamageinhypertension:carotidintimamediathicknessandplaqueEnricoAgabitiRosei,
MariaLorenzaMuiesan..............................................................................................................19Home
bloodpressuremonitoringGianfrancoParati,GrzegorzBilo,SverreE.Kjeldsen,Giuseppe
Mancia.......................................................................21HypertensioninchildrenandadolescentsEmpar
Lurbe...............................................................................................................................................................
23HypertensionandcoronaryheartdiseaseJeanPhilippeBaguet,GillesBaroneRochette,JeanMichel
Mallion.............................................................................25ResistanthypertensionSerapErdine,Eren
Arslan,AntonioCoca.....................................................................................................................27
Microalbuminuriaintype1diabetesmellitusJosepRedon,JoseLuis
Rodicio....................................................................................................................................29Interactions
betweenantihypertensiveagentsandotherdrugsPeterA.vanZwieten,SandorAlfoldi,Csaba
Farsang..................................................................................................31Beneficialcombinationsoftwoor
moreantihypertensiveagentsPeterA.vanZwieten,SandorAlfoldi,Csaba
Farsang..................................................................................................33Theclinicalvalueofambulatory
bloodpressuremonitoringJeanMichelMallion,JeanPhilippeBaguet,GianfrancoParati,Giuseppe
Mancia........................................................35Highbloodpressure,smokingandcardiovascularriskHelios
PardellJosL.Rodicio,DagmaraHering,AnnaSzyndler,Krzysztof
Narkiewicz.............................................37TreatmentofhypertensionindialysedpatientsIstvnKiss,
CsabaFarsang,JoseL.Rodicio..................................................................................................................39
Highbloodpressure,alcohol,andcardiovascularriskRamonEstruch,AntonioCoca,JosL.
Rodicio............................................................................................................43Exerciseandhypertension
AthanasiosJ.Manolis,AndreasPittaras,CostasTsioufis,Peter
Kokkinos....................................................................45HypertensionandarrhythmiaJeanPhilippe
Baguet,SerapErdine,JeanMichelMallion............................................................................................47
HypertensionandobstructivesleepapnoeaJeanPhilippeBaguet,KrzysztofNarkiewicz,JeanLouisPpin,
PatrickLevy,RenaudTamisier,AnneLaureBorel,GianfrancoParati,JeanMichel
Mallion..........................................................................................49Controlofhypertensioninpatients
withperipheralarterydiseaseDenisL.
Clement.........................................................................................................................................................51
Preventionoftype2diabetesmellituswithantihypertensivedrugsPeterM.Nilsson,RenataCfkov,
SverreE.Kjeldsen,GiuseppeMancia.......................................................................53Treatmentof
hypertensiveurgenciesandemergenciesEnricoAgabitiRosei,MassimoSalvetti,Csaba
Farsang...............................................................................................55Treatmentofhighbloodpressurein
theelderlySverreE.Kjeldsen,AudE.Stenehjem,IngridOs,ThomasHedner,GordonT.
McInnes................................................57HypertensionandheartfailureEnricoAgabitiRosei,Maria
LorenzaMuiesan,WolfangKiowski..................................................................................59Hypertension
andmacrovasculardiseaseStphane
Laurent........................................................................................................................................................61
SexualdysfunctioninhypertensionAthanasiosJ.Manolis,MichaelDoumas,MargusViigimaa,Krzysztof
Narkiewicz.......................................................63Discoveringthegeneticdeterminantsofhypertension
SandoshPadmanabhan,OlleMelander,ClaireHastie,AnnaF.
Dominiczak................................................................65Themicrocirculationandthehaemodynamicsof
hypertensionHarryA.J.StruijkerBoudier,EnricoAgabiti
Rosei........................................................................................................67StatinsandhypertensionRenata
Cfkov,PeterM.Nilsson.................................................................................................................................
69MicroalbuminuriainessentialhypertensionJosepRedon,FernandoMartinez,JoseM.
Pascual......................................................................................................71HypertensioninathletesRobert
H.Fagard.........................................................................................................................................................
73MetabolicsyndromeinhypertensionJosep
Redon................................................................................................................................................................
75HypertensionandstrokeCristinaSierra,Antonio
Coca......................................................................................................................................77Dietary
sodiumintakeandhypertensionMichelBurnier,MurielleBochud,Roland
Schmieder...................................................................................................79Hypertensiveretinopathy
RolandE.
Schmieder...................................................................................................................................................81
Hypertensionandatrialfibrillation,withanemphasisonpreventionSverreE.Kjeldsen,TonjeA.Aksnes,
RolandE.Schmieder...........................................................................................83Managementof
pheochromocytomaparagangliomaMaurizioCastellano,JacquesW.Lenders,PierreFrancoisPlouin,
EnricoAgabitiRosei................................................85PrimaryaldosteronismFrancoMantero,GianPaolo
Rossi,EnricoAgabitiRosei..............................................................................................87Subclinical
braindamageandhypertensionChristopheTzourio,PeterM.Nilsson,AngeloScuteri,Stphane
Laurent....................................................................89HypertensionandsleepJeanLouisPpin,Anne
LaureBorel,JeanPhillipeBaguet,RenaudTamisier,PatrickLvy,JeanMichel
Mallion................................................................................................................................91Perioperative
screeningandmanagementofhypertensivepatientsAthanasiosJ.Manolis,SerapErdine,ClaudioBorghi,
KostasTsioufis..........................................................................93Cardiovascularriskprofileand
antihypertensivetreatmentMichaelHechtOlsen,EvaPrescott,PeterM.Nilsson,Renata
Cfkov..........................................................................95Theroleofuricacidinhypertension,
cardiovascularevents,andchronickidneydiseaseupdateAdelE.
Berbari............................................................................................................................................................
97HypertensionandaorticdiseaseJeanPhilippeBaguet,OlivierChavanon,CarmineSessa,Frdric
Thony,PierreLantelme,GillesBaroneRochette,JeanMichel
Mallion...............................................................................................................99IntroductionThe
EuropeanSocietyofHypertensionhasonaregularbasisissuedScientificNewsletters:Updateon
HypertensionManagementwithinformationonthelatestnewsandresearch.Fortyninenewsletterswere
publishedbetween2000and2010.Theyhaveprovidedimportantinsightsintothediagnosticsandthe
managementofhypertensionandotherassociateddiseases,andgeneratedsubstantialinterestwithinthe
medicalcommunity.Overthepast10years,theESHnewslettersweredistributedassinglepage
documentsduringourannualmeetings.Furthermore,theywereavailableinPDFformatontheESHPortal.
Intheinterestofnotonlypreserving,butofindexingandmakingthemmoreaccessibleforthe
hypertensioncommunity,wehavedecidedtoreviseallpreviousissuesandcollatethemwithnewmaterial
from2011intoonesinglevolume.WebelievethatthispublicationwillbecomplementarytootherESH
educationalmaterial,suchastheEuropeanGuidelinesontheManagementofHypertension,numerous
positionstatements,andtheESHManualofHypertension.Hopefully,eachofyouwillfindthisnew
volumeofmaterialtobeusefulinyourclinicalpractice.Sincerely,SverreE.KjeldsenKrzysztof
NarkiewiczESHNewsletterEditor20002005ESHNewsletterEditor200520111TREATMENTOF
HYPERTENSIONINPATIENTSWITHTYPE2DIABETESMELLITUSPeterM.Nilsson1,Renata
Cfkov2,3,4,SverreE.Kjeldsen51DepartmentofClinicalSciences,LundUniversity,University
Hospital,Malm,Sweden2CentreforCardiovascularPrevention,ThomayerUniversityHospitaland
CharlesUniversityMedicalSchoolI,3DepartmentofMedicineII,CharlesUniversityMedicalSchoolI,4
DepartmentofPreventiveCardiology,InstituteforClinicalandExperimentalMedicine;Prague,Czech
Republic5DepartmentofCardiology,UllevaalUniversityHospital,Oslo,NorwayEuropeanSocietyof
HypertensionScientificNewsletter:UpdateonHypertensionManagement2011;12:No.1Rrevised
versionIntroductionHypertensionindiabetesisoneofthemostwidespread,important,andtreatable
cardiovascularriskfactorsinclinicalpractice.Datafromrandomisedtrialshaveshownthebenefitsof
improvedbloodpressurecontrolinpatientswithtype2diabetes[1],butthebloodpressuregoalisstillnot
wellestablishedduetolackofevidence.Recentinternationalandnationalguidelinesandrecommendations
haveemphasisedthescreening,evaluation,andvigoroustreatmentofelevatedbloodpressure(BP)if
combinedwithdiabetes[24],especiallysystolicBP.Epidemiologicaldataindicatesomeimprovingtrends
inbloodpressurecontrol,reflectingincreasedawarenessandmoreappropriatetreatmentovertime[5].
RandomisedclinicaltrialsincludinghypertensivepatientswithdiabetesSeveralinterventiontrialshave
formedtheevidencebasefortreatmentofhypertensionindiabetes.IntheSystolicHypertensioninthe
ElderlyProgram(SHEP),lowdose,diureticbasedtreatment(chlorthalidone)wasfoundtobeeffective
comparedwithplaceboinpreventingCVcomplicationsinelderlypatientswithtype2diabetesmellitus
andisolatedsystolichypertension[6].Similarly,theSystolicHypertensioninEurope(SystEur)trial
comparedcalciumantagonistbasedtreatment(nitrendipine)withplaceboinelderlypatientswithisolated
systolichypertensionandinasubgroupwithtype2diabetes(n=492).InSystEur,treatmentforfiveyears
prevented178majorCVeventsinevery1000diabeticpatientstreated[7],i.e.approximately6patientshad
tobetreatedforfiveyearstopreventonemajorCVevent.TheHypertensionOptimalTreatmentStudy
(HOT)[8]investigatedtheintensityofantihypertensivetreatmentusingacalciumantagonist(felodipine)
asbaselinetherapyinhypertensivepatientsaveraging62yearsofageand170/105mmHginbaselineBP,
including1501patientswithtype2diabetes.InHOT[8]theincidenceofmajorCVeventswaslowered(p
=0.005)from24.4to18.6and11.9events/100patientyears,respectively,intherandomisedtertilesof
diabetespatientswhohadachieved85,83,and81mmHg,respectively,indiastolicBP.Approximately20
patientsneededtobetreatedfor5yearstopreventonemajorCVeventwhenBPwasfurtherloweredfrom
84to81mmHginthesepatients.TightBPcontroltopreventmacroandmicrovascularcomplicationswas
alsosuccessfulaftermorethan8yearsoffollowupof1148hypertensivepatientsintheUnitedKingdom
ProspectiveDiabetesStudy(UKPDS),especiallyforpreventionofstrokeandretinopathy[9].However,no
significanteffectdifferencewasfoundbetweencaptoprilandatenolol[10],butpatientsonatenololneeded
significantlymoreoralantiglycaemicdrugsduetoweightincrease.TheCaptoprilPreventionProject
(CAPPP)[11]comparedtheeffectsofanACEinhibitorwithdiuretic/bblockertreatmentinmiddleaged
hypertensivepatientsofwhom572hadtype2diabetesatbaseline;therewerefewerCVeventson
captopril,and(asinHOPE)fewerhypertensivepatientsdevelopedtype2diabetesonACEinhibitor
comparedtostandardtherapy.IntheSwedishTrialinOldPatientswithHypertension2(STOP2)study
allpatientswereabovetheageof70years,andasmanyas719ofthemhadtype2diabetesatbaseline;
however,CVmortalitywasthesameonstandardtherapy,ACEinhibition,orcalciumantagonisttreatment
[12].Inaddition,nearlynormotensivesubjectswithdiabetesmaysometimesbenefitfromtheuseofdrugs
withbloodpressureloweringproperties.TheresultsoftheHeartOutcomesPreventionEvaluation(HOPE)
StudyandtheMicroalbuminuria,Cardiovascular,andRenalOutcomes(MICRO)HOPEsubstudy[13]
showedthattreatmentwiththeangiotensinconvertingenzyme(ACE)inhibitorramipril,comparedwith
placebo,significantlyloweredtheriskofcardiovascular(CV)events(by25%)andovertnephropathyin
peoplewithtype2diabeteswithapreviousCVeventoratleastoneotherCVriskfactor,including56%
withahistoryofhypertension.Uncontrolleddiabetichypertensives(BP>160/90mmHg)were,however,
notrandomised.HOPEwasnotahypertensiontrial,butgivesastrongargumentinfavourofblockadeof
thereninangiotensinsysteminCVriskpatientswithdiabetes.IntheLosartanInterventionForEndpoint
reduction(LIFE)trial[14]asubgroupof1195patientswithdiabetes,hypertension,andsignsofleft
ventricularhypertrophy(LVH)onelectrocardiogramswererandomisedtoeitherlosartanbasedoratenolol
basedtreatment.Mortalityfromallcauseswas63and104inthelosartanandatenololgroups,respectively;
RR0.61(0.450.84),p=0.002.IntheAntihypertensiveandLipidLoweringTreatmenttoPreventHeart
AttackTrial(ALLHAT)[15]asubgroupof12,063patients(36%)withdiabeteswererandomisedto
treatmentwithchlorothalidone,amlodipine,orlisinopril.Therewerenodifferencesintheprimary
compositeCVoutcomebetweenthesethreedrugs,usedinaveryheterogenousstudypopulation.Asimilar
resultofequitybetweentreatmentarmsfortheprimarycompositeCVendpointwasfoundinthe
NifedipineGITSStudy:InterventionasaGoalinHypertensionTreatment(INSIGHT)basedonasub
analysisof1302patientswithhypertensionanddiabetesrandomisedtoeithernifedipineslowreleaseor
conventionaltherapy[16].TheAngloScandinavianCardiacOutcomeTrial(ASCOT)hasshown
substantialbenefitsinpatientsrandomisedtoatreatmentbasedonamlodipine,withperindoprilasaddon
therapyifneeded,versusatenolbasedtreatment,withthiazideasaddontherapyifneeded,forthe
reductionofstrokeandtotalmortality[17].TheASCOTstudywasstoppedprematurelybecauseofthe
differenceinallcausemortality,indicatingthebenefitsofanamlodipinebasedtreatmentincomparisonto
olderdrugalternativesafter5.5yearsmedianfollowup.Thoughnotsignificant,comparedwiththe
atenololbasedregimen,fewerindividualsontheamlodipinebasedregimenhadaprimaryendpoint(429
vs.474;unadjustedHR0.90,95%CI0.791.02,p=0.1052),fatalandnonfatalstroke(327vs.422;0.77,
0.660.89,p=0.0003),totalcardiovasculareventsandprocedures(1362vs.1602;0.84,0.780.90,p<
0.0001),andallcausemortality(738vs.820;0.89,0.810.99,p=0.025).Patientswithdiabeteshadthe
samebenefitsofthistreatmentasnondiabetics,withnoheterogeneitybetweensubgroups[17].Inthe
ADVANCEtrialitwasshownthattheadditionofacombinationofperindoprilandindapamidetopatients
onantihypertensivetreatmentwasassociatedwithsubstantialclinicalbenefits,comparedwithplacebo
treatment[18].Therelativeriskofamajormacrovascularormicrovasculareventwasreducedby9%(861
[15.5%]activevs.938[16.8%]placebo;hazardratio0.91,95%CI0.831.00,p=0.04).Theseparate
reductionsinmacrovascularandmicrovasculareventsweresimilarbutwerenotindependentlysignificant.
Therelativeriskofdeathfromcardiovasculardiseasewasreducedby18%(211[3.8%]activevs.257
[4.6%]placebo;0.82,0.680.98,p=0.03),anddeathfromanycausewasreducedby14%(408[7.3%]
activevs.471[8.5%]placebo;0.86,0.750.98,p=0.03).Theactivelytreatedgrouphadameansystolic
bloodpressureundertreatmentof135mmHg.2IntheACCOMPLISHtrial(60%patientswithdiabetes)it
wasshownthatthefixedcombinationofbenazaprilandamlodipineresultedinarelativeriskreductionof
cardiovasculareventscomparedtothefixedcombinationofbenazaprilandhydrochlorothiazide[19].
Finally,intheActiontoControlCardiovascularRiskinDiabetesBloodPressure(ACCORDBP)studya
totalof4733participantswithtype2diabeteswererandomlyassignedtointensivetherapytargetinga
systolicpressureoflessthan120mmHg,orstandardtherapytargetingasystolicpressureoflessthan140
mmHg[20].Theprimarycompositeoutcomewasnonfatalmyocardialinfarction,nonfatalstroke,ordeath
fromcardiovascularcauses.Themeanfollowupwas4.7years.After1year,themeansystolicblood
pressurewas119.3mmHgintheintensivetherapygroupand133.5mmHginthestandardtherapy
group.Theannualrateoftheprimaryoutcomewas1.87%intheintensivetherapygroupand2.09%inthe
standardtherapygroup(hazardratiowithintensivetherapy,0.88;95%confidenceinterval[CI],0.73to
1.06;p=0.20).Theannualratesofdeathfromanycausewere1.28%and1.19%inthetwogroups,
respectively(hazardratio,1.07;95%CI0.85to1.35;p=0.55).Theannualratesofstroke,aprespecified
secondaryoutcome,were0.32%and0.53%inthetwogroups,respectively(hazardratio,0.59;95%CI,
0.39to0.89;p=0.01).Seriousadverseeventsattributedtoantihypertensivetreatmentoccurredmoreoften
intheintensivetherapygroup(3.3%)thaninthestandardtherapygroup(1.3%)(p<0.001).Thus,in
patientswithtype2diabetesathighriskofcardiovascularevents,targetingasystolicbloodpressureofless
than120mmHg,ascomparedwithlessthan140mmHg,didnotreducetherateofacompositeoutcome
ofmajorcardiovascularevents.Recentobservationalstudiessupporttheviewthatanachievedsystolic
bloodpressurelevelbelow130mmHgisofbenefitforstrokepreventionbutnotforreductionof
cardiovascularevents[21,22].SummaryThegeneralconsensusforthetreatmentofhypertensionintype2
diabetesisnowtoaimforawellcontrolledSBPof130139mmHgand,ifpossible,closertothelower
valuesinthisrange,buttheexactBPgoalhasnotbeenfullyestablished[4].Suchastrategyisusually
basedonpolypharmacywithsynergisticdrugcombinations.Thisshouldbepartofanoverallriskfactor
control,alsoaddressingsmoking,dyslipidaemia,microalbuminuria,andhyperglycaemiatooptimisethe
control[23].TreatmentwithanRASblockingagenthasbeenshowntobeeffectiveinpreventingmacro
andmicrovasculareventsinhighriskdiabeticswithcontrolledhypertension.Conclusions1.Patientswith
type2diabetesshouldbetreatedforhypertensionwhenBPisabove140and/or90mmHg,aimingata
systolicBPwellbelowthisthresholdbutnotbelow120mmHg.2.Thesepatientsusuallyneedtwoor
moredrugs/combinationtherapytoreachtheBPtarget,especiallyforsystolicBP.3.ThoughACE
inhibitorshavebeenproventobecardiovascularprotectiveandsomeangiotensinIIreceptorblockers
nephroprotective,thereisnoconsensusonthedrugofchoiceforallhypertensivetype2diabeticpatients.
4.Moststudiessupportthenotionthatbloodpressurereductionperseismoreimportantthanindividual
propertiesofspecificdrugsinmostcases.5.Blockadeofthereninangiotensinsystemseemstobean
appropriatechoiceasoneofthepartnerdrugsinofferingcombinationtherapytohypertensivepatientswith
diabetesorglucoseintolerance.6.Itisrecommendedthattrendsbefollowedinthequalityofhealthcare
forpatientswithhypertensionanddiabetes,forexamplebylocal,regional,ornationalregisters.References
1.ZanchettiA,RuilopeLM.Antihypertensivetreatmentinpatientswithtype2diabetesmellitus:what
guidancefromrecentcontrolledrandomizedtrials?JHypertens2002;20:20992110.2.ChobanianAV,
BakrisGL,BlackHR,etal.;andtheNationalHighBloodPressureEducationProgramCoordinating
Committee.TheSeventhReportoftheJointNationalCommitteeonPrevention,Detection,Evaluation,and
TreatmentofHighBloodPressure.TheJNC7Report.JAMA2003;289:25602571.3.WilliamsB,
PoulterNR,BrownMJ,etal.Guidelinesformanagementofhypertension:reportofthefourthworking
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2158.5.NilssonPM,GudbjrnsdottirS,EliassonB,CederholmJ;fortheSteeringCommitteeofthe
NationalDiabetesRegister,Sweden.Hypertensionindiabetestrendsincontrolandrelationto
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CurbJD,PresselSL,CutlerJA,etal.Effectofdiureticbasedantihypertensivetreatmentofcardiovascular
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withdiabetesandsystolichypertension.NEnglJMed1999;340:677684.8.HanssonL,ZanchettiA,
CarruthersSG,etal.Effectsofintensivebloodpressureloweringandlowdoseaspirininpatientswith
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antihypertensivetreatmentsinpreventingcardiovasculareventsinelderlydiabeticpatients:resultsfromthe
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18:16711675.13.HeartOutcomesPreventionEvaluation(HOPE)StudyInvestigators.Effectsoframipril
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angiotensinconvertingenzymeinhibitororcalciumchannelblockervs.diuretic.TheAntihypertensiveand
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HypertensionScientificNewsletter:UpdateonHypertensionManagement3HYPERTENSIONIN
PREGNANCY:RECOMMENDATIONSFORDIAGNOSISANDTREATMENTRenataCfkov1,2,31
CentreforCardiovascularPrevention,ThomayerUniversityHospitalandCharlesUniversityMedical
SchoolI,2DepartmentofMedicineII,CharlesUniversityMedicalSchoolI,3DepartmentofPreventive
Cardiology,InstituteforClinicalandExperimentalMedicine;Prague,CzechRepublic2011;12:No.2R
revisedversionHypertensivedisordersinpregnancyremainamajorcauseofmaternal,foetal,andneonatal
morbidityandmortalitynotonlyinlessdeveloped,butalsoinindustrializedcountries.Pregnantwomen
withhypertensionareathigherriskofseverecomplicationssuchasabruptioplacentae,cerebrovascular
accident,organfailure,anddisseminatedintravascularcoagulation.Thefoetusisatriskofintrauterine
growthretardation,prematurity,andintrauterinedeath.Physiologically,bloodpressure(BP)fallsinthe
secondtrimester(ameandecreaseof610mmHginmeanarterialpressure).Inthethirdtrimester,it
returnstoprepregnancylevels.Thisfluctuationoccursinbothnormotensiveandchronicallyhypertensive
women.DefinitionofhypertensioninpregnancyThedefinitionofhypertensioninpregnancypreviously
includedanelevationinBPduringthesecondtrimesterfromabaselinereadinginthefirsttrimester,orto
prepregnancylevels,butadefinitionbasedonabsolutebloodpressurevalues(systolicbloodpressure
140mmHgordiastolicbloodpressure90mmHg)isnowpreferred.BloodpressuremeasurementItis
essentialtoconfirmhighBPreadingsontwooccasions,usingmercurysphygmomanometryinthesitting
positionasthegoldstandard.KorotkoffPhaseVisnowrecommendedformeasurementofDBPin
pregnancy.OnlyvalidatedmeasuringdevicesandvalidatedambulatoryBPmonitoring(ABPM)devices
shouldbeusedinpregnancy(see:www.dableducational.org).Classificationofhypertensioninpregnancy
Hypertensioninpregnancyisnotasingleentitybutcomprises:preexistinghypertension,which
complicates15%ofpregnanciesandisdefinedasBP140/90mmHgthateitherpredatespregnancyor
developsbefore20weeksofgestation.Hypertensionusuallypersistsmorethan42dayspostpartum.It
maybeassociatedwithproteinuria;gestationalhypertension,whichispregnancyinducedhypertension
withorwithoutproteinuria.Gestationalhypertensionassociatedwithsignificantproteinuria(>300mg/lor
>500mg/24hordipstick2+ormore)isknownaspreeclampsia.Hypertensiondevelopsafter20weeksof
gestation.Inmostcases,itresolveswithin42dayspostpartum.Gestationalhypertensionischaracterized
bypoororganperfusion;preexistinghypertensionplussuperimposedgestationalhypertensionwith
proteinuria.PreexistinghypertensionisassociTable1.Basiclaboratoryinvestigationsrecommendedfor
monitoringpatientswithhypertensioninpregnancyHaemoglobulinandhaematocritHaemoconcentration
supportsdiagnosisofgestationalhypertensionwithorwithoutproteinuria.Itindicatesseverity.Levelsmay
belowinveryseverecasesbecauseofhaemolysisPlateletcountLowlevels<100,000109/Lmay
suggestconsumptioninthemicrovasculature.Levelscorrespondtoseverityandarepredictiveofrecovery
rateinpostpartumperiod,especiallyforwomenwithHELLPsyndrome*SerumAST,ALTElevated
levelssuggesthepaticinvolvement.IncreasinglevelssuggestworseningseveritySerumLDHElevated
levelsareassociatedwithhaemolysisandhepaticinvolvement.Mayreflectseverityandmaypredict
potentialforrecoverypostpartum,especiallyforwomenwithHELLPsyndrome*Proteinuria(24hurine
collection)Standardtoquantifyproteinuria.If>2g/day,veryclosemonitoringiswarranted.If>3g/day,
deliveryshouldbeconsideredUrinalysisDipsticktestforproteinuriahassignificantfalsepositiveand
falsenegativerates.Ifdipstickresultsarepositive(1),24hurinecollectionisneededtoconfirm
proteinuria.Negativedipstickresultsdonotruleoutproteinuria,especiallyifDBP90mmHgSerumuric
acidElevatedlevelsaidindifferentialdiagnosisofpreeclampsiaandmayreflectseveritySerumcreatinine
Levelsdropinpregnancy.Elevatedlevelssuggestincreasingseverityofhypertension;assessmentof24h
creatinineclearancemaybenecessary*HELLPHaemolysis,ElevatedLiverenzymelevels,andLow
PlateletcountatedwithfurtherworseningofBPandproteinexcretion3g/dayin24hoururinecollection
after20weeksgestation;itcorrespondstochronichypertensionwithsuperimposedpreeclampsiain
previousterminology;antenatallyunclassifiablehypertensionhypertensionwithorwithoutsystemic
manifestation,ifBPwasfirstrecordedafter20weeksofgestation.Reassessmentisnecessaryatorafter
42dayspostpartum.Ifhypertensionisresolvedbythen,theconditionshouldbereclassifiedasgestational
hypertensionwithorwithoutproteinuria.Ifthehypertensionisnotresolvedbythen,theconditionshould
bereclassifiedaspreexistinghypertension.Oedemaoccursinupto60%ofnormalpregnanciesandisno
longerusedinthediagnosisofpreeclampsia.RecommendedlaboratoryinvestigationsHypertensive
disordersinpregnancy,particularlygestationalhypertensionwithorwithoutproteinuria,mayinduce
changesinthehaematologic,renal,andhepaticprofiles,whichmayadverselyaffectprognosisandboth
neonatalandmaternaloutcomes.Basiclaboratoryinvestigationsrecommendedformonitoringpatients
withhypertensioninpregnancyarepresentedinTable1.Themajorityofwomenwithpreexisting
hypertensioninpregnancyhavemildtomoderatehypertension(140179/90109mmHg),andareatlow
riskofcardiovascularcomplicationswithintheshorttimeframeofpregnancy.Womenwithessential
hypertensionandnormalrenalfunctionhavegoodmaternalandneonatalprognosis;theyarecandidatesfor
nonpharmacologicaltherapybecausethereisnoevidencethatdrugtreatmentresultsinimprovedneonatal
outcome.Withantihypertensivetreatment,thereseemstobeonlylessriskofdevelopingsevere
hypertension.NonpharmacologicalmanagementandpreventionofhypertensioninpregnancyNon
pharmacologicalmanagementshouldbeconsideredforpregnantwomenwithSPBof140150mmHgor
DBPof9099mmHgorboth,measuredinaclinicalsetting.Ashorttermhospitalstaymayberequired
fordiagnosisandforrulingoutseveregestationalhypertension(preeclampsia),inwhichtheonlyeffective
treatmentisdelivery.Management,dependingonBP,gestationalage,andpresenceofassociatedmaternal
andfoetalriskfactorsincludesclosesupervision,limitationofactivities,andsomebedrestintheleft
lateralposition.Aregulardietwithoutsaltrestrictionisadvisedassaltrestrictionmayinducelow
intravascularvolume.Preventiveinterventionsaimed4atreducingtheincidenceofgestational
hypertension,especiallypreeclampsia,includingcalciumsupplementation(2g/d),fishoilandnutrient
supplementation,andlowdoseacetylsalicylicacidtherapy,havefailedtoproduceconsistentlythebenefits
initiallyexpected,especiallyinthefoetus.Calciumsupplementationofatleast1g/dduringpregnancy
almosthalvedtheriskofpreeclampsiawithoutcausinganyharm.Theeffectwasgreatestforhighrisk
women.However,theevidenceforaddedcalciuminthepreventionofhypertensivedisordersis
conflicting.Lowdoseaspirinis,however,usedprophylacticallyinwomenwhohaveahistoryofearly
onset(<28weeks)preeclampsia.Increasedenergyintakeisnotbeneficialinthepreventionofgestational
hypertension.AlthoughweightreductionmaybehelpfulinreducingBPinnonpregnantwomen,itisnot
recommendedduringpregnancyinobesewomen.Weightreductioncanbeassociatedwithreduced
neonatalweightandlowersubsequentgrowthininfantsofdietingobesemothers.Thevalueofcontinued
administrationofantihypertensivedrugstopregnantwomenwithchronichypertensioncontinuestobean
areaofdebate.Whilethereisaconsensusthatdrugtreatmentofseverehypertensioninpregnancyis
requiredandbeneficial,treatmentoflessseverehypertensioniscontroversial.Althoughitmightbe
beneficialforthemotherwithhypertensiontoreduceherBP,lowerBPmayimpairuteroplacental
perfusionandtherebyjeopardizefoetaldevelopment.Muchoftheuncertaintyaboutthebenefitsof
loweringBPinpregnantwomenwithmildpreexistinghypertensionstemsfrompublishedtrialsthatare
toosmalltodetectamodestreductioninobstetricalcomplications.Pharmacologicalmanagementof
hypertensioninpregnancyWhilethegoaloftreatinghypertensionistoreducematernalrisk,theagents
selectedmustbeefficaciousandsafeforthefoetus.SBP170orDBP110mmHginapregnantwoman
shouldbeconsideredanemergency,andhospitalizationisabsolutelyessential.Pharmacologicaltreatment
withintravenouslabetalolororalmethyldopaornifedipineshouldbeinitiated.Intravenoushydralazine
shouldnolongerbethoughtofasthedrugofchoiceasitsuseisassociatedwithmoreperinataladverse
effectsthanotherdrugs.Otherwise,thethresholdsatwhichtostartantihypertensivetreatmentare:SBPof
140mmHgorDBPof90mmHginwomenwithgestationalhypertension(withorwithoutproteinuria),
preexistinghypertensionbefore28weeksofgestationorwiththesuperimpositionofgestational
hypertensionorwithhypertensionandsubclinicalorgandamageorsymptomsatanytimeduring
pregnancy.ThethresholdsinothercircumstancesareSBPof150mmHgandDBPof95mmHg.Fornon
severehypertensionmethyldopa,labetalol,calciumantagonists,andbetablockersarethedrugsofchoice.
Betablockersappeartobelesseffectivethancalciumantagonists.Calciumchannelblockersare
consideredtobesafeiftheyarenotgivenconcomitantlywithmagnesiumsulphate(riskofhypotensiondue
topotentialsynergism).ACEinhibitors,angiotensinIIantagonists,anddirectrenininhibitorsarestrictly
contraindicatedinpregnancy.Theplasmavolumeisreducedinpreeclampsia;diuretictherapyistherefore
inappropriateunlessthereisoliguria.Magnesiumsulphateintravenouslyisrecommendedforthe
preventionofeclampsiaandthetreatmentofseizures.Womenwithpreexistinghypertensionareadvised
tocontinuetheircurrentmedicationexceptforACEinhibitors,angiotensinIIantagonists,anddirectrenin
inhibitors.InwomenwithpreexistinghypertensionwithDBP100mmHg(lowerwhenendorgan
damageorunderlyingrenaldiseaseispresent)andinwomenwithacutehypertension(DBP105mm
Hg),methyldopa,labetalol,orcalciumchannelblockersarerecommended(seeTable2).Delivery
inductionInductionofdeliveryisappropriateingestationalhypertensionwithproteinuriaandadverse
conditionssuchasvisualdisturbances,coagulationabnormalities,orfoetaldistress.Hypertensionand
lactationBreastfeedingdoesnotincreaseBPinthenursingmother.Bromocryptin,whichisusedto
suppresslactation,mayinducehypertension.Allantihypertensiveagentstakenbythenursingmotherare
excretedintobreastmilk.Mostoftheantihypertensivedrugsarepresentatverylowconcentrations,except
forpropranololandnifedipine,theconcentrationsofwhichinbreastmilkaresimilartothoseinmaternal
plasma.LongtermcardiovascularconsequencesinpregnancyinducedhypertensionWomenwith
gestationalhypertensionorpreeclampsiaareatincreasedriskofhypertensionandstrokeinlateradultlife
aswellasofischaemicheartdisease.Hypertensivedisordersinpregnancyhavebeennewlyrecognizedas
animportantriskfactorforCVDinwomen.Therefore,lifestylemodifications,regularBPcontrol,and
controlofmetabolicfactorsarerecommendedafterdeliverytoavoidcomplicationsinsubsequent
pregnanciesandtoreducematernalcardiovascularriskinthefuture.Table2.Antihypertensivedrugsin
pregnancyCentralalphaagonistsMethyldopaisthedrugofchoicebblockersAtenololandmetoprolol
appeartobesafeandeffectiveinlatepregnancyAlpha/bblockersLabetalolhascomparableefficacywith
methyldopa;inthecaseofseverehypertensionitcouldbegivenintravenouslyCalciumchannelblockers
OralnifedipineorIVisradipinecouldbegiveninhypertensiveemergencies.Potentialsynergismwith
magnesiumsulphatemayinducehypotensionACEinhibitors,angiotensinIIFoetalabnormalitiesincluding
deathcanbecaused,andthesedrugsarecontraindicatedinpregnancyantagonists,directrenininhibitors
DiureticsDiureticsarerecommendedforchronichypertensionifprescribedbeforegestationorifpatients
appeartobesaltsensitive.TheyarenotrecommendedinpreeclampsiaDirectvasodilatorsHydralazineis
nolongertheparenteraldrugofchoicebecauseofitsperinataladverseeffectsReferences1.TheTask
ForcefortheManagementofArterialHypertensionoftheEuropeanSocietyofHypertension(ESH)andof
theEuropeanSocietyofCardiology(ESC).2007GuidelinesfortheManagementofArterialHypertension.
JHypertens2007;25:11051187.2.TheJointNationalCommitteeonPrevention,Detection,Evaluation
andTreatmentofHighBloodPressure.ThesixthreportoftheJointNationalCommitteeonPrevention,
Detection,EvaluationandTreatmentofHighBloodPressure.ArchInternMed1997;157:24132446.3.
HelewaME,BurrowsRF,SmithJ,etal.ReportoftheCanadianHypertensionSocietyConsensus
Conference:1.Definitions,evaluationandclassificationofhypertensivedisordersinpregnancy.CanMed
Assoc1997;157:715725.4.MoutquinJM,GarnerPR,BurrowsRF,etal.ReportoftheCanadian
HypertensionSocietyConsensusConference:2.Nonpharmacologicmanagementandpreventionof
hypertensivedisordersinpregnancy.CanMedAssoc1997;157:907919.5.ReyE,LeLorierJ,BurgessE,
etal.ReportoftheCanadianHypertensionSocietyConsensusConference:3.Pharmacologictreatmentof
hypertensivedisordersinpregnancy.CanMedAssoc1997;157:12451254.6.ConsensusReport:
NationalHighBloodPressureEducationProgramWorkingGroupReportonHighBloodPressurein
Pregnancy.AmJObstetGynecol1990;163:16891712.7.PodymowT,AugustP.Antihypertensivedrugs
inpregnancy.SeminNephrol2011;31:7085.8.ConsensusStatement:Managementofhypertensionin
pregnancy.Executivesummary.MedicalJAustral1993;158:700702.9.LevineRJ,EwellMG,Hauth
JC,etal.Shouldthedefinitionofpreeclampsiaincludeariseindiastolicbloodpressureof>90mmHgin
associationwithproteinuria?AmJObstetGynecol2000;183:787792.10.SibaiBM,MabieWC,Shamsa
F,VilnarMA,AndersonGD.Acomparisonofnomedicationversusmethyldopaorlabetalolinchronic
hypertensionduringpregnancy.AmJObstetGynecol1990;162:960967.11.GruppodiStudio
IpertensioneinGravidanza.Nifedipineversusexpectantmanagementinmildtomoderatehypertensionin
pregnancy.BrJObstetGynaecol1998;105:718722.12.HofmeyrGJ,AtallahAN,DuleyL.Calcium
supplementationduringpregnancyforpreventinghypertensivedisordersandrelatedproblems.Cochrane
DatabaseSystRev2006;3:CD001059.13.OlsenS,OsterdalML,SalvigJD,etal.Durationofpregnancy
inrelationtofishoilsupplementationandhabitualfishintake:arandomisedclinicaltrialwithfishoil.Eur
JClinNutr2007;61:976985.14.DuleyL,HendersonSmartDJ,MeherS,KingJF.Antiplateletagents
forpreventingpreeclampsiaanditscomplications.CochraneDatabaseSystRev2007;2:CD004659.15.
MageeLA,ChamC,WatermanEJ,OhlssonA,vonDadelszenP.Hydralazinefortreatmentofsevere
hypertensioninpregnancy:metaanalysis.BMJ2003;327:955960.16.deSwietM.Maternalblood
pressureandbirthweight.Lancet2000;355:8182.17.vonDadelszenP,OrnsteinMP,BullSB,etal.Fall
inmeanarterialpressureandfetalgrowthrestrictioninpregnancyhypertension:ametaanalysis.Lancet
2000;355:8792.18.NationalHighBloodPressureEducationProgramWorkingGroupReportonHigh
BloodPressureinPregnancy.NIHPublicationNo.003029;originallyprinted1990;revisedJuly2000.19.
DekkerG,SibaiB.Primary,secondary,andtertiarypreventionofpreeclampsia.Lancet2001;357:209
215.20.MageeLA,OrnsteinMP,vonDadelszenP.Fortnightlyreview:managementofhypertensionin
pregnancy.BMJ1999;318:13321336.21.TheMagpieTrialCollaborativeGroup.Dowomenwithpre
eclampsia,andtheirbabies,benefitfrommagnesiumsulphate?TheMagpieTrial:arandomisedplacebo
controlledtrial.Lancet2002;359:18771890.22.SteegersEA,vonDadelszenP,DuvekotJJ,PijneborgR.
Preeclampsia.Lancet2010;376:631644.23.WilsonBJ,WatsonMS,PrescottGJ,etal.Hypertensive
diseasesofpregnancyandriskofhypertensionandstrokeinlaterlife:resultsfromcohortstudy.BMJ
2003;326:845.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management5HOWWELLISHYPERTENSIONCONTROLLEDINEUROPE?SerapErdine
CerrahpasaMedicalFaculty,CardiologyDepartment,Istanbul,Turkey2011;12:No.3revisedversion
IntroductionDespiteincreasedawarenessoftheimportanceofloweringbloodpressuretovaluesbelow
140/90mmHg,theoutcomesofachievingthistargetremaindisappointing[14].Theruleofhalves,
coinedintheUnitedStatesduringthe1960s,seemsstilltobevalidtodescribetheobservationthatonly
halfofthosewithhypertensionwereawareofit;andofthosewhowereaware,onlyhalfwerereceiving
treatment;andofthathalfreceivingtreatment,onlyhalfhadtheirhypertensioncontrolled[5].Arecent
reviewondifferencesinprevalence,awareness,treatment,andcontrolofhypertensionbetweendeveloping
anddevelopedcountiessupportedtherueofhalves[6]andshowedthattherewerenosignificant
differencesbetweendevelopedanddevelopingcountriesregardingtheprevalence,awareness,treatment,
andcontrolofhypertension,exceptforahigherprevalenceamongmenindevelopedcountries.Evenin
randomizedcontrolledtrials,wherepatientmotivationandphysicianexpertiseareensured,ithasbeen
difficulttoachieveoptimalbloodpressuredespiteasignificantdifferenceintheobservedresponserates
[7].ResultsofsurveysTheNationalHealthandNutritionExaminationSurvey19992004database
indicatesthatthebloodpressurecontrolrateinhypertensivesubjectsintheUnitedStateswas29.22.3%
in19992000and36.82.3%in20032004[8].InCanada,only15.8%hadbloodpressuretreated,and
controlled.Higherratesoftreatmentandcontrolwereobservedamongolderadults,thosewithtype2
diabetes,andthosewithapreviousmyocardialinfarction[9].Thesituationisnobetterintherestofthe
worldandvariesconsiderablybetweencountriesandregions(Figure1)[3,4].Hypertensioncontrolrates
alsovarywithincountriesbyage,gender,race/ethnicity,socioeconomicstatus,education,andqualityof
healthcareandareparticularlylowinsomeeconomicallydevelopingcountries[3,4].Several
epidemiologicalsurveysinEuropeancountriesinvolvingrandomsampleseithersociodemographically
representativeofthetotaladultpopulationorselectedduringclinicalvisitsalsoshowthatalthoughthe
improvementovertheyearshasbeenencouraging,patientswithwellcontrolledbloodpressure,attaining
targetbloodpressuregoalsof<140/90mmHg,representasmallfractionofthehypertensivepopulation
(Figure2)[3,1016].IntheadultEnglishpopulation,theratesofawarenessandtreatmenthaveincreased
since1994,andcontrolratesamonghypertensivemenandwomenhaveapproximatelydoubledto21.5%
and22.8%,respectively[10].RecentdatafromtheCzechRepubliconcardiovascularmortalityandblood
pressurelevels,prevalence,awareness,treatment,andcontrolofhypertensionfrom1985to2007/2008
indicateanimprovementinbloodFigure2.Percentageofpatientswhoreachthebloodpressuregoal(<
140/90mmHg)inEurope[916]Figure1.Percentageofpatientswithcontrolledbloodpressure(<140/90
mmHg)indifferentcountriesaroundtheworld[34]pressurecontrolfrom3.9to24.6%overthesame
period[11].Arterialhypertensionrepresentsaseriousmedical,social,andeconomicprobleminPoland,
andtheNATPOLPLUSstudycarriedoutintheyear2002hasshownthattheoverallcontrolrateis12%,
andthecontrolrateintreatedhypertensivesis21%[16].Datafromnationalsurveysonhypertension
treatmentandcontrolinEuropehavedemonstratedthatageadjustedcontrolratesintreatedhypertensive
patientsaged3564yearswere21%forSweden,28%forItaly,and30%forGermany[12].Inamulti
centre,crosssectionalstudyofthepopulationgreaterthan60yearsofageinSpanishprimarycarecentres
amonghypertensivesubjects,35.7%hadtheirbloodpressureundercontrol[13].TheHypertensionStudy
inGeneralPracticeinHellas(Hypertenshell),acrosssectionalstudyforassessingtheprevalence,levelof
awareness,treatment,andcontrolofhypertensioninGreece,hasdemonstratedthat32.8%weretreatedand
controlled(men33.3%,women32.3%)[14].Apopulationbasedcrosssectionalepidemiologysurvey
carriedoutin2003inTurkeyshowedthatsubjectswhowereawareoftheirconditionandtreatedhada
controlratioof20.7%[17].RecentdataaboutTurkeyfromtheobservationalTRES1Studyshowedthat
bloodpressurecontrolwasimprovedafterphysicianeducationonESHguidelinesfrom26.5%to55.1%(p
<0.001)andcontrolwaspoorerwhenthebaselinebloodpressurevalueswerehigher[18].TheBPCARE
StudyderiveddataabouthypertensivepatientsfromEasternEuropeancountries(Albania,Belarus,Bosnia,
theCzechRepublic,Latvia,Romania,Serbia,Slovakia,andUkraine),showingthatalthough87%of
patientswereundercombinationtherapy,bloodpressurecontrolwas27.1%.Bloodpressurecontrolwas
foundtobevariableamongdifferentcountries,worseforsystolicthanfordiastolicbloodpressure,slightly
betterinpatientsfollowedbyspecialiststhanbygeneralpractitioners,unrelatedtopatientage,and
unsatisfactoryinhighriskhypertensivesandinpatientswithcoronaryheartdisease,stroke,orrenalfailure
[19].Inthetreatedhypertensivepopulation,thenumberofpatientswithinadequatebloodpressurecontrol
hasbeenfoundtobehighnotonlywhenmeasuredintheclinic,butalsowhenassessedbyambulatory
bloodpressuremonitoringorhomemeasurement(Table1)[20,21].Inadequatebloodpressurecontrol
amongpatientsreceivingtreatmentforhypertensionindicatesalackofsatisfactorybloodpressurecontrol
withantihypertensivedrugtherapyandisnotareflectionofthewhitecoateffect[20,21].6Table1.
Percentageoftreatedhypertensivepatientswithsatisfactorybloodpressurecontrol[17,18]DBPSBPSBP
andDBPcontrolledcontrolledcontrolled<140/90mmHg(clinic)17.5%12.6%8.9%<120/85mmHg
(24hour)26.5%16.4%15.4%ConclusionsThehighbloodpressurereadingscommonlyfoundintreated
hypertensiveindividualsrevealthatinadequatebloodpressurecontrolisaglobalproblemandcannotbe
solelyascribedtoalackofaccesstomedicalcareorpoorcompliancewiththerapy.Achievingblood
pressurecontrolremainsadauntingchallengegiventhepositiveandcontinuousrelationshipbetween
levelsofbloodpressure,bothsystolicanddiastolic,andtheriskofcardiovasculardisease[22].Much
remainstobelearnedtounderstandtheobstaclesforadequatebloodpressurecontrolinthepopulation,and
effortsneedtobeintensifiedtoimproveBPcontrolrates.References1.GuidelinesCommittee.2003
EuropeanSocietyofHypertensionEuropeanSocietyofCardiologyguidelinesforthemanagementof
arterialhypertension.JHypertens2003;21:10111053.2.ChobanianAV,BakrisGL,BlackHR,etal.
TheSeventhReportoftheJointNationalCommitteeonPrevention,Detection,Evaluation,andTreatment
ofHighBloodPressure:theJNC7report.JAMA2003;289:25602572.3.ErdineS,AranSN.Current
statusofhypertensioncontrolaroundtheworld.ClinExpHypertens2004;26:731738.4.KearneyP,
WheltonM,ReynoldsK,etal.Worldwideprevalenceofhypertension:asystematicreview.JHypertens
2004;22:1119.5.MarquesVidalP,TuomilehtoJ.Hypertensionawareness,treatmentandcontrolinthe
community:istheruleofhalvesstillvalid?JHumHypertens1997;11:213220.6.PereiraM,LunetN,
AzevedoA,BarrosH.Differencesinprevalence,awareness,treatmentandcontrolofhypertensionbetween
developinganddevelopedcountries.JHypertens2009;27:963975.7.ManciaG,GrassiG.Systolicand
diastolicbloodpressurecontrolinantihypertensivedrugtrials.JHypertens2002;20:14611464.8.Ong
KL,CheungBM,ManYB,etal.Prevalence,awareness,treatment,andcontrolofhypertensionamong
UnitedStatesadults19992004.Hypertension2007;49:6975.9.PetrellaRJ,MerikleEP,JonesJ.
Prevalence,treatment,andcontrolofhypertensioninprimarycare:gaps,trends,andopportunities.JClin
Hypertens(Greenwich)2007;9:2835.10.PrimatestaP,PoulterNR.Improvementinhypertension
managementinEngland:resultsfromtheHealthSurveyforEngland2003.JHypertens2006;24:1187
1192.11.CifkovaR,SkodovaZ,BruthansJ,etal.Longitudinaltrendsincardiovascularmortalityand
bloodpressurelevels,prevalence,awareness,treatment,andcontrolofhypertensionintheCzech
populationfrom1985to2007/2008.JHypertens2010;28:21962203.12.WolfMaierK,CooperRS,
KramerH,etal.HypertensiontreatmentandcontrolinfiveEuropeancountries,CanadaandtheUnited
States.Hypertension2004;43:1017.13.RedonJ,CeaCalvoL,LozanoJV,etal.Differencesinblood
pressurecontrolandstrokemortalityacrossSpain:thePrevenciondeRiesgodeIctus(PREVICTUS)
study.Hypertension2007;49:799805.14.EfstratopoulosAD,VoyakiSM,BaltasAA,etal.Prevalence,
awareness,treatmentandcontrolofhypertensioninHellas,Greece:theHypertensionStudyinGeneral
PracticeinHellas(HYPERTENSHELL)nationalstudy.AmJHypertens2006;19:5360.15.AmarJ,
ChamontinB,GenesN,etal.Whyishypertensionsofrequentlyuncontrolledinsecondaryprevention?J
Hypertens2003;21:11991205.16.ZdrojewskiT,SzpakowskiP,BandoszP,etal.Arterialhypertension
inPolandin2002.JHumHypertens2004;18:557562.17.AltunB,AriciM,NergizogluG,etal.
Prevalence,Awareness,TreatmentandControlofHypertensioninTurkey(PatenT)in2003.JHypertens
2005;23:18171823.18.ErdineS,ArslanE,SenocakM,etal.ImpactofPhysicianEducationonBlood
PressureControlinthePrimaryCareSetting:ResultsFromTres1Study:6C.06JHypertens2010;28:
e240.19.GrassiG,CifkovaR,LaurentS,etal.Bloodpressurecontrolandcardiovascularriskprofilein
hypertensivepatientsfromcentralandeasternEuropeancountries:resultsoftheBPCAREstudy.Eur
HeartJ2011;32:218225.20.SegaR,CesanaG,ValagussaF,ManciaG,ZanchettiA.Ambulatoryblood
pressurenormality:resultsfromthePAMELAStudy.AnnExperClinMed1995;2:2526.21.ManciaG,
SegaR,MilesiC,CesanaG,ZanchettiA.Bloodpressurecontrolinthehypertensivepopulation.Lancet
1997;349:454457.22.MacMahonS,PetoR,CutlerJ,CollinsR,SorlieP,NeatonJ.Bloodpressure,
stroke,andcoronaryheartdisease.Lancet1990;335:765774.EuropeanSocietyofHypertension
ScientificNewsletter:UpdateonHypertensionManagement7HYPERTENSIONINCHRONICRENAL
FAILUREJoseL.Rodicio,JoseM.AlcazarFacultyofMedicine,ComplutenseUniversity,Madrid,Spain
2011;12:No.4revisedversionHypertensionisoneofthemostimportantcomplicationsresultingfrom
chronicrenalfailure.Renalparenchymaldiseaseisthemostfrequentformofsecondaryhypertension,
comprisingabout5%ofallhypertensioncases.Theprevalenceofhypertensionindifferentparenchymal
diseasesisshowninTable1.Theprevalenceofarterialhypertensionisrelatedtoseverityofrenal
insufficiency,reaching8090%inendstagerenalfailure.Figure1showsthemechanismsbywhich
chronicrenalfailurecontributestohypertension.Sodiumandwaterretentionplayanimportantroledueto
theirdifficulteliminationbythekidney.Theconsequencesareanincreaseofexchangeablesodium,
vascularwallsodium[1],andanexpansionoftheextracellularvolumewithanincreaseincardiacoutput.
Thereninangiotensinsystemisstimulated,especiallyinpatientswithmildtomoderatechronicrenal
failure.Thisresultsinhaemodynamicchangessuchasvasoconstrictionandsympatheticnervoussystem
activation,aswellasnonhaemodynamicactionssuchastheactivationofendothelialcells,mesangial
cells,inflammation,andfibrosis.TheoutcomefromthiseffectofangiotensinIIisprogressiverenal
damageandhypertension[2].Thesympatheticnervoussystemisactivatedwithconsequentincreasesin
norepinephrinelevels,peripheralresistance,andcardiacoutput.Baroreceptordesensitizationisalsofound
inpatientswithendstagerenaldisease[3].Endotheliumfunctionisalsoimpaired.Nitricoxide,a
vasodilatoragent,isreducedinchronicrenalfailuremainlyduetoanincreaseoftheinhibitor
asymmetricaldimethylarginine(ADMA)[4].Prostaglandinsandkininshavebeenfoundtobenormal,
high,orlowinrenalfailureaccordingtodifferentauthors;however,theadministrationofnonsteroidanti
inflammatorydrugsproducesanincreaseinbloodpressure,adecreaseintheglomerularfiltrationrate,and
areductionofurinaryprostaglandins[5].Endothelinandthromboxane,bothofthemvasoconstrictor
agents,areelevatedinchronicrenalfailure.Theatrialnatriureticpeptideisalsoelevatedinrenalfailure,
favouringanincreaseofurinarysodiumexcretion,relaxationofthesmoothmusclecells,andinhibitionof
reninrelease[6].Erythropoietinadministrationinpatientswithchronicrenalfailureisacommonpractice
andcanproducehypertensioninabout20%ofpatientsduetoanincreaseinplateletcytosoliccalcium[7].
Themostimportantissuesinthebasalclinicalevaluationofarterialhypertensioninchronicrenalfailure
arelistedinTable2inwhichtwosectionsareclearlydifferentiated:clinicalhistorywithphysical
examination,andcomplementaryexaminations.Besidesmeasuringbloodpressureintheofficeandat
home,24hourambulatorybloodpressuremonitoringshouldbecarriedoutbecauseithasbeen
demonstratedthatpatientswhosenighttimebloodpressuredoesnotdecrease(nondippers)haveaworse
prognosiswithregardtomorbidity,mortality,andtheprogressionofchronicrenalfailure[8].Treatment
Arterialhypertensioninchronicrenalfailureisaseriouscomplicationthatmayleadtoendstagerenal
diseaseinashortperiodoftime.Forthisreason,boththeEuropeanSocietyofHypertensionand
CardiologyandtheseventhreportoftheJointNationalCommitteeGuidelinesrecommendareductionin
bloodpressurebelow130/80mmHginallpatientswithrenalfailureandatleastbelow120/80mmHg
particularlywhenproteinuriaissuperiorto1g/24h.Table1.Prevalenceofhypertensioninrenal
parenchymaldiseaseFocalglomerulosclerosis7585%Diabeticnephropathy6575%
MembranoproliferativeMembranousnephropathy3545%glomerulonephritis6070%
MesangioproliferativeIgAnephropathy2030%glomerulonephritis3040%Minimalchangedisease10
15%Interstitialnephritis1525%Polycystickidneydisease5565%Figure1.Mechanismsunderlying
arterialhypertensioninchronicrenalfailureTable2.Thefollowingexaminationsarerequiredfor
appropriatediagnosisofarterialhypertensioninpatientswithchronicrenalfailureClinicalhistoryClinical
historyandphysicalFamilybackgroundofrenaldiseaseexamination(polycystickidney,AlportandFabry
disease)DateofdiagnosisofhypertensionBackgroundofdiabetesmellitusSymptomsofhaematuria,
oedema,lithiasisSymptomsofperipheralarterydisease,ischemicheartdisease,cerebrovasculardisease
Chronicadministrationofanalgesics,NSAID...PhysicalexaminationBloodpressure,weight,heightand
waistcircumferenceNeckpalpationandauscultationofbothcarotidarteriesPulmonaryandcardiac
auscultationAbdomen:abdominalmassesandbruitsLimbs:pulsepalpation,oedemaFundoscopy:
retinopathydegreeComplementaryRenalfunctionexaminationsDeterminationofserumcreatinine;
cystatinC,creatinineclearance,MDRDorCockcroftGaultformulasUrine:quantificationofproteinuria;
microormacroalbuminuria;protein/creatinineratioUrinesediment,microhaematuria,castsRenal
morphology:renalultrasonographyRenalmorphologyandfunction:urography,scintigraphyandisotopic
renalflowBloodsampledeterminations:haemoglobin,leukocytes,platelets,sugar,lipids,uricacid,
calcium,phosphorus,transaminases,ionogramandacidbasemeasurementsSystemicandviraldisease
withrenalinvolvementmarkers:complement,cryoglobulins,ANAantiDNA,immunoglobulins,ANCAS,
viralBandC,andHIVserologyRenalvascularization:scintigraphy,renalarteriographyRenalhistological
study:renalbiopsy8Table3.NonpharmacologicaltreatmentSodiumintake<60mmol/dayCholesterol
intakerestrictionProteinintake0.81.2g/kg/dayPotassiumintakerestrictionPhosphorusintakeSmoking
cessationandalcohol<750mg/dayrestrictionCaloricintakeModeratephysicalactivity> 35
additionofaselectivevitaminDreceptoractivationinpatientswithRAASinhibitionlowerstheresidual
albuminuriaandreducesrenalriskinpatientswithdiabeticnephropathy[21].Inmanycircumstancesof
chronicrenalfailure,anintegratedtreatment(antihypertensive,statinandantiplatelettherapy)shouldbe
considered.References1.SimonG.Increasedvascularwallsodiuminhypertension:whereisit,howdoes
itgetthereandwhatdoesitdothere?ClinSci1990;78:533540.2.JohnsonRJ,AlpersCE,Yoshimura
A,etal.RenalinjuryfromangiotensinIImediatedhypertension.Hypertension1992;19:464474.3.
AgarwallR.Hypertensioninchronickidneydiseaseanddialysis:Pathophysiologyandmanagement.
CardiolClin2005;23:237248.4.YadavS,BrecklinC.Asymmetricdimethylarginine:themissinglink
betweenchronickidneydiseaseandcardiovascularmortality?Kidney:acurrentsurveyofworldliterature
2007;16:47.5.SmithMC,DunnMJ.Theroleofprostaglandinsinhumanhypertension.AmJKidney
Dis1985;5:A32A39.6.SudaS,WeidmannP,SaxenhoferH,etal.Atrialnatriureticfactorinmildto
moderatechronicrenalfailure.Hypertension1988;11:483490.7.TepelM,WischniowskiH,ZidekW.
Erythropoietininducedtransmembranecalciuminfluxinessentialhypertension.LifeSci1992;51:161
167.8.LurbeA,RedonJ,KesaniA,etal.Increaseinnocturnalbloodpressureandprogressionto
microalbuminuriaintype1diabetes.NEnglJMed2002;347:797805.9.BirdrerG.Nutritioninchronic
renalfailure.In:Comprehensiveclinicalnephrology.JohnsonRJ,FeehallyJ(eds).Mosby,London2000:
147168.10.BrennerBM,CooperME,DeZeeuwD,etal.Effectsoflosartanonrenalandcardiovascular
outcomesinpatientswithtype2diabetesandnephropathy.NEnglJMed2001;345:861869.11.
Randomisedplacebocontrolledtrialofeffectoframiprilondeclineinglomerularfiltrationrateandriskof
terminalrenalfailureinproteinuric,nondiabeticnephropathy.TheGISENGroup(GruppoItalianodiStudi
EpidemiologiciinNefrologia).Lancet1997;349:18571863.12.WigginsKJ,KellyDJ.Aliskiren:anovel
renoprotectiveagentorsimplyanalternativetoACEinhibitors?.KidneyInt2009;76;2331.13.Parving
HH,PersonF,LewisJWetal.AliskirencombinedwithLosartanintype2diabetesandnephropathy.N
EnglJMed2008;358:24332446.14.RodicioJL,CampoC,RuilopeLM.Renaleffectsofcalcium
antagonists.NephrolDialTransplant1995;10:1722.15.HayashiK,WakinoS,SuganoN,etal.Ca++
channelsubtypesandpharmacologyinthekidney.CircRes2007;100:342353.16.BraterDC.Useof
diureticsinchronicrenalinsufficiencyandnephriticsyndrome.SeminNephrol1988;8:333341.17.
JacobS,RattK,HenriksenEJ.Antihypertensivetherapyandinsulinsensitivity.Dowehavetoredefinethe
roleofbetablockingagents?AmJHypertens1998;11:12581265.18.MackinnonM,ShurrayS,
AkbariA,etal.CombinationtherapywithanangiotensinreceptorblockerandanACEinhibitorin
proteinuricrenaldisease:asystematicreviewoftheefficacyandsafetydata.AmJKidneyDis2006;48:
820.19.ManciaG,LaurantS,AgabitiRoseiE,etal.ReappraisalofEuropeanGuidelineson
HypertensionManagement:AEuropeanSocietyofHypertensiontaskforcedocument.JHypertens2009;
27:21212158.20.RossingK,SchjoedtKJ,JensenBR,etal.Enhancedrenoprotectiveeffectsofultra
highdosesofirbesartaninpatientswithtype2diabetesandmicroalbuminuria.KidneyInt2005;68:1190
1198.21.DeZeeuwD,ArgawalR,AmdahlM,etal.SelectivevitaminDreceptoractivatonwith
pericalcitolforreductionofalbuminuriainpatientswithtype2diabetes(VITALStudy):arandomized
controlledtrial.Lancet2010;376:15431551.EuropeanSocietyofHypertensionScientificNewsletter:
UpdateonHypertensionManagement9HOWTOHANDLERENOVASCULAR
majoradvantageofthistechniqueisthatthelesioncanbemeasureddirectlyandtreatedimmediately.Ithas
thedisadvantageofbeinganinvasivetechniquewithpossiblecomplicationsduetotheiodinecontrastand
duetotheriskofatheroembolism.Figure1showsthealgorithmforthediagnosisofpatientswith
renovascularhypertension.OtherscreeningtestsRenalscintigraphyfollowingACEinhibitor:The
sensitivityandspecificityofthistestare7890%and8898%,respectively.Thisdecreaseswhenthe
lesionisbilateralandinkidneyfailure.Inpatientswithischaemicnephropathy,onlyrenalscintigraphyis
usedtodemonstratekidneyviability.Renalveinreninmeasurements:Thisisusedonrareoccasionsin
patientswithlesionsinbothrenalarteries.Inourexperience,whenthereisahighclinicalsuspicionof
RVHduetofibrodysplasia,renalarteriographycanbeuseddirectlytoconfirmthelesionandperforma
possibleangioplasty.Whensuspicionismoderate,Dopplerduplexshouldbeused,followedbyMRAor
CTA,dependingontheresultsandexperienceofeachcentre.TreatmentThefundamentalpurposeofthe
treatmentofrenovascularhypertensionistocontrolbloodpressureandpreserveorimprovekidney
function.Giventhedifferentaetiologiesandcoursesofthevascularlesions,bothdiseases,fibromuscular
dysplasiaandatherosclerosis,shouldbeanalysedseparately.FibromusculardysplasiaBloodpressurecan
becontrolledwithangiotensinconvertingenzymeinhibitors(ACEI)orangiotensinIIreceptorblockers
(ARB),orrennininhibitor,togetherwiththiazidediuretics.Ifbloodpressurecontrolisnotoptimal,a
calciumantagonistorbetablockermaybeadded[10].TheuseofACEI/ARBinpatientswithsevereand
bilaterallesionsmaycausehaemodynamicintraglomerularalterationsthatdeterioratetheglomerular
filtrationrate.Thismakesitnecessarytomonitorplasmacreatinineandserumpotassium.Renal
revascularization(angioplastyandsurgery)isindicatedinsevereandrefractoryhypertension,and
fundamentallywhenthereisprogressionofthelesionswithalossofrenalfunctionandmass.Intraluminal
angioplastyisthetechniqueofchoice:themorphologicalresultsaccordingtoangiographiccriteriashowa
beneficialgradeofdilationbetween83%and100%[1719].Thepercentageofrestenosisis12%to25%,
withanevolutiontimeoftwoyears[1718].Hypertensioniscontrolledin22%to59%ofthesepatients,
improvesin22%to74%,andisnotmodifiedin2%to30%ofthem[1720].However,arecentmeta
analysisontheeffectofrevascularizationinpatientswithfibromusculardysplasiaincluded50studiesof
patientstreatedwithangioplastyand25withsurgery.Hypertensionwascuredafterangioplastyorsurgery
in46and55%ofpatients,respectively[21].Revascularizationbysurgeryislimitedtocaseswith
aneurysmsintherenalarteryorangioplastyfailure.AtheroscleroticrenalarteryTheindicationsfor
revascularizationoftherenalarteriesareinconstantdispute.However,inspiteofcontrolledblood
pressure,atherosclerosislesionsmayadvanceovertime.Insomeseries,progressionmayreach45%to
60%inaperiodoflessthan10years[22].Completethrombosisoftherenalarteryhasbeendescribedin
3%to15%ofcases,whenthestenosiswasgreaterthan75%Figure1.Algorithmforthediagnosisof
patientswithrenovascularhypertension10Table2.Indicationsforrevascularizationinatherosclerotic
renalarterystenosisRenalfunctionProgressionofrenalarterystenosisLossofrenalmassACEI/ARB
inducedazotaemiaHypertensionRefractoryhypertensionCardiacsyndromeCongestiveheartfailureFlash
pulmonaryoedemaFigure2.Algorithmforthetreatmentofpatientswithrenovascularhypertension[23].
Furthermore,cardiovasculardiseaseinthispopulationisveryhigh,thesurvivalratebeingverylimited
(lessthan45%infiveyearsofevolution),especiallyinpatientswithbilaterallesions[5].Thetreatment
optionsincludedrugs,angioplastywithendoprosthesis(PTRAS),andrevascularizationsurgery.Lowering
lipidlevels,smokingcessation,andmaintainingacceptableglucoselevelsallrequireconsideration.Many
studieshavebeenpublishedwithdifferenttypesoftreatment,noninvasivewithantihypertensivedrugsand
revascularization,fundamentallywithangioplasty,inanattempttofinddifferencesinglobalandrenal
survival.Balketal.[24]conductedareviewoftheliteraturebetween1993and2005.Theyfound357
studies,onlytwoofwhichwererandomized.Itcanbededucedfromtherandomizedandcontrolledstudies
thatthecardiovascularmortalityatsixmonthswassimilarwithbothtreatments.Theangioplastytreatment
improvedthecontrolofbloodpressurewhenthelesionaffectedbothrenalarteries,or,insomecases,renal
function.Duetothemethodologicaldifferencesandthedifferentobjectivesestablishedinthestudies,it
wasnotpossibletodrawanyconclusionsthatwouldmakeitpossibletorecommendacertaintherapeutic
option,althoughinitialmedicaltreatmentseemstobethemostindicated.TheASTRALtrial[25]
comparedPTRAScombinedwithmedicaltherapytomedicaltherapyaloneforimprovementinrenal
function.In806patientswithARAs,differencesinrenalfunction,bloodpressure,kidneyand
cardiovascularevents,andmortalitywerenotdefinitive.Thedeclineinrenalfunctionovertimewas
slightlyslowerinthePTRASgroup,butnotstatisticallysignificant.Themedicalmanagementgroup
requiredaslightlyhighernumberofantihypertensivedrugs,butnotstatisticallysignificant.Numerous
criticismshavearisenlatelyaboutthemethodologyoftheASTRALtrial[26,27].Thecriteriafollowedto
assessthecalibreofthearterystenosiswerenotspecified.Additionally,therewasnocentrallaboratory
thatstandardizedandcomparedangiographicstudies.Themethodsusedtoincludepatientsinthe
revascularizationgrouporinmedicaltreatmentdependedontheresearchandwerenotproperlydefined.
TheCORALstudy[28]isarandomizedclinicaltrialcontrastingoptimummedicaltherapyaloneto
PTRASwithoptimummedicaltherapyonacompositecardiovascularandrenalendpoint:cardiovascular
andrenaldeath,myocardialinfarction,hospitalizationforcongestiveheartfailure,stroke,doublingof
serumcreatinine,andtheneedforrenalreplacementtherapy.Theprimaryentrycriteriaare:1)an
atheroscleroticrenalstenosisof>60%witha20mmHgsystolicpressuregradientor>80%withno
gradientnecessary;2)systolichypertensionof>155mmHgon>2antihypertensivemedications.RADAR
isanother[29]prospective,multicentrestudytoevaluatetheclinicalimpactofPTRASonimpairedrenal
functioninpatientswithARAS>70%.Threehundredpatientswillberandomizedtobestmedical
treatmentversusPTRASplusmedicaltreatment.TheCORALandRADARstudiesshouldshedsomelight
ontheexistingdoubtsandthepotentialbenefitsofrevascularizationwithPTRAS.Theindicationsto
performrevascularizationinatheroscleroticrenalarterystenosisareshowninTable2[9,10,27,30,31],
focusingonthreedifferentparameters:renalfunction,hypertension,andcardiacsyndrome.Inacuterenal
failuresecondarytoaorticandrenalarterythrombosis,wherethekidneyshaveanimportantcollateral
circulation(nonfunctioningkidneys),surgicaltreatmentwouldhaveaclearindication[32,33].Patients
withestablishedrenalischaemicdiseasewithlongevolution(creatinine>3.0mg/dl)anddecreaseofrenal
parenchymawithtriggeringfibrosiswouldnotbenefitfromanytypeofrevascularization.
RevascularizationtechniquesAngioplastywithendoprosthesis:inordertoimprovetheefficacyofthe
angioplastyanddecreasetheincidenceofrestenosisinostiallesions,itisessentialtoplacean
endoprosthesis(balloonexpandableintravascularstents)[34].Thespecificcomplicationsofthetechnique
includebruisesinthepuncturezones(20%),cholesterolatheroembolisms(10%),contrastinduced
nephropathy,anddissectionoftherenalandiliacarteries[34].Surgery:Thisisconsideredtobethe
techniqueofchoice1)inpatientswithpathologyintheaortoiliacarterieswhorequireacombined
revascularization,2)inverysevereostiallesions,and3)incompleterenalarterythrombosis.Theresults
publisheddescribeimprovementorstabilizationoftherenalfunctionin79%to90%,andprogressive
deteriorationin10%to20%,ofthesecases[22,27].Globalmortalitywas4.6%andwasassociatedwith
olderageandsymptomsofheartfailure[35].Someauthorsdescribegoodresultswithsurgical
revascularizationincasesofacutethrombosisoftherenalartery(nonfunctioningkidneys)aslongassome
minimumcriteriaarefulfilledforthesurgeryanditispossibletoplaceabypass[32,33].Figure2shows
thealgorithmforthetreatmentofpatientswithrenovascularhypertension.Inconclusion,ischaemicrenal
diseaseisacomplexdiseasewithextrarenalvascularlesionsthatincreasecardiovascularmorbidityand
mortality.Mostofthetime,renalarterylesionsareduetoatherosclerosisanditisrecommendedtobegin
withnoninvasivetechniques.Initially,excellentmedicaltherapywithblockadeofthereninangiotensin
systemandstatinmustbeused.Revascularizationisindicatedifthereisaprogressionofthelesionswith
lossofrenalmassandfunction.Decisionsshouldbebasedonindividualizedanalysisofeachpatient,
accordingtothecomplexityoftheirlesionsandtheexperienceofeachcentre.References1.JacobsonHR.
Ischemicrenaldisease:anoverlookedclinicalentity.KidneyInt1988;2344:9743.2.BreyerJA,
JacobsonHR.Ischemicnephropathy.CurrOpinNephrolHypertens1993;2:16224.3.WorkingGroupof
RenovascularHypertension.Detection,evaluationandtreatmentofrenovascularhypertension.Finalreport.
ArchInternMed1987;147:820829.4.SlovutD,OlinJ.Fibromusculardysplasia.NEnglJMed2004;
350:18621871.5.MaillouxLU,NapolitanoB,BellucciAG,etal.Renalvasculardiseasecausingend
stagerenaldisease.Incidence,clinicalcorrelatesandoutcomes.A20yearclinicalexperience.AmJ
KidneyDis1994;24:622629.6.VanAmptingJM,PenneEL,BeekFJ,KoomansHA.Prevalenceof
atheroscleroticrenalarterystenosisinpatientsstartingdialysis.NephrolDialTransplant2003;18:1147
1151.7.AlcazarJM,RodicioJL.Ischemicnephropathy:clinicalcharacteristicandtreatment.AmJKidney
Dis2000;36:883893.8.AlcazarJM,MarinR,GomezCampderaF,et.al.Clinicalcharacteristicsof
ischaemicrenaldisease.NephrolDialTransplant2001;6(Suppl1):7477.9.GarciaDonaireJA,Alcazar
JM.Ischemicnephropathy:detectionandtherapeuticintervention.KidneyInt2005;68(Suppl99):S131
S136.10.HirschAT,HaskalZJ,HertzerNR,etal.ACC/AMA2005PracticeGuidelinesforthe
managementofpatientswithperipheralarterialdisease.Circulation2006;113:e463e654.11.DeoA,
FogelM,CowperSE.Nephrogenicsystemicfibrosis:apopulationstudyexaminingtherelationshipof
diseasedevelopmenttogadoliniumexposure.ClinJAmSocNephrol2007;2:264.12.ZhangHL,SosTA,
WinchesterPA,GaoJ,PrinceMR.Renalarterystenosis:imagingoptions,pitfalls,andconcerns.Prog
CardiovascDis2009;52:209219.13.WilliamsGJ,MacaskillP,ChanSF,etal.Comparativeaccuracyof
renalduplexsonographicparametersinthediagnosisofrenalarterystenosis:pairedandunpairedanalysis.
AmJRoentgenol2007;188:798.14.DriegheB,MadaricJ,SarnoG,etal.Assessmentofrenalartery
stenosis:sidebysidecomparisonofangiographyandduplexultrasoundwithpressuremeasurements.Eur
HeartJ2008;29:517524.15.RadermacherJ,ChavanA,BleekJ,etal.UseofDopplerultrasonography
topredicttheoutcomeoftherapyforrenalarterystenosis.NEnglJMed2001;344:410417.16.Rocha
SinghK,JaffMR,LynneKelleyE.Renalarterystentingwithnoninvasiveduplexultrasoundfollowup:3
yearresultsfromtheRENAISSANCErenalstenttrial.CatherterVardiovascInterv2008;72:853862.17.
BonelliFS,McKusickMA,TextorSC,etal.Renalarteryangioplasty:technicalresultsandclinical
outcomein320patients.MayoClinProc1995;70:10411052.18.KlowNE,PaulsenD,VatneK,etal.
Percutaneoustransluminalrenalarteryangioplastyusingthecoaxialtechnique.Tenyearsofexperience
from591proceduresin419patients.ActaRadiol1998;39:594603.19.BirrerM,DoDD,MahlerF,
TrillerJ,BaumgartnerI.Treatmentofrenalarteryfibromusculardysplasiawithballoonangioplasty:a
prospectivefollowupstudy.EurJVascEndovascSurg2002;23:146152.20.SurowiecSM,Sivamurthy
N,RhodesJM,etal.Percutaneoustherapyforrenalarteryfibromusculardysplasia.AnnVascSurg2003;
17:650655.21.TrinquartL,MonnierVehierC,SapovalM,GagnonN,PouinPF.Efficacyof
revascularizationforrenalarterystenosiscausedbyfibromusculardysplasia:asystematicreviewedand
metaanalysis.Hypertension2010;56:522532.22.GrecoBA,BayerJA.Atheroscleroticischemicrenal
disease.AmJKidneyDis1997;29:167187.23.CapsMT,ZierlerRE,PolissarNL,etal.Riskofatrophy
inkidneyswithatheroscleroticrenalarterystenosis.KidneyInt1998;53:735742.24.BalkE,RamanG,
ChungM,etal.Effectivenessofmanagementstrategiesforrenalarterystenosis:asystematicreview.Ann
InternMed2006;145:901912.25.TheASTRALInvestigators.Revascularizationversusmedicaltherapy
forrenalarterystenosis.NEnglJMed2009;361:1953196226.BaumgartnerI,LermanL.Renovascular
hypertension:screeningandmodernmanagement.EurHeartJ2011;Jan27[Epubaheadofprint].27.
TextorS.Issuesinrenovasculardiseaseandischemicnephropathy:beyondASTRAL.CurrOpinNephrol
Hypertens2011;20:139145.28.CooperC,MurphyT,MatsumotoA,etal.Stentrevascularizationforthe
preventionofcardiovascularandrenaleventsamongpatientswithrenalarterystenosisandsystolic
hypertension:RationaleanddesignoftheCORALtrial.AmHeartJ2006;152:5966.29.Schwarzwalder
U,HaukM,ZellerT.RADARarandomized,multicentre,prospectivestudycomparingbestmedical
treatmentversusbestmedicaltreatmentplusrenalarterystentinginpatientswithhaemodynamically
relevantatheroscleroticrenalarterystenosis.Trial2009;10:60.30.ZalunardoN,TuttleK.Atherosclerotic
renalarterystenosis:Currentstatusandfuturedirections.CurrOpinNephrolHypertens2004;13:613621.
31.KrummeB,DonauerJ.Atheroscleroticrenalarterystenosisandreconstruction.KidneyInt2006;70:
15431547.32.LibertinoJA,ZinmanL,BreslinD,SwintonNW,LaggM.Revascularizationofischemic
nonfunctioningkidneywithrestorationofrenalfunction.JAMA1980;244:13401344.33.NovickAC.
Currentconceptsinthemanagementofrenovascularhypertensionandischemicrenalfailure.AmJKidney
Dis1989;13(Suppl1):33.34.LeertouwerTC,GussenhoverEJ,BoschJL,etal.Stentplacementforrenal
arterialstenosis:Wheredowestand?Ametaanalysis.Radiology2000;216:7885.35.CherrGS,Hansen
KJ,CravenTE,etal.Surgicalmanagementofatheroscleroticrenovasculardisease.JVascSurg2002;35:
236245.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement
11ISOLATEDSYSTOLICHYPERTENSION:CARDIOVASCULARRISKANDTREATMENT
BENEFITSCsabaFarsang1,PeterSleight21DepartmentofInternalMedicine,CardiometabolicCentre,
St.ImreHospital,Budapest,Hungary2DepartmentofCardiovascularMedicine,JohnRadcliffeHospital,
UniversityofOxford,UnitedKingdom2011;12:No.6revisedversionIntroductionThedefinitionof
isolatedsystolichypertension(ISH)accordingto2007ESH/ESCguidelines,reappraisedin2009[1,2],is:
asystolicbloodpressure(SBP)>140mmHg,diastolicbloodpressure(DBP)<90mmHg.Accordingly,
thedifferentgradesofISHaredefinedasfollows:Grade1:SBP<160mmHg,Grade2:SBP>160<
180mmHg,Grade3:SBP>180mmHg.PathogeneticfactorsImportantfactorsleadingtothe
developmentofhypertensionandparticularlyofISHareagerelatedvascularandneurohumoralchanges
withanendotheliumdependentNOdeficiencyand/orreducedNObioavailability.Arterialcompliance
deterioratesbecauseofstructuralandfunctionalchangesandincreasesincollagen,extracellularprotein
matrix,groundsubstance,andelastin,whichoccurwithage.Thesechangescreatestructuraland
mechanicalalterationsinthevesselintimaandmedia.Calciumbindstotheelastin,andundifferentiated
musclecellsofthemediaproliferateandmigratethroughtheelasticlaminaetotheintima.The
proliferationoftheconnectivetissueresultsinintimalthickeningandfibrosis,andincreasesthestiffnessof
thevesselswithpartiallossofcontractility.Consequently,arterialcompliancediminishes,andthesocalled
windkesselofthelargearteriesdecreases.Pulsepressureandpulsewavevelocityincreasewithanearlier
reflectionofpressurewavesfromtheperiphery,leadingtoadisproportionateincreaseinsystolicpressure,
whilediastolicbloodpressuredoesnotchange,ordecreasesparticularlyovertheageof60.Cardiac
output,strokevolume,intravascularvolume,andrenalbloodflowdecrease;plasmareninactivitymay
increase.Asaconsequenceofthesechanges,leftventricularmass(prevalenceofleftventricular
hypertrophyLVH),circulatingcatecholamines(particularlynoradrenaline),andtotalperipheralvascular
resistanceincrease.Baroreceptorsensitivitytobloodpressurechangesalsodecreases,resultinginhigher
bloodpressurevariability[35].ISHascardiovascularriskISH(usingtheolddefinitionofISH:systolic
bloodpressure>160mmHganddiastolicbloodpressure<90mmHg)increaseswithage,andbecomes
themostcommontypeofhypertensionamongpeopleover60yearsofage[6].Accordingtothe
cumulative24yeardatafromtheFraminghamStudy(witholddefinition),theincidenceofISHishigh
bothinwomen(533/1,000)andinmen(418/1,000)overtheageof65years.ISHwasthemostcommon
typeofdiagnosedhypertension(57.4%inmen,65.1%inwomen)inthoseover65years[7].Subjectswith
Grade1ISHwereatincreasedriskofprogressiontodefinite(Grade2)hypertensionorthedevelopmentof
cardiovasculardisease[8].SeveralstudieshaveshownthatISHincreasedtheriskforcardioor
cerebrovasculardiseasesordeath(includingsuddendeath).IntheMRFITstudyof316,099men,systolic
bloodpressurewasastrongerpredictorofoutcomethandiastolicbloodpressure,withanexcessriskof
cardiovasculardiseasesinsubjectswithstageIISH[912].Ontheotherhand,the24yearfollowupof
1,207,141SwedishmenrevealedastrongerassociationoftotalmortalitywithSBPthanDBP,withthe
lowestriskataSBPofabout130mmHg.TotalmortalitycontinuouslyincreasedaboveSBPof120mm
Hg[13].UntreatedISHpatientsshowedahighprevalenceofLVHwithconcentricremodelling[14],which
hasbeenshowntohaveapoorcardiovascularprognosis[15].Themetaanalysisof8outcometrials
involving15,693patientswithISH(medianfollowup3.8years)showedthattherelativehazardrates
associatedwitha10mmHghigherinitialsystolicbloodpressurewere1.26fortotalmortality,1.22for
stroke,butonly1.07forcoronaryevents.Independentofsystolicbloodpressure,diastolicbloodpressure
wasinverselycorrelatedwithtotalmortality,stressingtheroleofpulsepressureasariskfactor[16].
TreatmentbenefitsRandomisedclinicaltrialsprovidecompellingevidencethattreatmentofISHresultsin
significantbenefits.ThelandmarktrialofSystolicHypertensionintheElderlyProgram(SHEP)in4,716
patientsfirstprovedthebenefitonCVmorbidityandmortalityofantihypertensivetreatmentwith
chlorthalidone(withtheoptionofaddingatenololorreserpine).Nonfatalstrokewasreducedby37%,non
fatalmyocardialinfarctionby33%,andleftventricularfailureby54%.Therewerestrongtrendstowardsa
decreaseintransientischaemicattacks(25%),andintotal(13%),cardiovascular(20%),cerebrovascular
(29%),andcoronary(20%)mortality[17].Thistrialalsopointedoutthatserumuricacidindependently
predictedcardiovasculareventsinpatientswithISH.Thesepatientsexperiencedthesamebenefitfrom
diureticbasedtreatmentasthosewithlowbaselineserumuricacidlevels[18].TheSystolicHypertension
inEurope(SystEur)studywasthefirstlarge(4,695patientswithISH)studyoftheeffectofalonger
actingcalciumantagonist,nitrendipine(withoptionaladdonenalapriland/orhydrochlorothiazide),on
longtermmorbidityandmortalityrisks.Totalstrokeswerereducedby42%[19].IntheSystEurstudythe
rateofvasculardementiawasalsoreducedby50%[18],whileitwasnotchangedbythechlorthalidone
basedtherapyintheSHEPstudy[20];thereforeaspecificneuroprotectiveeffectofdihydropyridinetype
calciumantagonist,nitrendipine,washypothesized.TheSystChinatrialconfirmedthebeneficialeffectof
nitrendipineinpatientswithISHasitreducedtotalstrokesby38%,strokemortalityby58%,allcause
mortalityby39%,cardiovascularmortalityby39%,andfatalandnonfatalCVeventsby37%[21].
SubgroupanalysisoftheINSIGHTtrialshowedthatpatientswithISHwereslightlymoreresponsivethan
thosewithordinaryhypertensiontotreatmentbylongactingnifedipineGITS,assignificantlylesspatients
requiredadditionofaseconddrug.ThisstudyalsoshowedthatpatientswithISHwhosediastolicblood
pressuresignificantlydecreasedwithincreasingtherapyweresmokerswithexistingevidenceof
atherosclerosis[22].Staessensmetaanalysis[16]alsoshowedthatactivetreatmentreducedtotalmortality
by13%,cardiovascularmortalityby18%,allcardiovascularcomplicationsby26%,strokeby30%,and
coronaryeventsby23%.Theabsolutebenefitwaslargerinmen,inpatientsaged70yearsormore,andin
thosewithpreviouscardiovascularcomplicationsorwiderpulsepressure.Therapypreventedstrokesmore
effectivelythancoronaryevents.Thiazidebasedtreatmentwassuperiortobetablockersforreductionof
bloodpressureandpreventionofcardiovascularcomplications[2325].Recentinvestigationswithnewer
antihypertensiveagents,suchasACEinhibitorsandangiotensinAT1receptorantagonists,havealso
demonstratedimprovedbloodpressurecontrolofpatientswithISH[26,27].IntheISHsubgroupofthe
LosartanInterventionforEndpointReduction(LIFE)trial,losartanoratenololreducedbloodpressureby
28//9mmHg,butlosartan(ascomparedtoatenolol)reducedtheprimaryoutcome(cardiovasculardeath
stroke,myocardialinfarction)by25%(unadjustedp=0.02),totalmortalityby28%(p<0.046),
cardiovascularmortalityby46%(p<0.01),nonfatalandfatalstrokeby40%(p<0.02),andnewonset
diabetesby38%(p<0.04)[28].IntheISHsubgroupoftheStudyonCognitionandPrognosisinthe
Elderly(SCOPE)candesartanreducedtherelativeriskofstrokeby42%(p<0.050)witha2/1mmHgBP
differenceascomparedtothecontrolgroup[29].ESHGuidelinesformanagementofISHLifestyle
modificationsareadvisedasfirstlinetherapyforpatientswithISH(physicalexercise,reductionofsalt
intake,weightreductioninobesepatients,cessationofsmoking).Therecommendedtargetsystolicblood
pressureisequaltoorbelow140mmHg,andintheveryelderly(age>80years)tobelow150mmHg.If
lifestylemodificationsfailtoreachthetarget,drugtherapyisadvisedtocontrolbloodpressure.Diuretics,
longactingdihydropyridinetypecalciumantagonists,ACEinhibitors,andangiotensinAT1receptor
antagonistsareadvisedfortreatmentofpatientswithISH[1,2].12References1.ManciaG,DeBackerG,
DominiczakA,etal.2007GuidelinesfortheManagementofArterialHypertension.TheTaskForcefor
theManagementofArterialHypertensionoftheEuropeanSocietyofHypertension(ESH)andofthe
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AgabitiRoseiE,etal.ReappraisalofEuropeanguidelinesonhypertensionmanagement:aEuropean
SocietyofHypertensionTaskForcedocument.JHypertens2009;27:21212158.3.SafarME.Systolic
hypertensionintheelderly:arterialwallmechanicalpropertiesandthereninangiotensinaldosterone
system.JHypertens2005;23:673681.4.MesserliFH,VenturaHO,GladeLB,etal.Essential
hypertensionintheelderly:haemodynamics,intravascularvolume,plasmareninactivity,andcirculating
catecholaminelevels.Lancet1983;2:983986.5.GrassiG,SeravalleG,BertinieriG,etal.Sympathetic
andreflexalterationsinsystodiastolicandsystolichypertensionoftheelderly.JHypertens2000;18:587
593.6.StaessenJ,AmeryA,FagardR.Isolatedsystolichypertensionintheelderly.JHypertens1990;8:
393405.7.WilkingSVB,BelangerA,KannelWB,etal.Determinantsofisolatedsystolichypertension.
JAMA1988;260:34513455.8.KannelWB,DawberTR,McGeeDL.Perspectivesonsystolic
hypertension:theFraminghamStudy.Circulation1980;61:11791182.9.BlackHR.Individualized
selectionofantihypertensivedrugtherapyforolderpatients.AmJHypertens1998;11:62S67S.10.Curb
JD,BorhaniNO,EntwisleG,etal.Isolatedsystolichypertensionin14communities.AmJEpidemiol
1985;121:362370.11.NeatonJD,WentworthD.Serumcholesterol,bloodpressure,cigarettesmoking,
anddeathfromcoronaryheartdisease.Overallfindingsanddifferencesbyagefor316,099whitemen.
MultipleRiskFactorInterventionTrialResearchGroup.ArchInternMed1992;152:5664.12.
HimmelmannA,HednerT,HanssonL,etal.Isolatedsystolichypertension:animportantcardiovascular
riskfactor.BloodPress1998;7:197207.13.SundstrmJ,NeoviusM,TyneliusP.Associationofblood
pressureinlateadolescencewithsubsequentmortality:cohortstudyofSwedishmaleconscripts.BMJ
2011;342:d643.14.HeesenWF,BeltmanFW,MayJF,etal.Highprevalenceofconcentricremodelling
inelderlyindividualswithisolatedsystolichypertensionfromapopulationsurvey.Hypertension1997;29:
539543.15.KorenMJ,DevereuxRB,CasalePN,etal.Relationofleftventricularmassandgeometryto
morbidityandmortalityinuncomplicatedessentialhypertension.AnnInternMed1991;114:345352.16.
StaessenJA,GasowskiJ,WangJG,etal.Risksofuntreatedandtreatedisolatedsystolichypertensionin
theelderly:metaanalysisofoutcometrials.Lancet2000;355:865872.17.SHEPCooperativeResearch
Group.Preventionofstrokebyantihypertensivedrugtreatmentinolderpersonwithisolatedsystolic
hypertension.FinalresultsoftheSystolicHypertensionintheElderlyProgram(SHEP).JAMA1991;265:
32553264.18.FranseLV,PahorM,DiBariM,etal.Serumuricacid,diuretictreatmentandriskof
cardiovasculareventsintheSystolicHypertensionintheElderlyProgram(SHEP).JHypertens2000;18:
11491154.19.StaessenJA,FagardR,ThijsL,etal.Randomiseddoubleblindcomparisonofplaceboand
activetreatmentforolderpatientswithisolatedsystolichypertension.Lancet1997;350:757764.20.
ForetteF,SeuxML,StaessenJA,etal.Preventionofdementiainrandomiseddoubleblindplacebo
controlledSystolicHypertensioninEurope(SystEur)trial.Lancet1998;352:13471351.21.LiuL,
WangJG,GongL,etal.ComparisonofactivetreatmentandplaceboinolderChinesepatientswith
isolatedsystolichypertension.JHypertens1998;16:18231829.22.BrownMJ,CastaigneA,deLeeuw
PW,etal.Influenceofdiabetesandtypeofhypertensiononresponsetoantihypertensivetreatment.
Hypertension2000;35:10381042.23.KostisJB,Pressel,SL,CutlerJA,etal.Preventionofheartfailure
byantihypertensivedrugtreatmentinolderpersonswithisolatedsystolichypertension.JAMA1997;278:
212216.24.AvanziniF,AlliB,BetteliG,etal.Antihypertensiveefficacyandtolerabilityofdifferent
drugregimensinisolatedsystolichypertensionintheelderly.EurHeartJ1994;14:206212.25.
MesserliFH,GrossmanE,GoldbourtU.Arebblockersefficaciousasfirstlinetherapyforhypertensionin
theelderly?Asystematicreview.JAMA1998;279:19031907.26.TonkinA,WingL.Managementof
isolatedsystolichypertension.Drugs1996;51:738749.27.FarsangC,GarciaPuigJ,NiegowskaJ,et
al;forLosartanInvestigatorsGroup.Theefficacyandtolerabilityoflosartanversusatenololinpatients
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RB,etal;fortheLIFE(LosartanInterventionforEndpointReduction)StudyGroup.Effectsoflosartanon
cardiovascularmorbidityandmortalityinpatientswithisolatedsystolichypertensionandleftventricular
hypertrophy:aLosartanInterventionforEndpointReduction(LIFE)substudy.JAMA2002;288:1491
1498.29.PapademetriouV,FarsangC,ElmfeldtD,etal;fortheSCOPEStudyGroup.StrokePrevention
WiththeAngiotensinIIType1ReceptorBlockerCandesartaninElderlyPatientsWithIsolatedSystolic
Hypertension.TheStudyonCognitionandPrognosisintheElderly(SCOPE).JAmCollCardiol2004;44:
11751180.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management13PATIENTADHERENCEANDPHARMACOLOGICALTREATMENTOFARTERIAL
HYPERTENSIONMennoPruijm1,MariePauleSchneider2,MichelBurnier11ServiceofNephrology
andHypertension,DepartmentofMedicine,UniversityHospitalofLausanne,SwitzerlandCommunity
Pharmacy,DepartmentofAmbulatoryCare&CommunityMedicine,UniversityofLausanne,Switzerland
2011;12:No.7RrevisedversionIntroductionFormerUSSurgeonGeneralC.EveretKoopstatedthat
drugsdontworkinpatientswhodonttakethem,avirtuethatdescribesverywelltheproblemof
medicationtakingbehaviourinhypertension.Despitethefactthatanincreasingnumberofpatientsare
beingtreatedwithantihypertensives,targetbloodpressures(BP)arereachedinonlyonethirdofpatientsin
clinicalpractice[1,2].TheSeventhReportoftheJointNationalCommitteeonPrevention,Detection,
Evaluation,andTreatmentofHighBloodPressure(JNC7)hasidentifiedpoormedicationtaking
behaviour(referredtoasnoncomplianceornonadherence)asoneofthemaincausesoffailuretocontrol
BPinpatientswithhypertension[3].Resultsfromasystematicreviewofelectronicmonitoringstudies,for
example,indicatedthat9%to37%ofpatientshadinadequateadherencetoantihypertensivemedication
[4].Inturn,nonadherentpatientsremainathighriskforcardiovasculardiseaseincludingahigherriskof
stroke[5],andcanbeexpectedtoaccountforasignificantcostburdenthroughavoidablehospital
admissions,prematuredeaths,workabsenteeism,andreducedproductivity[6].DefinitionsTheEuropean
SocietyofHypertensionguidelinespublishedin2001statethatcompliancecouldbedefinedasthedegree
towhichthepatientconformstomedicaladviceaboutlifestyle,keepingappointments,andtaking
prescribedmedication[7].Overthelastdecade,thetermcompliancehasacquiredasomewhatnegative
connotation,merelyimplyingobediencetophysiciansorders.Therefore,nowadaysthetermadherenceis
preferredtocompliance,althoughtheuseofcomplianceisstillwidelyembeddedindailypracticeaswell
asinthemedicalliterature.Medicationadherencecanbedefinedastheextenttowhichapatients
behaviour,withrespecttotakingmedication,correspondswithagreedrecommendationsfromhealthcare
providers[8].Adherencecanbedividedintotwomaincomponents:persistenceandexecution.Persistence
isdefinedastheaccumulationoftimefrominitiationtodiscontinuationoftherapywhereastheexecution
referstothecomparisonbetweentheprescribeddrugdosingregimenandthepatientsdrughistorywhile
ontreatment.Thelatterdefinitionincludesdoseomissions(misseddoses)andthesocalleddrugholidays
(threeormoredayswithoutdrugintake)[9].Persistenceisusuallyexpressedintime,executionis
generallyreportedasthepercentageofprescribeddosestakenoveracertainperiodoftime.Different
definitionsofadequateadherencehavebeenusedinclinicalstudies,withgoodadherence
correspondingtoexecutionratesbetween80100%,andinsufficientadherencetoexecutionrateslower
than7080%[4].Ofnote,adherence(execution)canbemorethan100%,sincepatientscantakemorethan
theprescribeddose.However,thebestlevelofadherencevarieslargelyfromonepatienttoanother.
Therefore,thresholdsdonothavemuchclinicalsignificanceindailypracticebutadherenceandblood
pressureshouldbemonitoredsimultaneouslyandrepeatedlytoevaluatetheimpactofadherenceonblood
pressureandotherlongtermoutcomes.DetectionTheabilityofphysicianstorecognizenonadherencehas
alowsensitivity(<40%)butgoodspecificity(90%),suggestingthatphysiciansaregoodatdetectinggood
adherencebutnotatdetectingpooradherence[10].Methodshelpingphysicianstodetectnonadherence
canbegroupedintothreecategories:subjectivemethods(e.g.patientinterviews,patientdiaries),direct
methods(e.g.analysisofdruglevelsorbiologicalmarkersinbodilyfluids),andindirectmethods(e.g.
assessmentofapatientsclinicalresponse,physiologicalmarkers(heartratewithbetablockers),pill
counts,prescriptionrefills,electronicmonitoringofmedicationuse).Eachmethodhasitsadvantagesand
disadvantages.Forexample,pillcountsandpatientdiariestendtooverestimatemedicationconsumption
[11],prescriptionrefillrecordsareonlyavalidsourceofinformationaboutmedicationtakingbehaviour
whenthedatabaseiscomplete,anddrugdosingmethodsonlyprovideinformationaboutthemostrecent
doses.Besides,itisverydifficulttodiagnosepoorexecutionwiththesetraditionalmethods.Moreinsight
inspecificdrugintakepatternsofantihypertensiveshasbeengainedbyelectronicpillboxmonitors(e.g.
MedicalEventMonitoringSystem,MEMS;IntelligentDrugAdministrationSystem,IDASII),which
enablemonitoringoftheexecutiononadailybasisbyrecordingthetimeofeachopeningofthepill
containerortakingatabletoutofablisterpack[12].Despiteseveralshortcomings(indirectmethod,
relativelyexpensive,requiresknowhowforpackagingandforgeneratingaccurateresults),electronicpill
boxmonitoringisactuallyconsideredasthebestwaytodiagnosenonadherence,andhasadvancedour
knowledgeofmedicationtakingbehaviouranditsriskfactors[13].RiskfactorsforpooradherenceFirstof
all,itisimportanttorealizethatmedicationadherenceisadynamicparameter,meaningthatphasesof
goodadherencecanalternatewithphasesofpooradherenceinthesamepatient,dependingonlife
circumstances.Forexample,medicationadherencetendstoimprovearoundthetimeofascheduledclinical
visit,butdeclinesthereafter,aphenomenonknownaswhitecoatadherence[14].Second,persistence
decreasesprogressivelyovertime,withabouthalfofpatientsinterruptingtheirantihypertensivetreatment
withinoneyear[15].Ofnote,patientswhohavepoorexecution(omittingdoses,drugholidays,variability
inhourofintake)areathighestriskofquittingearly[15].Themostcommonlyreportedriskfactorsfor
nonadherenceareshowninTable1.Unfortunately,noriskfactororcombinationofriskfactorshas
allowedphysicianssofartoidentifywithcertaintynonadherentpatients[16].Moreover,twopromising
patientselfreportscales(theHillBoneCompliancetoHighBloodPressureTherapyScaleand
MoriskysSelfReportedMeasureofMedicationAdherence)recentlyfailedtopredictlowadherence
[17].Takentogether,whenriskfactorsasshowninTable1arediagnosed,physiciansshouldhave
heightenedawarenessforthepossibilityofnonadherence,butevenintheabsenceofanyriskfactor,low
adherenceispossible[18].AdherenceaccordingtoantihypertensivedrugclassesSeveralstudieshave
comparedmedicationadherenceofdifferentdrugclasses.ThelargesttrialsareoutlinedinTable2.Mostof
thesedataareretrospectiveandderivedfromprescriptiondatabasesthatgiveinsightinpersistencebutnot
inexecution.Despitedifferencesindesign,thesestudiesshowthesametendency,namelythatATII
blockersandACEinhibitorshaveaslightlyhigherpersistencethancalciumantagonistsandbetablockers,
andthatpersistencewithdiureticsisthelowest.Themainreportedreasonsfordrugdiscontinuationare
perceivedtreatmentfailureandsideeffects[19].Insummary,Table2showsthatratesofpersistentpatients
declinewithtimeinalldrugsuntilaround50%;mostnonpersistentpatientsarelostearlyduringthefirst
yearsoffollowup.Largerandomized,prospectiveclinicaltrialshaveshownhigherpersistencerates.On
average,druginterruptionsoccurin15%ofpatientstakingACEinhibitorsandin20%ofpatientstaking
betablockers,diuretics,orcalciumantagonistsinthesetrials[20].However,randomizedclinicaltrials
areprobablybiasedsincetheytendtoselectthemoreadherentpatientsforparticipation,andlack
generalizabilitytothepopulationtreatedincommunitypracticesettings.Independentlyofthedrugclass
used,somemedicationrelatedaspectsmeritattention.Ithasbeenshownthatadherenceishigherin
patientswhotaketheirmedicationinthemorningascomparedtotheevening,thelatterleadingtomore
doseomissions[15].Moreover,arecentmetaanalysisTable1.Riskfactorsfornonadherenceto
antihypertensivetreatment[13,27,28]DiseaserelatedPatientrelatedPhysicianrelatedTreatmentrelated
ChronicconditionDenialofdiseasestateLackoftimeComplexityofdosingregimenAsymptomatic
ParticularbeliefsFailuretoincreasetherapyDurationoftreatmentNoimmediateconsequencesYoungage
toreachtreatmentgoalNonmanagedsideeffectsofnonpersistenceorpoorSocialisolationLongwaiting
timeinofficeCostsoftreatmentexecutionPsychiatricillnessLackofcommunicationandMalegender
integratedcarebetweenLoweducationlevelphysician,patientandLackofknowledgeofdisease
pharmacistLackofinvolvementLackofspecificeducationintreatmentplaninadherenceMissed
appointments14including9studies(ofwhich4wereretrospectivestudiesinpatientswithhypertension)
and20,242patientsfoundthattherapywithfixeddosecombinationsdecreasestheriskofnonadherence
by24%(oddsratio0.76,95%confidenceinterval0.710.81;p<0.0001)inthehypertensivepopulation
[21].RecommendationstoimprovemedicationadherenceSincemanyfactorsinfluenceadherence,itisnot
asurprisethatnosingleinterventionhasbeenshowntorobustlyenhancemedicationtakingbehaviour.Of
note,moststudiesinthisfieldareobservational;randomizedcontrolledtrialsaredifficulttoperform(for
example,cannotbeblinded),andaresparse.Strategiesthathaveproventobeeffectiveareoftencomplex
andthusnoteasilyfeasibleinthelongterm[22].OneexceptionmightbetheCOM99study,arandomized
multicentretrialcomparingalowintensityinterventiongroup(combinationofpillcount,educational
information,andadesignatedfamilymembertosupportadherence)withacontrolgroupin877patients
aged>50yearswithuncontrolledhypertension.Patientsintheinterventiongroupwerelesslikelytohave
uncontrolledBPandmorelikelytobeadherent(monitoredwithelectronicpillboxes)after6monthsof
followup;differencesof~2mmHginSBPpersistedafter5yearsoffollowup,butdisappearedafter18
monthsforDBP[23].Tailoringadherenceimprovingmethodstoeachpatientisimportantsinceamethod
thatworksinonepatientmightnotbeconvenientorsuccessfulinanother.Inourpersonalexperience,the
mostimportantpointfortheclinicianistoconsiderthepossibilityofnonadherenceincaseofapparent
inefficacyofadrugbeforeraisingthedose,andtoevaluateadherencewhenindoubt.Incaseofconfirmed
nonadherence,oneshouldsearchforunderlyingreasonsandpossiblestrategiestoimprovelongterm
adherence,andoneshouldestablishtreatmentgoalsinmutualagreementwiththepatient[24].However,
patientsnaturallyminimizenonadherenceissuesinordertopleasetheirphysician,especiallywhenthey
feelnegativelycontrolled.Todecreasetheriskfornonadherence,physiciansshouldtalkaboutitwiththeir
patientwhenstartingthefirstantihypertensivedrugandshouldaddressthetopicrepetitivelyatselected
encounters.Moreover,healthcaresystemsshouldevolveandaddressthislongtermissueinterdisciplinarily
byreinforcingseamlesscarebetweenallinvolvedhealthcaregivers,whoshouldbeeducatedinthe
clinicaldomainofmedicationnonadherenceandincommunicationskills[25].Infact,patientsexperience
individualorculturalbeliefsabouttheirantihypertensivetreatment,whichmakesenseintheirlifeand
whichneedtobeaddressedspecificallybytrainedhealthcareprofessionals.Basedoncurrentliteratureand
clinicalexperience,thefollowingrecommendationscanbegiven,mainlyconsistingofoptimizingall
factorsinvolvedinnonadherence[13,15,18,26].Patientrelatedfactors:Educatepatientsabouttheir
diseaseandtheimpactoftreatment,andencouragetheirparticipationtoinformationsessions.Involvethe
patientindecisionmakingandmonitoring(homebloodpressurereadings).Encourageemotionaland
practicalsupportfromfriendsandfamily.Encouragenondrugtherapiessuchaslifestylechanges.
Physicianrelatedfactors:Beawareofthepossibilityofnonadherenceatalltimesincaseofnon
effectivenessofprescribeddrugs.Establishtreatmentgoals.Tailortreatmentandadherencesupportto
thepatientsneeds.Shareresponsibilitiesfordrugmanagementandgetinsightintothepatientsdaily
organization.Keepincontactwithpatientswhomissappointments.Cooperatecloselywithpharmacists.
Medicationrelatedfactors:Encouragetheuseofmedicationtakingsystems.Selectdrugswitha
favourablesideeffectprofileandlongplasmahalflife,thelattertomaintainpharmacologicalactionfor
oneortwodosingcyclesafteromitteddoses.Startatalowdose,andincreasethedoseslowly.Privilege
combinationtherapytohighdosemonotherapy.Scheduledosingindividually;morningdosesareoften
preferredbypatients.Complexdosingregimens(severaltimesaday)shouldbeavoided.Takeinto
accountcostsandreimbursement.Healthcaresystemrelatedfactors:Organizeconvenientcarefor
patients.Promoteseamlesscarebetweenallhealthcareproviders,especiallyphysiciansandpharmacists
inambulatorycare.Improveeducationofhealthcareprofessionalsinmedicationadherenceand
communicationskills.ConclusionsGoodmedicationadherenceisimportanttoachieveoptimalblood
pressurecontrol,andisassociatedwithreducedriskofadversecardiovascularoutcomesandreduced
hypertensionrelatedcosts.Patientswithhypertensionwhohavepoormedicationtakingbehaviourremain
largelyunrecognized,andthedevelopmentofprogramstodetecttheseindividualsandsupportlongterm
adherenceisanimportantissue.Moreover,thereisaneedforcomprehensiveinterventionsthatuse
cognitive,behavioural,andaffectivestrategiestailoredtothepatientsparticularneeds.Theseinterventions
shouldbebasedonobjectiveandreliableassessmentofmedicationtakingbehaviour,andshouldbetested
inwelldesignedclinicaltrials.Table2.Studiescomparingpersistenceratesofdifferentantihypertensive
drugs[20,29,30]SstudynOutcome(persistence)ATIIblockersACEinhibitorsCalciumantagonists
BetablockersDiureticsJones,199510,2226monthpersistencene45%41%49%41%Blooms,1998
21,7231yearpersistence64%58%50%43%38%Caro,199922,9184.5yearpersistencene53%47%
49%40%Morgan,200482,8241yearpersistence56%56%52%54%49%Perreault,200521,0113year
persistence59%58%58%57%48%Polluzzi,20056,0433yearpersistence52%43%39%47%23%
Simons,200848,69033monthpersistence84%84%72%nenenenotevaluatedReferences1.Ong
KL,CheungBM,ManYB,LauCP,LamKS.Prevalence,awareness,treatment,andcontrolof
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CooperRS,KramerH,etal.HypertensiontreatmentandcontrolinfiveEuropeancountries,Canada,and
theUnitedStates.Hypertension2004;43:1017.3.ChobanianAV,BakrisGL,BlackHR,etal.Seventh
reportoftheJointNationalCommitteeonPrevention,Detection,Evaluation,andTreatmentofHighBlood
Pressure.Hypertension2003;42:12061252.4.WetzelsGE,NelemansP,SchoutenJS,PrinsMH.Facts
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thetherapeuticregimenonthedevelopmentofstrokeamonghypertensivemenandwomeninGaza,
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hypertension,itscomplications,anditscomorbidities.MedCare2001;39:599615.7.MallionJM,
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W,WeberE.Dynamicsofdrugregimencomplianceitsassessmentbymicroprocessorbased
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2008;2:CD000011.23.PladevallM,BrotonsC,GabrielR,etal.Multicenterclusterrandomizedtrialofa
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https://www.nice.org.uk/nicemedia/pdf/CG76NICE. 25. Carter BL, Rogers M, Daly J,
echocardiographycanmeasureotherparameters(regionalandglobalLVsystolicanddiastolicfunction,
leftatriumdimensionsandvolume),allassociatedwithanincreasedincidenceofmajorCVevents.LV
massmeasurementmaybeobtainedbycardiacmagneticresonance,withahigherreproducibilitythan
echocardiography;theimprovementinreproducibilityhasrelevantpracticalimplicationssuchasmore
precisedetectionofserialchangesinindividualpatientsinashortertimeintervalandTable1.LVHand
riskofcardiovascular(CV)eventsReferenceNo.patientsAverageCVeventsfollowup(yrs)Levy52436
Decreaseinvoltagevs.nochangeetal.FraminghamEKGOR0.46(95%CI0.260.84)1994population
biannualOR0.56(95%CI0.301.04)examinationIncreaseinvoltagevs.nochangeOR1.86(95%CI
1.143.03)OR1.61(95%CI0.912.84)Matthew82812.812.3%inpatientswithLVHetal.HighCV
regression/absence2001riskpatients15.8%inpatientswithLVHpersistence/developmentFagard4159
6.114%decreaseincardiacetal.Olderpatientseventsfor1mVchange2004withsystolicinEKGvoltage
hypertensionOkin91934.820.4%decreaseincompositeetal.Patientswithendpointfor10.5mm2004
EKGLVH(1SD)SokolowLyonIndex15.4%decreaseincompositeendpointfor1050mmmsec
(1SD)CornellproductsmallersamplesizedesigninclinicaltrialstargetingLVHregressionduring
antihypertensivetreatmentPrognosticvalueofLVHanditsregressionbytreatmentAlargenumberof
studieshavereportedontherelationshipbetweenLVHatbaselineexamination,measuredeitherbyEKG
orbyechocardiography,andtheriskofsubsequentmorbidormortalcardiovascularandrenaleventsin
clinicalorepidemiologicalpopulations[5].Despitethefactthatelectrocardiographyhasalowsensitivity
forLVHdetection,LVHdiagnosedbytheSokolowLyonindexortheCornellvoltagedurationproductis
anindependentpredictorofcardiovascularevents[5].DirectmeasurementofLVmassby
echocardiography(Mmode,undertwodimensionalcontrol)hasproventobeastrongpredictoroftherisk
ofcardiovascularmorbidityandmortality;subjectswithLVHconsistentlyhave2to4ormorefoldhigher
ratesofcardiovascularcomplications,independentofotherriskfactorssuchashypercholesterolaemia,age,
andbloodpressuremeasuredintheclinicorby24hourbloodpressuremonitoring[5].Concentric
hypertrophyappearstocarrythehighestriskandeccentrichypertrophyanintermediaterisk.Thepresence
ofinappropriateLVmassisalsoassociatedwithanincreasednumberofcardiovascularevents,evenin
hypertensivepatientswithoutLVH[12].TheprognosticsignificanceofchangesinEKGcriteriaofLVH
hasbeendemonstratedintheFraminghampopulation[13],inhighCVriskpatients[14],andin
hypertensiveswithisolatedsystolichypertension[15]orwithEKGLVH[16](Table1).Other
observational,prospective studies have examined the potential clinical
baseline, followed by their family doctors, in the LIFE study all patients
had EKG LVH, were older, at higher cardiovascular risk, were
randomized to receive 18 antihypertensive treatment, and were
followed according to a clinical prospective protocol. The prognostic
significance of LVM changes in subgroups of patients at higher CV risk
(diabetics, patients with previous stroke or MI) deserves further
investigation. Changes in geometric adaptation seem to imply a
prognostic value, independent of changes in LV mass. The persistence
or the development of a concentric geometry during treatment has
been found to be associated with a greater incidence of cardiovascular
events, independent of changes in LV mass [23]. The LIFE study has
provided results that confirm the prognostic influence of LV geometry,
in addition to changes in LV mass [24]. The better prognosis associated
with regression of LVH may be related to the improvement of systolic
and diastolic function, to the increase of coronary flow reserve, and to
the decrease of cardiac arrhythmias. ESC/ESH guidelines suggest that
echocardiography should be performed in patients at low or
intermediate CV risk in order to better identify the global
cardiovascular risk, and to more appropriately start pharmacological
treatment [8]. In fact, it has been shown that an increase of
echocardiographic LV mass can be identified in 2530% of
hypertensive patients with a low or moderate CV risk (based on risk
factor evaluation and EKG), thus substantially changing the original
risk stratification [25, 26]. There is no evidence that an
echocardiographic study can modify the therapeutic strategy in
patients at high or very high CV risk. In patients at high CV risk, and in
particular in patients with aortic valve disease or in patients with
asymptomatic LV dysfunction, echocardiography may be useful to
better define and follow cardiac anatomic and functional alterations.
Regression of echocardiographically determined inappropriate LVM
during treatment is associated with an improvement in prognosis, and
the evaluation of changes in LVM appropriateness may add prognostic
information, in particular in patients with persistence or development
of traditionally defined LVH At this time the echocardiographic
instrumentation for LV mass measurements is largely available in most
western countries, and hopefully with reduction of price its use will be
expanded worldwide. Among other diagnostic procedures, usually
reserved for specific indications, nuclear magnetic resonance provides
the most precise measurements of LV mass and cardiac tissue
constitution; however, the cost of NMR prevents large-scale use in
hypertension. Techniques based on reflectivity of cardiac ultrasound
imaging have been used in order to assess the degree of cardiac
fibrosis and to improve the ability of increased LV mass to predict
outcome, together with the use of new biomarkers, such as circulating
markers of collagen tissue composition. It has been demonstrated that
an effective, long-term antihypertensive treatment, inducing a gradual,
clinicaleventsTraditionalriskfactors,includingmalesex,ageing,beingoverweight,elevatedblood
pressure,diabetes,andsmoking,areallpositivelyassociatedwithcarotidIMTinobservationaland
epidemiologicalstudies.Hypertension,andparticularlyhighsystolicBPvalues,seemstohavethegreatest
effectonIMT[19].About30%ofhypertensivesubjectsmaybemistakenlyclassifiedasatlowor
moderateaddedriskwithoutultrasoundforcarotidarterythickeningorplaque,whereasvasculardamage
placestheminthehighaddedriskgroup[20].Alsosomenewriskfactors,includingvariouslipoproteins,
plasmaviscosity,andhyperhomocysteinaemiahavedemonstratedanassociationwithincreasedIMT.
PatientswithmetabolicsyndromehavehigherIMTthanpatientswithindividualmetabolicriskfactors.
CarotidIMThasalsobeenfoundtobeassociatedwithpreclinicalcardiovascularalterations,intheheart,in
thebrain,inthekidney,andinthelowerlimbarteries.Severalstudieshavedemonstratedandconfirmed
theimportantprognosticsignificanceofintimamediathickness,asmeasuredbyultrasound.Intheir
prospectivestudy,Salonenetal.[13]observedin1288Finnishmalesubjectsthattheriskforcoronary
eventswasexponentiallyrelatedtotheincreaseofintimamediathicknessinthecommoncarotidandinthe
carotidbifurcation.Inalargersampleofmiddleagedsubjects(13,780)enrolledintotheARIC
(AtheroscleroticRiskIntheCommunities)study[14]intimamediathickness,measuredbyultrasound,was
associatedwithanincreasedprevalenceofcardiovascularandcerebrovasculardiseases.IntheRotterdam
study[2]theintimamediathicknesswasshowntopredicttheriskofmyocardialinfarctionand
cerebrovasculareventsduringameanfollowupperiodof2.7years.TheCHS[3]hasprospectively
evaluated4400subjectsagedmorethan65yearsforafollowupperiodof6years;theannualincidenceof
myocardialinfarctionorstrokeincreasedinthehighestquintilesofintimamediathicknessmeasuredinthe
commonandtheinternalcarotidarteries.Arecentmetaanalysisofdatacollectedin8studiesingeneral
populations,including37,197subjectswhowerefollowedupforameanof5.5years,hasdemonstrated
thatforanabsolutecarotidIMTdifferenceof0.1mm,thefutureriskofmyocardialinfarctionincreasesby
10%to15%,andthestrokeriskincreasesby13%to18%[16](Table1).Ithasnotbeendemonstrated
whetheradecreaseofIMTprogressionisassociatedwithareductionofcardiovasculareventsandan
improvementinprognosis;theretrospectiveanalysisofsomestudieshasgivenconflictingresults.Nodata
areavailableontheprognosticsignificanceofplaquecompositioncharacteristics.20Table2.Effectof
antihypertensivetreatmentonchangesinIMTintrialswithantihypertensivedrugs(modifiedfromref[20])
AntihypertensiveComparisonChangeIMTm/yeartreatment(95%confidenceintervals)Alltrials
Placebo7m(12to2)(n=1780)(n=1549)p=0.01ACEinhibitorsPlacebo6m(12to0.4)(n=
1161)(n=929)p=0.41BetablockersPlacebo10m(33to13)(n=428)(n=434)p=0.02Alltrials
Diuretics/bblockers3m(5to0.3)(n=2285)(n=2279)p=0.03CalciumantagonistsDiuretics/b
blockers5m(9to1)(n=1811)(n=1808)p=0.007ACEinhibitorsDiuretics/bblockers1m(5
to2)(n=319)(n=321)p=0.52ACEinhibitorsCalciumantagonists23m(42to4)(n=142)(n=
145)p=0.02EffectoftreatmentTherapeuticdoubleblindtrialshaveshownthatantihypertensivedrugs
mayhaveamoreorlessmarkedeffectoncarotidIMTprogression.Arecentmetaregressionanalysis[21]
including22randomizedcontrolledtrialshasevaluatedtheeffectsofanantihypertensivedrugversus
placebooranotherantihypertensiveagentofadifferentclassoncarotidintimamediathickness.Theresults
haveshownthatcomparedwithnotreatment,diuretics/betablockers,orACEinhibitors,CCBsattenuate
therateofprogressionofcarotidintimamediathickening.Inthepreventionofcarotidintimamedia
thickening,calciumantagonistsaremoreeffectivethanACEinhibitors,whichinturnaremoreeffective
thanplaceboornotreatment,butarenotmoreactivethandiuretics//betablockers(Table2).Theodds
ratioforallfatalandnonfatalcardiovasculareventsintrialscomparingactivetreatmentwithplacebo
reachedstatisticalsignificance(p=0.007).TheresultsofthePHYLLISstudyhavereportedthatin
hypertensiveandhypercholesterlaemicpatients,theadministrationofpravastatinpreventstheprogression
ofcarotidintimamediathicknessseeninpatientstreatedwithhydrochlorothiazide,butthecombinationof
pravastatinandtheACEinhibitorFosinoprilhadnoadditiveeffect[22].Fewstudies,includingarelatively
smallnumberofpatients,haveshownalowerthicknessofintimamediaduringtreatmentwithangiotensin
IIantagonistsinrespecttopatientstreatedwithbetablockers[23].Arecentstudy(MORE,Multicentre
OlmesartanAtherosclerosisRegressionEvaluation)assessingtheeffectoflongtermtreatmentwithan
AT1receptorantagonist(olmesartan)andwithabetablocker(atenolol)oncarotidatherosclerosis,withthe
useofthenoninvasive3Dplaquemeasurement,hasconfirmedthegreaterreductionofplaquevolumewith
theAngiotensinIIblockerinrespecttothebetablocker[24].Nosignificantchangesinplaquecomposition
wereobservedafter4yearsoftreatmentwitheitherlacidipineoratenololinpatientsparticipatingintothe
ELSAstudy,suggestingthattreatmentwithacalciumantagonistmayslowIMTprogressionwithout
influencingthecharacteristicsofplaquetissue[25].ConclusionsAnultrasoundexaminationofthe
common,bifurcation,andinternalcarotidarteriesshouldbeperformedinhypertensivepatientswith
concomitantriskfactors,suchassmoking,dyslipidaemia,diabetes,andfamilyhistoryforcardiovascular
diseases.However,beforewidelyproposingroutinemeasurementofIMTinclinicalpracticeforstratifying
cardiovascularrisk,methodologicalstandardizationforIMTmeasurementneedstobefurther
implemented.QuantitativeBmodeultrasoundofcarotidarteriesrequiresappropriatetraining.Inthe
presenceofincreasedIMTorplaqueinthecarotidarteriesanaggressiveapproachtoriskfactor
modificationsshouldbeconsidered.References1.MuiesanML,PasiniGF,SalvettiM,etal.Cardiacand
vascularstructuralchanges:prevalenceandrelationtoambulatorybloodpressureinamiddleagedgeneral
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AW,KoudstaalPJ,HofmanA,GrobbeeDE.Commoncarotidintimamediathicknessandriskofstroke
andmyocardialinfarctiontheRotterdamStudy.Circulation1997;6:14321437.3.OLearyDH,PolakJF,
KronmalRA,etal.;fortheCardiovascularHealthStudyCollaborativeresearchGroup.Carotidintimaand
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ResearchGroup.Circulation1994;90:16791687.5.TangR,HenningM,ThomassonB,etal.Baseline
reproducibilityofBmodeultrasonicmeasurementofcarotidarteryintimamediathickness:theEuropean
LacidipineStudyonAtherosclerosis(ELSA).JHypertens2000;18:197201.6.ZanchettiA,Agabiti
RoseiEA,DalPalC;fortheVerapamilinHypertensionandAtherosclerosisStudy(VHAS)Investigators.
TheVerapamilinHypertensionandAtherosclerosisStudy(VHAS):resultsoflongtermrandomized
treatmentwitheitherverapamilorchlortalidoneoncarotidintimamediathickness.JHypertens1998;16:
16671676.7.BotsM,EvansG,RileyW,GrobbeeDE.CarotidIntimaMediaThicknessMeasurementsin
InterventionStudiesDesignOptions,ProgressionRates,andSampleSizeConsiderations:APointofView.
Stroke2003;34:29852994.8.TouboulPJ,HennericiMG,MeairsS,etal.MannheimCarotidIntima
MediaThicknessConsensus(20042006).AnUpdateonBehalfoftheAdvisoryBoardofthe3rdand4th
WatchingtheRiskSymposium13thand15thEuropeanStrokeConferences,Mannheim,Germany,2004,
andBrussels,Belgium,2006.CerebrovascDis2006;23:7580.9.PainiA,BoutouyrieP,CalvetD,etal.
Multiaxialmechanicalcharacteristicsofcarotidplaque:analysisbymultiarrayechotrackingsystem.Stroke
2007;38:117123.10.SalonenR,HaapanenA,SalonenJT.Measurementofintimamediathicknessof
commoncarotidarterieswithhighresolutionBmodeultrasonography:Interandintraobservervariability.
UltrasoundMedBiol1991;17:225230.11.BorhaniNO,MercuriM,BorhaniPA,etalFinaloutcome
resultsoftheMulticenterIsradipineDiureticAtherosclerosisStudy(MIDAS)JAMA1996;276:785791.
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Thromb1994;14:12971304.13.SalonenJT,SalonenR.Ultrasonographicallyassessedcarotid
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467.17.PuatoM,FagginE,RattazziMetal.;onbehalfoftheStudyGrouponArterialWallStructure.In
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FerreroS,etal.Assessmentofcarotidplaquecompositioninhypertensivepatientsbyultrasonictissue
characterization:avalidationstudy.JHypertens2002;20:15891596.19.ZanchettiA,BondMG,Hennig
M,etal.Calciumantagonistlacidipineslowsdownprogressionofasymptomaticcarotidatherosclerosis:
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intimamediathicknessandplaquevolumechangesfollowing2yearangiotensinIIreceptorblockade.The
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12031209.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management21HOMEBLOODPRESSUREMONITORINGGianfrancoParati1,2,3,GrzegorzBilo3,
SverreE.Kjeldsen4,GiuseppeMancia1,2,31DepartmentofClinicalMedicineandPrevention,
UniversityofMilanoBicocca,Milan,Italy2CentroInteruniversitariodiFisiologiaClinicaeIpertensione,
Milan,Italy3DepartmentofCardiology,S.LucaHospital,IstitutoAuxologicoItaliano,Milan,Italy4
DepartmentofCardiology,OsloUniversityHospital,Ullevaal,Oslo,Norway2009;10:No.12Rrevised
versionIntroductionHomebloodpressure(BP)monitoringismoreandmorefrequentlyemployedin
clinicalpracticetoassessasubjectsBPstatusinhypertensiondiagnosisandfollowup.Thisincreasinguse
isduetoanumberofadvantagesofhomeBPoverconventionalofficeBPmeasurement,andtotherapid
technologicaldevelopmentinthefieldleadingtoaccurateandcheapautomatedBPmonitoringdevicesthat
areeasytouseinthepatientshome(Table1)[1].Thegrowinginterestinthisapproachistestifiedbythe
almostsimultaneouspublicationin2008ofupdatedESHguidelinesforhomeBPmonitoring[2]andthe
USrecommendationsonthesametopic[3].Featuresofhomebloodpressuremonitoringanditsreference
valuesThemainadvantagesofhomeBPoverofficeBPmonitoringarerelatedtotheabilityoftheformer
approachtoprovideamuchlargernumberofmeasurements[4],obtainedautomaticallybyvalidated
devicesoverextendedperiodsoftimeinsubjectsdailylifeconditions.Theaveragevaluesderivedfrom
repeatedhomeBPmeasurementsaremorereproduciblethanofficeBP[5,6],arenotaffectedbyobserver
biasorenddigitpreference[7],andaredevoidofasystematicerrorrelatedtothepresenceofthewhite
coateffect[8].Ingeneral,homeBPtendstobelowerthanofficeBPandsimilartodaytimeambulatory
BP.Infact,basedonbothepidemiologicalandoutcomestudies,thecommonlyacceptedthresholdfor
hypertensiondiagnosiswithhomeBPmonitoring(correspondingtoanofficeBPthresholdof140/90mm
Hg)is135/85mmHg,whichisthesameaswithaveragedaytimeambulatoryBP[2,911].More
longitudinalandoutcomestudiesarestillneeded,however,todeterminethehomeBPtargetsfor
antihypertensivetreatment,aswellasthehomeBPdiagnosticthresholdstobeusedinhighrisksubjects,
suchasthosewithdiabetesandkidneydisease.Table1.Advantagesandlimitationsofhomeblood
pressuremonitoring([2]modifiedbypermission)AdvantagesAnumberofmeasurementsduringtheday
andoverseveraldays,weeks,ormonthsarepossibleAssessmentoftreatmenteffectsatdifferenttimesof
thedayandoverextendedperiodsNoalarmreactiontoBPmeasurementGoodreproducibilityBetter
prognosticvaluethanisolatedofficeBPreadingsRelativelylowcostPatientfriendliness(withsemi
automatedandautomateddevices)InvolvementofpatientinhypertensionmanagementPossibilityof
digitalstorage,printout,PCdownload,orteletransmissionofBPvalues(insomedevices/systems)
ImprovementofpatientcompliancetotreatmentImprovementofhypertensioncontrolratesLimitations
Needforpatienttraining(shortforautomateddevices)Possibleuseofinaccuratedevices(needtocheck
theirvalidation)MeasurementerrorsLimitedreliabilityofBPvaluesreportedbypatientsInductionof
anxiety,resultinginexcessivemonitoringTreatmentchangesmadebypatientsonthebasisofcasualhome
measurementswithoutdoctorsguidanceNormalitythresholdsandtherapeutictargetsstilldebatedLackof
nightBPrecordingsBPbloodpressurePrognosticsignificanceRecently,anumberofstudieshavebeen
publishedwhichdocumenttheprognosticvalueofhomeBPintermsofcardiovascularevents[1217].All
thesestudieshavedemonstratedthathomeBPmaybeabetterriskpredictorthanofficeBP.Moreover,the
resultsofPAMELAsuggestthathomeBPmightprovideadditionalprognosticinformationindependentof
thatprovidedby24hourambulatoryBPmonitoring(ABPM)[12].Whenproperdiagnosticthresholdsare
considered,theclassificationofsubjectssuchashypertensiveornormotensiveBPbasedonhome
monitoringisnotalwaysinaccordancewiththatbasedonofficeBP,afindinginlinewithprevious
observationsbasedonacomparisonbetweenofficeBPandABPM.Whilesomesubjectscanbeclassified
astruenormotensive(bothofficeandhomeBPnormal)orsustainedhypertensive(bothofficeandhome
BPelevated),inothersubjectseitheranassociationbetweenelevatedofficeBPandnormalhomeBP
(isolatedofficehypertensionorwhitecoathypertension)orbetweennormalofficeBPandelevatedhome
BP(maskedhypertension)canbeobserved.Asshownbyseveralstudies,isolatedofficehypertensionmay,
ifanything,onlymoderatelyincreasecardiovascularriskcomparedwithtruenormotensivesubjects,while
maskedhypertensionisassociatedwithacardiovascularriskclosetothatofsustainedhypertension[8,12,
17,18].Thus,unlesshomeBP(orABPM)isused,inthelattercase,ahighBPrelatedcardiovascularrisk
willnotbeidentified,withtheconsequentinabilitytoadequatelymanagesubjectswithmasked
hypertension,whoconstitute1020%ofthegeneralpopulation(Figure1).Usefulnessofhomeblood
pressuremonitoringInthediagnosisofhypertension,homeBPmonitoringdoesnotsubstituteofficeBP
butisausefulcomplementarytoolindefiningBPrelatedcardiovascularriskmoreaccurately,especiallyin
patientsinwhomofficeBPprovidesquestionableresults(highBPvariability,pronouncedwhitecoat
effect,inconsistentrelationwithorgandamage,etc.)[1,2].Inthisregard,homeBPmonitoringmaybe
usedasafirstlinetool,beingcheaperthanABPM.HomeBPmonitoringisevenmoreusefulinthefollow
upoftreatedhypertensivepatients.Thisisbecauseofitsprognosticvalue,lowcost,andadditional
advantagesrelatedtotheFigure1.Classificationofsubjectsbasedonofficeandhomebloodpressure(BP)
beingaboveorbelowtherespectiveacceptedthresholdsforhypertensiondiagnosis(modifiedfrom[2],by
permission).Sustainedhypertensivesareatgreatestriskofcardiovascularevents,andtruenormotensive
subjectsatlowestrisk.Whitecoatandmaskedhypertensiveslieinbetween,subjectswithisolatedoffice
hypertensionhavingariskclosertothatoftruenormotensives,andsubjectswithmaskedhypertension
carryingariskclosertothatoftruehypertensivepatients22factthathomeBPmonitoringmay,byitself,
improveBPcontrol[19]probablybypromotingpatientsinvolvementinthemanagementoftheirhighBP
conditionandthusfavouringtheiradherencetoprescribedantihypertensivetreatment[20].Therefore,
homeBPmonitoringmaybeparticularlyvaluableinrefractoryhypertension,oftencausedbypoor
compliance[1,2].HomeBPmonitoringmayalsobeusefulinclinicalresearch[21].Inclinicaltrials,home
BPmeasurements,beingmorereproducibleandfreefromthewhitecoateffect,improvethestatistical
powerandminimizeoreliminatetheplaceboeffectandmaythusfacilitatethedetectionofdifferencesin
BPbetweentreatments[22,23].Moreover,morningandeveninghomeBPvaluesmaybeusedfor
assessingthedurationofactionofagivendrugordrugcombination,andforevaluatingtheeffectsof
differentdosingpatterns[24].HomeBPisalsoaninterestingoptionforobtaininginformationonBPlevels
inoutcomestudieswithlargepopulationsandlongfollowup,whereitmaybeconsideredaparticularly
suitabletool,beingmoreprecisethanofficeBPandlessexpensiveandeasiertoimplementonalargescale
thanABPM[2].PracticalissuesAnumberofmethodologicalrequirementshavetobefulfilledinorderto
maximizetheclinicalvalueoftheinformationobtainedbyhomeBPmonitoring.Measurementconditions
shouldbestandardizedsimilarlyaswithofficeBP(Table2).Onlyfullyautomatedoscillometricupperarm
devices,validatedaccordingtointernationallyacknowledgedprotocols,arecurrentlyrecommended(lists
ofvalidateddevicesareavailableatdedicatedwebsites,e.g.www.dableducational.org)[2].The
auscultatorytechniqueisnotrecommendedwithhomeBPmonitoringbecauseitisdifficultforpatientsand
isassociatedwithproblemsofdeviceaccuracy(especiallyinthecaseofaneroiddevices),withthepossible
exceptionofpatientswithsignificantarrhythmias(atrialfibrillation),inwhomtheoscillometrictechnique
isinaccurate.Fingerdevicesshouldnotbeusedatall.Validatedwristdevicesmightbeconsideredbutonly
inselectedcases(e.g.obesesubjectswithconicalarmshape,elderlysubjectswithmotorimpairment),
althoughtheirroutineuseisnotrecommendedatthepresenttime[2].Forclinicaldecisions,theaverage
valueofanumberofhomeBPmeasurementsshouldbeused.WhileevenafewhomeBPreadingsmay
provideinformationofprognosticsignificance,alargernumberofthemprovideinformationthatismore
reproducibleandmorecloselyassociatedwithriskofevents[4].Therefore,itisproposedthatanaverage
ofmeasurementsobtainedover7days(twointhemorningbeforedrugintakeiftreatedandtwoin
theevening)beforeeachdoctorsvisitshouldbeused,discardingthevaluesoftheinitialday,whichare
higherandlessstable[2,4].PatienteducationiscrucialforthecorrectperformanceofhomeBP
monitoring[25].Itshouldincludeinformationabouthypertensionandcardiovascularrisk,traininginBP
measurement,adviceontheequipment,andinformationaboutmeasurementprotocolandinterpretationof
BPreadings.Inparticular,selfmodificationoftreatmentbypatientsbasedonhomemeasuredBPvalues
shouldbediscouraged,andhomeBPmonitoringshouldalwaysbeperformedunderthesupervisionofthe
physicianinchargeofthepatient.Specialtrainingfordoctorsandnursesmightbeneededaswell.When
careistakentoensurethattheaboverequirementsarefulfilled,thevastmajorityofsubjectsareexpected
tobeabletoperformgoodqualityandclinicallyvaluablehomeBPreadings[26].Finally,homeBPmaybe
veryusefulinspecialpopulationssuchaspregnantwomen,highrisksubjects(e.g.thosewithdiabetesor
renaldisease),children,andelderlysubjectsalthoughfurtherstudiesarestillneededtodefinediagnostic
thresholdsforhomeBPinthesegroups,andonlyafewdevicesvalidatedtobeusedinthesespecial
conditionsarecurrentlyavailable[2].Recentevidenceemphasizestwoadditionaladvantagesassociated
withuseofHomeBPmonitoring.First,useofselfBPmeasurementsathomeoveraprolongedfollowup
timeallowsnotonlymeanHomeBPlevelstobeassessed,butalsothevariabilityinHomeBPbetween
daystobequantified.ThismaybeclinicallyrelevantbecausedatafromtheOhasamastudyhaveprovided
evidencethatanenhanceddaytodayvariabilityinHomeBPcarriesanincreasedriskofcardiovascular
mortality[27].Second,inafewrecentstudies,theadditionoftelemonitoringofhomeBPtoroutinepatient
managementwasshowntoimprovetherateofhypertensioncontrol.Thiswaslargelyduetobetterpatient
compliancewithtreatment,and/ortopatientsactivecooperationintitratingtheirongoingdrugtherapy
followinginstructionsbytheirphysicians.[2832].Thisisanadvantageofparamountimportancebecause
inreallifelowcompliancetotreatmentisanextremelycommonphenomenon,whichcanbeheldas
majorlyresponsibleforthepoorrateofBPcontrolthatcharacterizesthehypertensivepopulation[33].
ConclusionsHomeBPmonitoringoffersmanyadvantagesoverclinicBPmeasurements,andmayimprove
theoverallmanagementofhypertension[2832,34].Itsuseinclinicalpracticeiscurrentlysupportedby
robustscientificevidence,butpropermethodology,adequatepatienttraining,andcorrectdata
interpretationareindispensableforthesafeandeffectiveuseofthismethodinhypertensiondiagnosis,
monitoring,andtreatment.Table2.Methodologicalrequirementsforthecorrectimplementationofhome
bloodpressuremeasurementsMeasurementsobtainedover5minutes,afteraperiod30minutes
withoutsmokingoringestingcaffeinePatientseatedforatleast5min,withhis/herbacksupportedandthe
armrestingonthetableTheloweredgeofthecuffbeingabout2.5cmabovethebendoftheelbowandthe
cuffitselfbeingpositionedatheartlevelPatientimmobileandnottalkingduringthemeasurement
Repeatedreadingstaken12minutesapartMeasuredbloodpressurevaluesrecordedimmediatelyonlog
bookand/orstoredindevicememory)[2]References1.ManciaG,DeBackerG,DominiczakA,etal.
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trialsfortheassessmentofantihypertensivedrugefficacy.AmJHypertens2002;15:101104.6.Brook
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625631.7.BurnierM,GasserUE.Enddigitpreferenceingeneralpractice:acomparisonofthe
conventionalauscultatoryandelectronicoscillometricmethods.BloodPress2008;17:104109.8.Parati
G,BiloG,ManciaG.Whitecoateffectandwhitecoathypertension:Whatdotheymean?CardiovascRev
Rep2003;24:477484.9.ThijsL,StaessenJA,CelisH,etal.Referencevaluesforselfrecordedblood
pressure.Ametaanalysisofsummarydata.ArchInternMed1998;158:481488.10.ThijsL,Staessen
JA,CelisH,etal.Theinternationaldatabaseofselfrecordedbloodpressuresinnormotensivesand
untreatedhypertensivesubjects.BloodPressMonit1999;4:7786.11.OBrienE,AsmarR,BeilinLet
al.;onbehalfoftheEuropeanSocietyofHypertensionWorkingGrouponBloodPressureMonitoring.
EuropeanSocietyofHypertensionrecommendationsforconventional,ambulatoryandhomeblood
pressuremeasurement.JHypertens2003;21:821848.12.ManciaG,FacchettiR,BombelliM,GrassiG,
SegaR.Longtermriskofmortalityassociatedwithselectiveandcombinedelevationinoffice,home,and
ambulatorybloodpressure.Hypertension2006;47:846853.13.OhkuboT,AsayamaK,KikuyaM, et
diuretics.Afewplacebocontrolledstudiesareavailable,buttherearealmostnoheadtoheadstudies
directlycomparingtheefficacyandsafetyofdifferentantihypertensivedrugsinchildrenoradolescents.
CombinationtherapyInchildrenwithrenaldisease,monotherapyisoftennotsufficienttoachieve
adequateBPcontrol.Therefore,earlycombinationtherapyisrequired.Earlydosecombinationof
antihypertensiveagentsismoreefficientandhasalowerrateofadversedrugreactioncomparedtothatof
highdosemonotherapy.Antihypertensivedrugsofdifferentclasseshavecomplementaryeffects,resulting
inahigherdegreeofBPreductionandalowerrateofadversedrugreaction.Thebestchoicesof
antihypertensivedrugcombinationsarethoserecommendedintheESH2009reappraisalofGuidelines
[23].Fixeddosecombinationsoftwodrugsarerarelyusedinchildren,sinceindividualbased
contributionsarepreferred,butfixedcombinationsmayhaveaplaceintreatingadolescentstoimprove
compliance.Treatmentofassociatedriskfactors:lipidloweringagentsandglycaemiccontrolThenew
guidelinesoftheAmericanAcademyofPaediatrics(AAP)recommendmeasuringlipoproteinsstartingat
age2inoverweight,hypertensive,ordiabeticchildrenorinthosewithafamilyhistoryofdyslipidaemiaor
earlycoronaryarterydisease[24].Iflipidvaluesarewithinageandgenderspecificnormalranges,
childrenshouldberetestedin3to5years.Forthoseoutofnormalranges,initialtreatmentshouldbe
focusedonrecommendingadietlowincholesterol(<200mg/day)andsaturatedfat(<7%ofcalories)
supplementedwithplantsterolsanddietaryfibres(childsage+5g/dayupto20gat15yearsofage)[25].
IncreasedphysicalactivitymaybeusefulformodifyingHDLCandtriglycerides.AccordingtotheAAP,
statinsshouldbeconsideredforchildren8yearsandolderifanyofthefollowingconditionsexist:a)LDL
Cremains190mg/dl(4.94mmol/L);b)LDLCremains160mg/dl(4.16mmol/L)andthereisafamily
historyofearlycoronaryarterydiseaseorthepresenceofotherriskfactorsasobesity,hypertension,or
smoking;orc)LDLCremains130mg/dl(3.38mmol/l)inchildrenwithdiabetesmellitus.TheFoodand
DrugAdministration(FDA)andEuropeanMedicinesAgency(EMEA)hasapprovedtheuseofpravastatin
forchildrenwithfamilialhypercholesterolaemiawhoare8yearsandolder.Itshouldbenoted,however,
thatAAPrecommendationsarecontroversial:theyarenotevidencebasedandthelongtermeffectsof
statinsonchildrenareunknown.TheuseofezetimibeisapprovedintheUSA(butnotinEurope)onlyfor
thoserarechildrenwithfamilialhomozygoushypercholesterolaemiaorwithsitosterolaemia.Bileacid
sequestrantsaredifficulttotolerateoverthelongterm.Fibratesmaybeusedinadolescentswith
triglycerides500mg/dlwhoareatincreasedriskofpancreatitis[24,25].Theincreasingprevalenceof
paediatrictype2diabetescoincideswithincreasingobesityinchildren.Mostobesechildrenhaveinsulin
resistance(60%),5%haveimpairedglucosetolerance(IGT),1%impairedfastingglucose,and0.2%type2
diabetes[11].Reducingoverweightandimpairedglucosetolerancemayhelppreventordelaythe
developmentoftype2diabetesinhighriskyouths.Behaviouralmodification(dietarychangesand60
minutesdailyofphysicalactivity),usingtechniquestomotivatechildrenandfamilies[11],iseffectiveat
reducinginsulinlevelsandrevertingimpairedglucosetolerancetonormal.Metforministheonlyoral
medicationthathasbeenadequatelystudiedinchildrenandapprovedbytheFDAandsomeEuropean
Agenciesforuseinchildrenover10yearsofagewithtype2diabetes.Inobeseinsulinresistantchildren,
metforminhasbeenshowntohavefavourableeffectsonbodycomposition,fastinginsulin,andfasting
glucose[26].ConclusionsItisclearthatpaediatrichighBPwillfurthercontributetothecurrentepidemic
ofcardiovasculardiseaseunlessitisgiventheattentionitdeservesbypolicymakers,healthcareproviders,
schools,parents,caregivers,andsocietyasawhole.Theroleoflearnedsocieties,particularlytheEuropean
SocietyofHypertension,iscrucialnotonlyforspreadingtheguidelinesthroughoutallEuropeanCountries,
butalsoforobtainingtheiracceptancebynationalhypertensionsocietiesandleagues.References1.
NationalHeart,Lung,andBloodInstitute.ReportoftheSecondTaskForceonBloodPressureControlin
Children1987.Pediatrics1987;79:125.2.BaoW,ThreefootSA,SrinivasanSR,BerensonGS.Essential
hypertensionpredictedbytrackingofelevatedbloodpressurefromchildhoodtoadulthood:theBogalusa
HeartStudy.AmJHypertens1995;8:657665.3.VosLE,OrenA,BotsML,etal.Doesaroutinely
measuredbloodpressureinyoungadolescenceaccuratelypredicthypertensionandtotalcardiovascularrisk
inyoungadulthood?JHypertens2003;21:20272034.4.SunSS,GraveGD,SiervogelRM,etal.blood
pressureinchildhoodpredictshypertensionandmetabolicsyndromelaterinlife.Pediatrics2007;119:
237246.5.NationalHighBloodPressureEducationProgramWorkingGrouponHighBloodPressurein
ChildrenandAdolescents.Thefourthreportonthediagnosis,evaluation,andtreatmentofhighblood
pressureinchildrenandadolescents.NationalHeart,Lung,andBloodInstitute,Bethesda,Maryland.
Pediatrics2004;114:555576.6.MacMahonS,PetoR,CutlerJ,etal.Bloodpressure,strokeandcoronary
heartdisease.Part1,Prolongeddifferencesinbloodpressure:prospectiveobservationalstudiescorrected
fortheregressiondilutionbias.Lancet1990;335:765774.7.UrbinaE,AlpertB,FlynnJ,etal.American
HeartAssociationAtherosclerosis,Hypertension,andObesityinYouthCommittee.Ambulatoryblood
pressuremonitoringinchildrenandadolescents:recommendationsforstandardassessment:ascientific
statementfromtheAmericanHeartAssociationAtherosclerosis,Hypertension,andObesityinYouth
Committeeofthecounciloncardiovasculardiseaseintheyoungandthecouncilforhighbloodpressure
research.Hypertension2008;52:433451.8.OBrienE,SheridanJ,OMalleyK.Dippersandnon
dippers.Lancet1988;2:397.9.PickeringTG,JamesGD,BoddieC,etal.Howcommoniswhitecoat
hypertension?JAMA1988;259:225228.10.PickeringTG,DavidsonK,GerinW,SchwartzJE.Masked
hypertension.Hypertension2002;40:795796.11.LurbeE,CifkovaR,CruickshankJK,etal.
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McGavockJ.Overweight,physicalactivityandhighbloodpressureinchildren:areviewoftheliterature.
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cardiology:theBogalusaHeartStudy.PrevCardiol2005;8:234241.14.GrafC,RostSV,KochB,etal.
DatafromtheStEPTWOprogrammeshowingtheeffectonbloodpressureanddifferentparametersfor
obesityinoverweightandobeseprimaryschoolchildren.CardiolYoung2005;15:291298.15.LurbeE.
Childhoodbloodpressure:awindowtoadulthypertension.JHypertens2003;21:20012003.16.
GenovesiS,AntoliniL,GiussaniM,etal.Usefulnessofwaistcircumferencefortheidentificationof
childhoodhypertension.JHypertens2008;26:15631570.17.BarkerDJ,OsmondC,GoldingJ,KuhD,
WadsworthME.Growthinutero,bloodpressureinchildhoodandadultlife,andmortalityfrom
cardiovasculardisease.BMJ1989;298:564567.18.BansalN,AyoolaO,GemmellI,etal.Effectsof
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ageof2years.TheGenerationStudy.JHypertens2009;27:11521157.20.GeleijnseJM,GrobbeeDE.
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obesityacrossthelifecourse:aquantitativereviewofpublishedevidence.Pediatrics2005;115:1367
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progressionofrenalfailureinchildren.NEnglJMed2009;361:16391650.23.ManciaG,LaurentS,
AgabitiRoseiE,etal.ReappraisalofEuropeanguidelinesonhypertensionmanagement:aEuropean
SocietyofHypertensionTaskForcedocument.JHypertens2009;27:21212158.24.DanielsSR;Greer
FRandtheCommitteeonNutrition.LipidScreeningandCardiovascularHealthinChildhood.Pediatrics
2008;122:198208.25.LichtensteinAH,AppelIJ,BrandsM,etal.Dietandlifestylerecommendations
revision2006:AscientificstatementfromtheAmericanheartassociationnutritioncommittee.Circulation
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bodycompositioninobeseinsulinresistantchildren:arandomizedclinicaltrial.Diabetes2011;60:477
485.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement25
HYPERTENSIONANDCORONARYHEARTDISEASEJeanPhilippeBaguet,GillesBaroneRochette,
JeanMichelMallionHypertensionUnit,CardiologyDepartment,GrenobleUniversityHospital,BP217,
38043Grenoblecedex09,France2011;12:No.14RrevisedversionIntroductionHypertension(HT)isa
majorriskfactorforcoronaryheartdisease(CHD).AmongthenumerousriskfactorsassociatedwithCHD,
HTplaysamajorrolegivenitshighfrequencyanditsphysiopathogenesis.Thus,roughly20%ofthe
generaladultpopulationmanifestHTwithanetmalepredominance,and25%ofpatientswithCHDhave
HT[1].CHDisthefirstcauseofmorbidityandmortalityinhypertensivepatients.Numerousotherrisk
factorsforCHD,suchasdyslipidaemia,diabetes,insulinresistance,obesity,lackofphysicalexerciseand
certaingeneticmutations,arefrequentlyassociatedwithHT[2].Furthermore,hypertensivepatientshavea
greaternumberofcardiovascularriskfactorsthannormotensivepatients.IntheINTERHEARTstudy,
historyofhypertensionwassignificantly(oddsratio1.91)relatedtoacutemyocardialinfarction[3].
EpidemiologicalstudieshaveshownthatsmokingandhypercholesterolaemiaincreasetheriskforCHD
associatedwithHTinamultiplicativeratherthaninanadditivemanner[4].Furthermore,althoughHT
aloneisweaklypredictiveofindividualriskfortheoccurrenceofCHD,theassociationbetweenthelevel
ofbloodpressure(BP)andtheriskofCHDisindependentofotherfactors.LevelofBPandriskofCHD
NumerousepidemiologicalstudieshaveshownthatthepresenceofHTincreasestheriskofCHD,notonly
inatriskpopulationsbutalsointhegeneralpopulation.TheprevalenceofCHDiscloselyrelatedtotheBP
level,especiallysystolicBP.ThishasbeenshowninstudiesofclinicalBPandalsoinstudiesusing
ambulatoryBPmeasurements(ABPM)[5].Otherwise,theincreaseinpulsepressureisapredictivefactor
ofcoronarymortality[6].TherelationshipbetweenBPlevelandCHDseemslinear,continuous,and
independent[7].Indeed,theJshapedcurveoftherelationshipbetweenBPlevelandtheriskofCHD
comesfromretrospectivestudiesinpatientswithcardiovascularantecedentsbeforeantihypertensive
treatmentwasinstituted.ProspectivetherapeutictrialsdidnotshowanincreaseinriskofCHDinthelower
levelsofBP.Afteramyocardialinfarctiontheriskofasubsequentfatalornonfatalcoronaryeventis
greaterifBPisraised[8].InreferencetoABPMstudies,ithasbeenreportedthatnondipperhypertensive
patients(nighttimefallinBP<10%)haveacardiovascularrisk,inparticularaCHDrisk,multipliedby
three[9].ThefallinBPundertreatmentisassociatedwithareductionincardiovascularevents,moresofor
strokethanforcoronaryevents.Thus,areductionby5mmHgindiastolicBPreducesbyonefifththerisk
ofCHD,andareductionof10mmHgleadstonearlyaonethirdreductioninCHDrisk[1].Accordingtoa
metaanalysisof37,000patientsfollowedupover5years,treatmentofmoderateHTreducedby14%the
coronarymorbidityandmortalitybyprimaryprevention[10].Likewise,themetaanalysisbyMacMahon
etal.showedthatafallinBPinhypertensivesubjectsover60yearsreducedmajorcoronaryeventsby
19%[11].PhysiopathogenesisofmyocardialischaemiainHTThereisamultiplicityofmechanisms
relatedtoHTthatleadtothedevelopmentofmyocardialischaemia.Theseactbyleadingtoaninequality
betweenthetransportandconsumptionofoxygenbythemyocardium.AccelerationofatherosclerosisHT
isanimportantriskfactorforatherosclerosisandinparticularinthecoronarybed.Thereductioninthe
lumenofthecoronaryarteriesbyatheromatousplaquesreducesmyocardiumbloodflow,therebyfavouring
ischaemia.Theseplaquesmayeventuallybreakandthusformperipheralemboliorespeciallythrombusin
situbymeansofplateletaggregationthatisresponsibleforacutecoronarysyndromes.Leftventricular
hypertrophyLeftventricularhypertrophy(LVH)isoneofthemostimportantriskmarkersforCHDand
suddendeathindependentofthelevelofBP[12].ThisisthecasewhetherLVHisdiagnosedbyECGorby
echocardiography.LVHreducescoronaryflowreserveandfavoursthedevelopmentofventricular
arrhythmias.Thisreductionincoronaryflowreserveissecondarytostructuralandfunctionalmodifications
inthemyocardium(myocardialcomponent)andinthearteries(vascularcomponent),andalsotoanomalies
inthecontrolofcoronarybloodflow(nervouscomponent)[13].LVHincreasesmetabolicandoxygen
demandsofthemyocardium,increasescoronaryflowandcoronaryvascularresistances,butdiminishes
coronaryflowreserve.Thisisassociatedwithdisturbanceofdiastolicfunctionoftheleftventriclethat
leadstoafallinperfusionofthemyocardium.Furthermore,LVHisresponsiblefordysfunctionofthe
mechanoreceptorsintheleftventricle,therebyleadingtoanomaliesincoronaryvasculartone.Anomalies
ofthemicrocirculationHTisassociatedwithanomaliesofthecoronarymicrocirculationwitha
perivascularfibrosis,athickeningofthemedia,areductioninthenumberofcapillariespergramof
musculartissue,andadiminutionofthevascularlumen[14].EndothelialdysfunctionTheendothelium
dependentvascularrelaxationisalteredinHT[15].Thishasbeenwelldemonstratedbythereductionin
thevasodilatorresponseafteranintraarterialinjectionofacetylcholineinthehypertensivesubjectwhile
theresponsetonitratederivativesisnotaltered[16].Thisendothelialdysfunctionbringsintofunction
numerousmediatorssuchasnitricoxide,prostacyclins,factorsactingonthedifferentiationandthegrowth
ofvascularsmoothmusclecells,orcyclooxygenasedependentcontractionfactor.Theanomaliesin
endothelialfunctionexplaininparttheincreaseintheriskofCHDinHTsincetheyfavour
vasoconstriction,thrombogenesis,andtheactionofproliferativesubstances.InsulinresistanceInsulin
resistanceisfrequentlyfoundinessentialHT.Thisleadstohyperinsulinismthatisanindependent
predictivefactorofCHD.ThisinsulinresistanceisoftenassociatedwithlowlevelsofHDLcholesteroland
elevatedlevelsoftriglycerides.Thesemayresultinanaccelerationoftheatheroscleroticprocess.
SympatheticactivationTheregulationofmyocardialbloodflowis,inpart,mediatedbythesympathetic
nervoussystem.HTisaccompaniedbyanexaggeratedsympatheticresponsetophysiologicalstimulithat
favoursmyocardialischaemia.DetectionofCHDinthehypertensivepatientRepolarisationanomaliesare
frequentlyfoundontheECGsofhypertensivepatients,inparticularnegativeTwavesinthelateralleads
indicatingsystolicoverloadoftheleftventricle,frequentlyassociatedwithLVH.TheexerciseECGis
difficulttointerpretinHTsinceaSTdepressioninV5andV6isfrequentespeciallyinthepresenceof
LVH.Thesefindingsareoflowspecificityformyocardialischaemia.Myocardialscintigraphyisalsooften
abnormalinHTbecauseofLVHandanomaliesofcoronarymicrocirculation[17].Stressechocardiography
canalsobeperformedinhypertensivesubjectstodetectmyocardialischaemia.Ifdiagnosticdoubtpersists
afteranoninvasivetestinhypertensivesubjectswithchestpain,coronaryangiographyisoftennecessary.
Ithasbeenshownthatroughly30%ofhypertensiveshavesilentepisodesofmyocardialischaemiaduetoa
reductionincoronaryflowreserve,endothelialdysfunctionandanomaliesintheautonomicnervous
system.TreatmentofHTandCHDAnisolatedfallinBPwithtreatmentdoesnotcompletelyreducethe
riskofCHDinessentialHT.ThisconfirmsthecomplexityoftherelationshipbetweenCHDandHTsince
numerousfactorsotherthanHTareimplicated,aspreviouslydiscussed.TreatmentofHTinpatientswith
26CHDmustbemoreaggressivethanintheabsenceofCHD.Indeed,theriskofarecurrentcoronary
eventinthispopulationisveryhigh,andalleffortsshouldbeexpendedinordertolowerBP,especially
sincewemayexpectabettercompliancewithtreatmentafteracoronaryevent.Inprimaryprevention,
successivestudieshaveshownthebenefitofthiazidediureticsandbetablockersoncardiovascularevents.
Subsequently,calciumchannelblockersandangiotensinconvertingenzyme(ACE)inhibitorshavebeen
showntobeeffectiveinthesamesituation,justasangiotensin2receptorantagonists(ARBs)havebeen
[18].AllthesetreatmentshaveanidenticaleffectonthefallinBPandonthepercentageofresponders[19,
20].Thethiazidediuretics,betablockers,calciumchannelblockers,andACEinhibitorshaveasimilar
effectofreductionincardiovascularmorbidityandmortality.Thesamedrugsleadtoamodestreductionin
coronaryevents,oftheorderof20%.Althoughithasnotbeendefinitivelyproven,theregressioninLVH
byantihypertensivetreatmentallowsimprovementinmyocardialperfusiontherebyreducingtheriskof
CHD.Inthiscontext,ACEinhibitorsandARBsmayhaveamoremarkedeffectthantheothertherapeutic
classesasregardsregressioninLVH[21,22].Asregardssecondaryprevention,therearenostudiesof
diuretics.Thetherapeuticclasseswhichhavebeenproventopreventrecurrenceofcoronaryevents,
whetherassociatedwithHTornot,arebetablockers[2325],ACEinhibitors[2629],ARBs[30],and
calciumchannelblockerssuchasverapamilincaseofcontraindicationofbetablockersorinassociation
withtrandolapril[31,32].Inpatientssurvivingamyocardialinfarction,earlyadministrationofbeta
blockers,ACEinhibitors,orARBsreducetheincidenceofrecurrentmyocardialinfarctionanddeath[33].
AntihypertensivetreatmentisalsobeneficialinHTpatientswithchronicCHD[33].Thebenefitappearsto
berelatedtothedegreeofBPreduction.ReappraisalofEuropeanguidelinesonhypertensionmanagement
indicatethatitisreasonabletolowersystolicBPdowntothe130139mmHgrangeinpatientswith
concomitantCHD[34].Intensivelipidmanagementandantiplatelettherapyarealsoindicated[33].
ConclusionsTheprevalenceofHTisveryhighinthegeneralpopulationandmoresoinpatientswith
CHD.ThemechanismsbywhichHTfavoursthedevelopmentofCHDaremultipleandarenotsimply
limitedtothepresenceofatheromainthecoronaryarteries.NoninvasivediagnostictestsforCHDare
ofteninadequateinHT.HT,asamajorriskfactorforCHD,canbepartiallyreversedbyantihypertensive
treatmentthathasavitalrolebothinprimaryandsecondaryprevention.References1.CollinsR,
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RESISTANTHYPERTENSIONSerapErdine1,ErenArslan2,AntonioCoca31CardiologyDepartment,
IstanbulUniversityCerrahpasa,MedicalSchool,Istanbul,Turkey2InternalMedicineDepartment,Istanbul
UniversityCerrahpasa,MedicalSchool,Istanbul,Turkey3HypertensionUnit,InternalMedicine
Department,HospitalClinic,UniversityofBarcelona,Spain2011;12:No.15revisedversionDefinition
andprevalenceHypertensionisamajorhealthproblemaffectingapproximately30%ofpeoplebytheage
of60years.Somepatientswithhypertensionaredifficulttocontroldespitetheuseofcombinationsof
antihypertensivedrugs,andareconsideredasresistanttotreatment.Hypertensionisusuallydefinedas
resistantorrefractory(RH)totreatmentwhenatherapeuticplanthatincludesattentiontolifestyle
measuresandtheprescriptionofatleastthreedrugs(includingadiuretic)atcorrectdoseshasfailedto
lowersystolic(SBP)anddiastolicbloodpressure(DBP)togoallevels,excludingisolatedoffice
hypertension[1].TheestimatedprevalenceofRHinlargepreventionofmorbidityandmortalitytrialsin
hypertension,suchastheALLHAT,VALUE,ASCOTT,andCONVINCEtrials,is715%[26].Older
studiesestimatedtheprevalenceofRHintertiarycarecentresas518%[712],whereasalargecohort
studybyAldermanetal.foundthatonly2.9%wereresistanttoantihypertensivetherapy[13].Several
clinicaltrialssuggestthatRHisincreasinglycommon.IntheSystolicHypertensioninEurope(SystEur)
study,43%ofpatientswerereportedtoberesistant[14],butisolatedsystolichypertensionintheelderlyis
adifferentconditionusuallynotincludedintheestimatesofprevalenceofRH.Inotherstudiesinhigh
riskhypertensivepatients,suchastheLIFE(LosartaninterventionforEndpointReductionin
Hypertension)study[15],whichenrolledhypertensivepatientswithleftventricularhypertrophy,26%were
estimatedasresistant,butnotallfulfilledthestrictcriteriaofRH[1].However,thesefiguresoverestimate
theprevalenceofRHintheoverallhypertensivepopulationastheyarelimitedtoolderorhighrisk
patients.Finally,arecentpositionpaperbytheAmericanHeartAssociationonresistanthypertension
suggeststhatpatientswithcontrolledBPrequiring4medicationsshouldbeconsideredasresistantto
treatment[16].CausesandtherapeuticapproachesinresistanthypertensionThefirststeptoacorrect
diagnosisinapatientresistanttoantihypertensivetherapyistoruleoutapparentorfalseRHduetothe
whitecoateffect,pseudohypertensionornoncompliancewithtreatment[1,16].Assessmentof24hour
ambulatorybloodpressuremonitoring(ABPM)iscrucialforthediagnosisofwhitecoathypertension[17,
18].Inaddition,ABPMhasanimportantprognosticvalueinpatientswithtrueRH.Ithasbeenshownthat
patientswithRHwithameandaytimeDBP95mmHghaveasignificantfiveyearincreasein
cardiovascularevents[17].AsshowninTable1,theappropriatenessofthetherapeuticregimen,theuseof
illicitdrugs,possibledruginteractions,highsaltoralcoholintake,volumeoverload,obesity,andsleep
apnoeashouldbecarefullyinvestigated.Themostcommonexogenoussubstances/drugscompromising
hypertensioncontrolareNSAIDs,alcohol,recreationalandillicitdrugssuchascocaine,oral
contraceptives,psychotropics,andweightlossdrugs.Thereiswideindividualvariationintheeffectsof
drugs,andaminorityofpatientsmaybeparticularlysensitive;therefore,withdrawalfrompotentially
interferingmedicationfacilitatesbetterBPcontrol.Patientcomplianceisundoubtedlyamajorcomponent
ofsuccessfulBPcontrolandcanonlybeconfirmedbypatientselfreport.LackofBPcontrolhasbeen
attributedtopooradherencetotheprescribedregimeninapproximately50%ofpatients[1922].One
studyinpatientswithRH,inwhichcompliancewasassessedbytheMedicationEventMonitoringSystem
(MEMS)fortwomonths,foundaBPreduction<140/90inabout30%ofpatients,attributableonlyto
patientselfperceptionofbeingobserved,withoutanychangesinmedication[20].Pseudohypertension,
whichhasbeensuggestedtobemorecommonintheelderly,isdefinedasaconditioninwhichcuff
pressureisinappropriatelyhighcomparedtointraarterialpressureduetovascularstiffening.Lackof
targetorganinvolvementdespitehighauscultatoryBPlevelsorsymptomsofhypotensioninapatientwith
apparentRHmayindicatepseudohypertension.Oslersmanoeuvre,whichwasproposedasascreening
method,provedtohavelittlepredictivevalue[23,24].ThankstoABPMstudies,isolatedoffice(white
coat)hypertensionisanincreasinglyimportantformofspurioushypertension.ArecentstudybyOikawaet
al.demonstratedtheimportanceofthewhitecoateffectasacauseoffalseRH[25].Plasmavolume
expansion,whichcanbemeasuredusingI125radiolabeledalbumin,iscommoninpatientswithRH[26].
Astudyof279patientswithRHfoundhigheraldosteroneandnatriureticlevelsincomparisonwith
controls[27].PopulationbasedstudiessuggestalinearrelationshipbetweendietarysaltintakeandBP[28,
29].ExcessivesodiumcanblunttheantihypertensiveeffectsofACEinhibitorsanddiuretics:therefore,
dietarysaltrestrictionshouldbestrictlyrecommendedtoallpatientswithRH.Theresultsofthe
FraminghamStudyindicateanassociationbetweenBMI(>2530kg/m)andtreatmentresistance.The
closerelationshipbetweenobesityandRHisaresultofcomplexmechanismsinobesepatients,including
increasedsympatheticnervoussystemactivation[3032],baroreflexdysfunctionandsleepapnoea
syndrome[33],increasedrenalandcardiacsympatheticactivity[34],thedirecteffectsofadiposetissue,
andabnormalitiesinthereninangiotensinsystem[35,36].Each10%increaseinweightisassociatedwith
a6.5mmHgincreaseinSBP[37,38].Forthisreason,weightreductionshouldberecommendedtoall
overweighthypertensivepatients.Asignificantassociationbetweenhypertension,especiallyRH,andsleep
apnoeahasbeendemonstrated[39,40].Inarecentstudy[41]obstructivesleepapnoea(OSA)
(apnoea/hypopnoeaindex>5)wasfoundin79.6%ofpatientswithtrueRH,whilemoderatesevereOSA
wasdiagnosedin53.7%andwasmorefrequentinmenthaninwomen(77.4%vs.21.7%).Afterallthese
possiblecausesofRHhavebeenreasonablyruledout,secondarycausesshouldbeconsidered.Recently,
stimulatedreninprofiling,thesocalledphysiologictailoringofmanagement,hasbeensuggestedin
casesofRH[42].Reportssuggestthathyperaldosteronismisthemostcommonsecondarycause(832%)
followedbyrenalfailureandrenalarterystenosis[4345].Recognitionthatmostpatientsdonothavelow
serumpotassiumlevels,whichhadbeenseenasaprerequisiteforthediagnosisofprimary
hyperaldosteronism,hasledtoincreaseddetectionofthedisease[46].Inpatientswithlowreninresistant
hypertension,screeningforaldosteronismismandatory.Primaryhyperaldosteronismrespondswellto
appropriatesurgicalormedicaltreatment.Inrenovasculardisease,revascularizationpreservesrenal
functionbuttheeffectonbloodpressurecontrolislimited[47].Renalfailureshouldbetreatedaccording
totheaetiology.Aftereliminatingallthepreviouslymentionedcausalfactors,trueessentialRHisarare
finding,estimatedtoaffectlessthan5%ofpeoplewithhypertension[48].Table1.Underlyingcausesof
resistanthypertensionCausesofresistanthypertensionPooradherencetotherapeuticplansFailureto
modifylifestyles,including:weightgainhighalcoholintake(NB:bingedrinking)Continuedintakeof
agentsthatraisebloodpressure(liquorice,cocaine,glucocorticoids,nonsteroidalantiinflammatorydrugs,
etc.)ObstructivesleepapnoeaUnsuspectedsecondarycauseIrreversibleorminimallyreversibleorgan
damageVolumeoverloaddueto:inadequatediuretictherapyprogressiverenalfailurehighsodium
intakehyperaldosteronismCausesofspuriousresistanthypertensionIsolatedoffice(whitecoat)
hypertensionFailuretouselargecuffonlargearmPseudohypertension28Thepharmacologicalapproach
toRHpatientsalreadytreatedwiththreeantihypertensivedrugsmaybeguidedbynoninvasive
haemodynamicstudiesassessingthecardiacindex,systemicresistance,andintrathoracicvolumeby
bioimpedance.Dependingonthehaemodynamicevaluation,vasodilators,diuretics,orbetablockersmay
beaddedoreliminated,anddosesincreasedorreduced[49].Thecloserelationshipbetweenthe
aldosteronestatusandRHhasprovidedarationalefortherecommendationofaddinglowdose
spironolactoneasthefirststepinreducingandcontrollingbloodpressureinRH.Recenttrialshaveshown
thebenefitofaddingspironolactonetothebaselinestrategyofanACEinhibitororARBassociatedwitha
calciumchannelblockerandathiazidediureticinRHpatients[5055].Lowdosespironolactone(12.5
mg/dwiththepossibilityofuptitrationto50mg/d)shouldbeconsideredinallpatientswhoseBPremains
abovedesiredlevelsdespitemedicationwiththreedrugs[56].Recentresearchonthepathogenesisof
hypertensionhasleadtonewtreatmentconceptsinvolvingtheneurohumoralregulationofBP[57].
Electricalcarotidbaroreceptorstimulationbydevicespermanentlyplacedaroundthebifurcationsofthe
carotidarteriesreducesBPthroughsympatheticinhibition[5860].Baroreceptorstimulationmayhave
benefitsinBPreductioninconditionswithsympatheticnervoussystempredominancesuchasobesity[61],
obstructivesleepapnoea[62],andisolatedsystolichypertension[63].TheDeviceBasedTherapyin
HypertensionExtensionTrial(DEButHET)showedthatcarotidreceptorstimulationbyanimplantable
devicereducedofficeSBPandDBP,andheartratein21RHpatients[64],althoughthefindingsrequire
confirmationinclinicalstudiesincludinglargenumbersofpatients.Detaileddataonthelongtermeffects
oftheprocedurearealsorequired.ThepivotalroleofthekidneyinBPregulationisduemainlytoits
afferentandefferentinnervationsandtoreninrelease.Denervationofrenalafferentnervesby
radiofrequencycatheterbasedtreatmentresultedinsignificantbloodpressurereductioninanimals[65]and
inhypertensivepatients[6668].Theadditionalbenefitsoftheprocedureareasystemicreductionin
norepinephrinespillover,anincreaseinrenalperfusion,improvementsinthehalvingofcirculatingplasma
reninlevels,andareductionininsulinresistance[69].ConclusionsTrueresistanthypertensionshouldbe
diagnosedonlyaftertheabovementionedcontributingfactorshavebeenreasonablyruledout.Multiple
exogenousfactorsmaymakebloodpressurecontroldifficult,inadditiontothelessfrequentsecondary
causesofhypertension.Thetreatmentofresistanthypertensionincludestheeliminationofexogenous
factorsandtheuseofthemaximumtolerateddosesofcombinedantihypertensiveagents,includingrennin
angiotensinsystemblockadewithanACEIorARBs,acalciumchannelblocker,alongactingthiazide
diuretic,andlowdosespironolactone.Increasingunderstandingofthepathophysiologyofhypertension
mayallowthedevelopmentofnewinterventionalandpharmaceuticaltherapiesforresistanthypertension.
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47.SafianRD,TextorS.Renalarterystenosis.NEJM2001;344:431442.48.GargJP,ElliottWJ,Folker
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bloodpressureinsubjectswithresistanthypertension.Hypertension2007;49:839845.51.Nishizaka
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spironolactoneinthetreatmentofpatientswithrefractoryhypertension.AmJHypertens2002;15:333
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spironolactoneinthemanagementofresistanthypertension:asurveillancestudy.JHypertens2007; 25:
tothedevelopmentofstrategiestoreducetheoccurrenceofnewcases.Severalmainfactorshavebeen
identified.Amongthem,metaboliccontrol,bloodpressurelevelsandgeneticfactorsarethemoststudied
althoughsomeothershavealsobeenimplicated.Alargebodyofevidenceimplicatespoormetabolic
controlwiththeriskofdevelopingmicroalbuminuria.Elevatedlevelsofglucoseincreasetherisk,notonly
fortheshortterm,throughthegenerationofadvancedglycatedproteins,activatinganisoformofthe
proteinkinaseCandincreasingthesensitivitytoangiotensinII.Likewise,thevariabilityofHbA1cpredicts
thedevelopmentandprogressionofincipientandovertrenaldisease[12].Intensiveglucoselowering
treatmentreducestheriskofdevelopingmicroalbuminuria[13].Whatiscontroversialiswhetherornot
thereisaglycaemicthresholdforrisk.Datacomingfromcrosssectional,followup,andintervention
studieshasnotsupportedtheexistenceofathreshold,andeffortstoreduceHbA1cshould,therefore,be
continuedatalllevels[14].Severalstudieshavereportedthatsystemicbloodpressureisnotraisedpriorto
theonsetofmicroalbuminuria.Usingambulatorybloodpressuremonitoring,however,ithasbecome
evidentthatinType1diabeticswithmicroalbuminuria,nocturnalbloodpressureisalreadyhigherthanin
Type1diabeticswithnormoalbuminuriaorinagematchedcontrolsubjects[15].Consequently,these
studieshaveshownthatinType1diabeticsthepresenceofmicroalbuminuriaisoftenassociatedwith
subtlealterationsinbloodpressure,characterizedbyanondippingstatus[16].Therelationshipbetween
nighttimeBPandurinaryalbuminexcretionhasbeenpreviouslydocumented,andtheBPparameterwhich
bestcorrelatedwithurinaryalbuminexcretionwasnighttimeBP.HighBPduringsleepleadstorenal
damageduetothetransmissionofsystemicBPintoglomerularandtubulointerstitialstructuresandis
facilitatedbythelowpreglomerulartoneduringrecumbenceandrestingconditionsthatismoremarkedin
diabeticsubjectsthaninnormalsubjects.AlthoughthereisapotentialroleforsystemicBPtransmissionto
actasarenaldamageinducingmechanism,otherevidencesupportsthethesisthathighersleepBPmaybe
aconsequenceoftheincipientrenaldamageitselfleading,consequently,tohighersleepBP.Neitherthe
causenortheconsequenceinterpretationofthesedataismutuallyexclusive.Theimpactoflowering
nocturnalBPonreducingthedevelopmentofnephropathyand/orcardiovasculardamageremainstobe
confirmedinthefuture.Familialclusteringofdiabeticnephropathysuggeststhepresenceofgenetically
transmissiblefactorsthatmodulatetheriskofnephropathy.TheInsertion/Deletionofangiotensin
convertingenzyme(ACE)genehasbeenoneofthefirst,anditisthemoststudiedgeneduetothe
influenceofthepolymorphismontheactivityofACE,akeyenzymeinangiotensinIIgeneration[17].
Associationwiththepolymorphismofothercandidategenesislessconsistentandthestudiesofgenome
widescan(GWAS)havenotprovidedmorepreciseinformationyet.Otherfactorsassociatedwiththe
developmentofmicroalbuminuriaareinflammation,obesity,andsmoking[18],althoughtheirinteraction
withthethreemainfactorsisdifficulttoassess.TreatmentofmicroalbuminuriaGlycaemiccontrolisthe
firstgoaltobeachievedindiabeticsubjects[19].Althoughrandomizedstudiescomparingtherenaleffect
ofintensifiedbloodglucosecontroltoconventionaltreatmentdidnotdemonstratesignificantdifferences,
longtermintensifiedtherapyintheDiabetesControlandComplicationsTrial(DCCT)[20]reducedthe
riskof30proteinuriaby54%.AchievingHbA1c< 7% is a reasonable target, but a
etal.Renalandretinaleffectsofenalaprilandlosartanintype1diabetes.NEnglJMed2009;361:4051.
27.BilousR,ChaturvediN,SjlieAK,etal.Effectofcandesartanonmicroalbuminuriaandalbumin
excretionrateindiabetes:threerandomizedtrials.AnnInternMed2009;151:1120.EuropeanSocietyof
HypertensionScientificNewsletter:UpdateonHypertensionManagement31INTERACTIONS
BETWEENANTIHYPERTENSIVEAGENTSANDOTHERDRUGSPeterA.vanZwieten1,Sandor
Alfoldi2,CsabaFarsang21DepartmentsofPharmacotherapy,CardiologyandCardioThoracicSurgery,
AcademicMedicalCentre,TheNetherlands2CardiometabolicCentre,St.ImreHospital,Budapest,
Hungary2011;12:No.17revisedversionIntroductionThevastmajorityofhypertensivepatientsare
treatedwithantihypertensivedrugsformanyyears.Othertherapeuticagentsarefrequentlyused
simultaneously,thusgivingrisetothepossibilityofdrugdruginteractions.Itisestimatedthat610%of
adversedrugeventsareassociatedwithdrugdruginteractions[1].Thepotentialfordrugdrug
interactionsincreaseswithrisingage,sinceelderlypatientsareceivelargernumberofdrugs,butalso
becausetherenalexcretionofseveraltherapeuticagentsisimpairedintheelderlyasaresultofdiminishing
kidneyfunction[23].Theinteractionsbetweenantihypertensivedrugsandothertherapeuticagentswillbe
discussedandsummarizedinthepresentissueafterabriefgeneralexplanationofthevariousmechanisms
underlyingdrugdruginteractions.Thecombinationandmutualinteractionsbetweenvariouscategoriesof
antihypertensiveagentswillbedealtwithbyusinaseparateissueofthisnewsletter.MechanismsThere
areseveralmechanismsbywhichdrugsmayinteract[46],andmostofthesemechanismscanbe
categorizedaspharmacokinetic(involvingintestinalabsorption,distribution,metabolism,andelimination),
aspharmacodynamic,orasadditivetoxicity,respectively.Table1.Interactionsbetweenantihypertensive
andotherdrugsDrugs(class)InteractionwithMechanismEffectBetablockersVerapamildiltiazem
AdditiveeffectsAVconductionimpaired;riskofAVblockOralantidiabeticsBeta2receptorblockade
SymptomsofhypoglycaemiaaresuppressedBronchospasmolyticagentsBeta2receptorblockade
SuppressionofthebronchospasmolyticeffectDobutamineBeta1receptorantagonismTheinotropicaction
ofdobutamineisinhibitedMetoprololPropafenone,amiodarone,Enzymaticinhibition(CYP450)
accumulationofmetoprololdronedaroneThiazidediureticsDigoxinHypokalaemiaDigoxinbecomesmore
toxic(arrhythmogenic)LithiumionsRenalexcretionoflithiumionsimpairedAccumulationoflithium
ionsAlphablockersNoradrenalineAlpha1receptorblockadeNoradrenalineshowslessvasoconstrictor
activityAlcoholAlpha1receptorblockadepotentiatesOrthostatichypotensionalcoholinduced
hypotension[11]PDE5inhibitorsIncreasedcGMPavailabilitySeverehypotension(sildenafil,tadalafil,
vardenafil)CalciumantagonistsVerapamil,diltiazemBetablockerAdditiveeffectAVconduction
impaired;riskofAVblockAzoleantimycoticsEnzymaticinhibition(CYP450)AccumulationofDHP
CaantagonistDigoxinRenalexcretionofdigoxinDigoxinmayaccumulate;arrhythmogeniceffect
ProteaseinhibitorsInhibitionofhepaticdegradationAccumulationofverapamilordiltiazem(HIV
treatment)CimetidineIbid.Ibid.DihydropyridineBetablockerBetareceptorblockadeSuppressionof
reflextachycardia(favourable)CaantagonistsFelodipine,verapamilGrapefruitjuiceEnzymicinhibition
(CYP450system)Accumulationoffelodipine,verapamilACEinhibitorsDiuretics(thiazide)Additive
effectStronghypotensiveactionDiuretics(K+sparing)ReducedrenalexcretionofK+Hyperkalaemia
NSAIDsincludinghighdoseASARetentionofNa+andH2OReducedantihypertensiveeffectsLithium
ionsReducedexcretionoflithiumionsLithiumionsaccumulateDPP4inhibitor(vildagliptin)Inhibitionof
substancePdegradation[12]IncreasedriskofangioedemaAT1receptorVirtuallythesameInteractionsas
ACEIs(seeabove)DescribedbeforeantagonistsasACEinhibitors(exceptofDPP4inhibitor)Centrally
actingantihypertensivesAlphamethylDOPAFe2+ionsEnteralabsorptionofamethylDOPAReduced
antihypertensiveactionClonidineTricyclicantidepressantsAntagonismofcentrala2adrenoceptorsIbid.
BetablockersUnknownTheclonidinereboundphenomenonismorefrequentBothclonidineCentrally
actingdepressantAdditiveeffect,nonspecificSedation,fatigueandamethylDOPAagents(hypnotics,
tranquillizers,aneuroleptics,antiepileptics,someantidepressants,H1antihistaminicagents,alcohol)32
Table2.EffectofdruginteractionsonbloodpressureDrugsMechanismofactionIncreaseinBPInterferes
withantihypertensiveeffectSympathomimeticsNasaldecongestants(arec.)YESNOErgotalkaloids
Antimigrainedrugs(5HT)Bronchodilators(b2rec.)YESNONSAIDsSodiumretentionInhibitionof
vasodil.PGsYESYESOralcontraceptivesEstrogensandprogesteroneYESNOCorticosteroidsSodium
retentionYESYESPsychotropesChlorpromazine,tricyclics,MAOinhibitorsetc.YESNOErythropoietin
IncreaseinbloodviscosityYESNOCyclosporineHypothetical(viaNO)YESNOResinInhibitionofGI,
absorptionofantiHTdrugsYESYESAnabolicsteroidsSodiumretentionYESNOPharmacokinetic
interactionsTheinteractioninintestinalabsorptionisbestillustratedbyanexample:tetracylinesandother
broadspectrumantibioticsmayimpairtheabsorptionoforalcontraceptives(inparticularthosewithlow
doseprogestogensand/oroestrogens)andhencerendercontraceptionunsafe.Severaldrugsaresubjectto
inactivationviametabolicdegradationintheliver,catalysedbyvariousliverenzymes.Theformationof
theseenzymescanbeinducedorenhancedbydrugssuchasrifampicin,griseofulvin,andseveralanti
epileptics(carbamazepine,phenytoine,phenobarbital),butalsobyregularalcoholconsumption.This
process,whichrequiresseveralweeksoftreatmentandwhichisindicatedasenzymeinduction,enhances
themetabolicdegradationofseveraldrugs.Inpractice,enzymeinductionmayplayarelevantrolefororal
anticoagulants(coumarintype),corticosteroids(glucocorticoids),oralcontraceptives,orquinidine.
Accordingly,thesecategoriesofdrugsaremetabolized/inactivatedmorerapidlyandtheirdosesshould
thereforebeincreased.Acomparablebutoppositeproblemistheinhibitionofliverenzymesinvolvedin
thebiotransformationbyavarietyofdrugs,suchascimetidine,erythromycin,metronidazole,tricyclicanti
depressants,phenothiazineneuroleptics,andsulphonamides(alsoincotrimoxazole).Enzymeinhibitorsof
thistypeimpairthebiodegradationofcertaindrugsandhenceincreasetheireffect.Awellknownproblem
istheenhancedeffectofanticoagulants(asreflectedbybleeding)inducedbyadditionaltreatmentwithco
trimoxazole.Certaindrugsmayimpairtherenalexcretion[35]ofotheragents,usuallyattherenaltubular
level.Awellknownrelevantexampleistheriseintheplasmalevelandtoxicityofdigoxin,provokedby
verapamil,amiodarone,orquinidine.Similarly,thiazidediureticsmaydeceleratetherenaleliminationof
lithiumsaltsandhencereinforcetheirtoxicity.Abeneficialeffectofsuchaninteractionistheimpaired
excretionofpenicillinantibioticsinducedbysimultaneouslyadministeredprobenecid.Pharmacodynamic
interactionsandadditivetoxicity[46]Pharmacodynamicinteractionsbetweensimilarlyactingdrugsmay
leadtoadditiveorevenoveradditiveeffects(potentiation).Awellknownexampleisthecombinationof
IVverapamilandabblocker,whichmaycauseadditiveimpairmentofcardiacAVconductionandthe
riskofAVblock.Anotherpossibilityistheinhibitionofthetherapeuticeffectofadrugbyanadditional
agent.Overadditiveadversereactionsareillustratedbythefollowingexample:animportantinteraction,
probablycausedbynonspecificmechanisms,isthemutualenhancementofthecentralnervousdepressant
effectofalldrugsthatareknowntodampentheactivityofthecentralnervoussystem.Thisinteraction
holdsforhypnotics,anxiolytics(minortranquillizers),antipsychotics(neuroleptics,majortranquillizers),
antiepileptics,andopioidsbutalsofordrugswithcentralnervousdepressantadversereactions,suchas
antihistamines,centrallyactingantitussives(codeineetc.),andscopolamine[35,9].Furthermore,alcohol
enhancesthecentralnervousdepressanteffectofalloftheaforementionedtherapeutics.Accordingly,
enhancedsedation,impairedpsychomotorskills(driving),butalsorespiratorydepressionmayoccur.
AntihypertensiveagentsandotherdrugsThemostrelevantinteractionsbetweenantihypertensiveandother
drugshavebeenlistedinTable1,andtheeffectoftheseinteractionsonbloodpressurearelistedinTable
2.Afewcommentsmaybemade:itgoeswithoutsayingthatacombinationoftwoormoreanti
hypertensiveagentsmaybeexpectedtocauseanadditivebloodpressureloweringeffect,whichistobe
discussedinmoredetailinaforthcomingissueofthisnewsletter.Thecentralnervousdepressanteffectof
alldrugssuppressingtheactivityofthecentralnervoussystemenhancesthesideeffectsofcentrally
actingantihypertensives(reserpine,alphamethyldopa,guanfacine,clonidine)[46,10].Morerecently,a
greatdealofattentionhasbeenpaidtotheinteractionbetweenantihypertensivedrugsandNSAIDs.Asan
example:indomethacinandothernonsteroidalantiinflammatorydrugs(NSAIDs)maycounteractthe
antihypertensiveeffectofthiazidediuretics,bblockers,ACEinhibitors,andAT1receptorantagonistsasa
resultofsodiumandfluidretentionaswellasofdecreasedformationofvasodilatoryprostaglandins[78].
Ithasbeenclearlydemonstrated,however,thatlowdoseacetylsalicylicacid(ASA;Aspirin,75mgdaily)
doesnotinterferewiththeantihypertensiveactivityofACEinhibitorsandothertypesofantihypertensive
drugs[9].References1.KellyWN.Potentialrisksandprevention,part4:reportsofsignificantadverse
drugevents.AmJHealthSystPharm2001;58:14061412.2.PopplewellPY,HenschkePJ.Acute
admissionstoageriatricassessmentunit.MedJAust1982;1:343344.3.WilliamsonJ,ChopinJM.
Adversereactionstoprescribeddrugsintheelderly:amulticenterinvestigation.AgeAgeing1980;9:73
80.4.HanstenPhD.Importantdruginteractions.In:Basicandclinicalpharmacology.KatzungBG(ed).
5thed.PrenticeHallInt,EnglewoodCliffs1992:931942.5.StockleyIH.Druginteractions.5thed.
PharmaceuticalPress,London1999.6.OpieLH.Cardiovasculardruginteractions.In:Cardiovasculardrug
therapy.MesserliFH(ed).2nded.WBSaundersCompany,Philadelphia1996:347353.7.FogariR,
ZoppiA,CarrettaR,VeglioF,SalvettiA.Effectofindomethacinontheantihypertensiveefficacyof
valsartanandlisinopril:amulticentrestudy.JHypertens2002;20:10071014.8.BeilinLJ.Nonsteroidal
antiinflammatorydrugsandantihypertensivedrugtherapy.JHypertens2002;20:849850.9.ZanchettiA,
HanssonL,LeonettiG,etal.Lowdoseaspirindoesnotinterferewiththebloodpressureloweringeffects
ofantihypertensivetherapy.JHypertens2002;20:10151022.10.VanZwietenPA,EijsmanL.Drug
therapyincardiothoracicsurgery.2nded.VanZuidenCommunications,Alphena/dRijn2001:262269.
11.KawanoY,AbeH,KojimaS,etal.Interactionofalcoholandanalpha1blockeronambulatoryblood
pressureinpatientswithessentialhypertension.AmJHypertens2000;13:307312.12.BrownNJ,Byiers
S,CarrD,etal.DipeptidylpeptidaseIVinhibitoruseassociatedwithincreasedriskofACEinhibitor
associatedangioedemaHypertens2009;54:516523.EuropeanSocietyofHypertensionScientific
Newsletter:UpdateonHypertensionManagement33BENEFICIALCOMBINATIONSOFTWOOR
MOREANTIHYPERTENSIVEAGENTSPeterA.vanZwieten1,SandorAlfoldi2,CsabaFarsang21
DepartmentsofPharmacotherapy,CardiologyandCardioThoracicSurgery,AcademicMedicalCentre,
TheNetherlands2CardiometabolicCentre,St.ImreHospital,Budapest,Hungary2011;12:No.18revised
versionIntroductionInaprecedingcommunicationwedescribedthemostrelevantinteractionsbetween
antihypertensivedrugsandothertherapeutics[1].Inthepresentpaperwewilldealwiththecombinationof
differenttypesofantihypertensivedrugs.Approximatelyhalfofhypertensivepatientscanbesatisfactorily
controlledwithasingledrug,withtheusualadviceforappropriatechangesinlifestyle.Thismeansthatthe
other50%ofpatientsrequiretwoorevenmoreantihypertensivedrugsfortheadequatecontroloftheir
bloodpressure.Theneedfordrugcombinationtherapyhaslongbeenneglectedordismissedinacademic
medicine.Inparticulartheuseoftabletscontainingtwoorthreedifferentdrugsinafixeddosehasbeen
stronglycriticized.Thisviewhasclearlyrevertedtowardsanappreciationofcombinedtreatment,as
expressedinmorerecentlyissuedguidelines(2007ESHESC[2]andJNCVI[3]).Intheseguidelines,
combinationtherapyisadvocatedmoreexplicitlyforcertaintypesofhypertensivedisease,suchas:
isolatedsystolichypertension(ISH);acceleratedhypertension;inpatientswherebloodpressure(BP)
valueslowerthan140/90mmHgarerequiredtopreventtargetorgandamage(e.g.indiabetesmellitus:<
130/85mmHg,chronicparenchymatousnephropathy:<125/75mmHg).Thecombinationoftwoormore
drugsmaybeexpectedtoofferamorepronouncedloweringofincreasedbloodpressure,andthishas
indeedbeenobservedinnumerous,usuallyrathersmall,clinicalstudies.Forveryfewdrugs,their
combinationhasbeenincludeddeliberatelyinlargerandomisedinterventionstudies(e.g.thecombination
ofdiureticsandbblockers[4,5]).Furthermore,theuseofafixedcombination,inasingletablet,is
increasinglyappreciatedsinceitsignificantlyreducesthenumberoftabletstobetakendaily,thus
improvingpatientcompliance,amostrelevantsourceofinsufficienttherapeuticefficacyinhypertensive
patients.Fixeddosecombinationshavebeenenrichedbyverylowdosecombinations,whichmaynowbe
consideredasfirstlinetherapy.EffectivecombinationsoftwodifferentantihypertensivedrugsOverthe
years,severalcombinationsofantihypertensivedrugshavebeenstudiedandthesehaveshowntobe
effectiveinloweringelevatedbloodpressure.Inthischapterwewilldiscussaseriesofcombinations
whichareassumedtobeeffectiveandprobablybeneficialincertaingroupsofpatients.Althoughnotall
arebasedonlargeinterventionstudiesrequiredforevidencebaseddecisions,wehavechosenthese
combinationsonthebasisofhaemodynamicandpathophysiologicalconsiderations,mostlysupportedby
studiesaswellasbyourownexperience.Thiazidediuretics+betablockersThiscombinationhaslong
beenfavouredbyguidelinesforpatientswithuncomplicatedhypertensionwithouttargetorgandamageand
inpatientswithcongestiveheartfailure(CHF).Thiscombinationhasbeenincludedinseverallargescale
interventionstudies(e.g.STOP[4];MRC[5],ALLHAT[12])andcanbeconsideredasfirmlyestablished,
butevidenceisnowavailablethatthesedrugshavedysmetaboliceffectsandfacilitatenewonsetdiabetes
inpredisposedpatients,suchasthosewithmetabolicsyndromeorprediabetes,whichmaybeevenmore
pronouncedwhentheyareadministeredtogether.However,itshouldnotbeignoredthatbetablockersare
notahomogeneousclass,andthatvasodilatingbetablockers,suchasceliprolol,carvedilol,andnebivolol,
appearnottosharesomeofthenegativepropertiesdescribedforothercompounds.Thiazidediuretics+
ACEinhibitorsUsefulinpatientswithhypertensionandCHF,ISH,aswellashypertensionintheelderly
(whichisfrequentlyISH)andinp.Thiscombinationisconsideredtobeaverypotentantihypertensive
medication,andtheadditionofanACEinhibitortoadiuretic(orviceversa)shouldbeperformed
cautiously,inordertopreventatoorapiddecreaseinBP.Furthermore,bothACEinhibitorsanddiuretics
areconsideredasstandardtherapyinCHF.Diuretics+AT1blockers(ARB)Thisisproventobeamore
effectivecombinationforthetreatmentofhypertensionwithleftventricularhypertrophythanbetablockers
++diuretics[10].ISHisalsoaconditioninwhichthiscombinationcouldsuccessfullybeapplied[11].It
mayalsobebeneficialforthosewithhypertensionandCHF.Diuretics+imidazoline(I1)receptoragonists
Thiscombination,whichhasnotbeenstudiedonanylargescale,canbeconsideredifabetablockercannot
beaddedtoadiureticagentbecauseofcontraindications.Diuretics+calciumantagonist(dihydropyridines)
Dihydropyridinecalciumantagonists,knowntobepotentvasodilators,canconcomitantlybeadministered
withdiureticsinISHpatients,whoareusuallyelderly.Thereexistsevidencebothfordiuretics[4,5]and
fordihydropyridinecalciumantagonists[6](althoughnotsoclearlyfortheircombination)thattheyare
effectiveinloweringBPinISH,aswellasforprotectiveactivitytowardscomplicationsofhypertensive
disease.Importantly,theassociationofacalciumantagonistwithadiuretichasbeenusedintheFEVER,
ELSA,andVALUEtrials[2022]togreatbenefits.Alphablockers+betablockersThiscombinationmay
beusedinacceleratedhypertension.Thereislittleevidencefortheefficacyofthiscombination.
Acceleratedhypertensionisprobablybasedonsympathetichyperactivityanditssequelae.Forthisreason,
sympatholyticactivity,ascausedbybothdrugsofthecombination,appearstobealogicaltherapeutic
approach.Forsympatheticoveractivity,centrallyactingantihypertensives(clonidine,imidazolineI1
receptorstimulants)andnondihydropyridinecalciumantagonistsmayalsobeconsidered.Betablockers+
ACEinhibitorsAlthoughtheantihypertensiveeffectofthiscombinationislessthanthatofdiuretics+
betablockers[12],itcouldbeusedinhypertensivepatientsaftermyocardialinfarction(MI)inthosewith
coronaryheartdisease(CHD)orwithCHF[8].Calciumantagonists(dihydropyridinetype!)+beta
blockersPatientswithhypertensionandCHDcanbetreatedbythiscombination.Bothtypesofdrugs,as
wellasbeingefficaciousantihypertensives,areknowntodisplaybeneficialactivityinCHDpatients.The
fixedcombinationofthetwotypesofdrugscanhelpimprovepatientstherapeuticcompliance[17].
Calciumantagonists+ACEinhibitorsThiscombinationcanbesuggestedforthetreatmentofhypertensive
patientswithnephropathy,CHD,orestablishedatherosclerosis.Thecombinationdisplayspronounced
antihypertensiveactivity.CaantagonistsareknowntohaveantiischaemicactivityinCHD.ACE
inhibitorsareproventoberenoprotective,particularlyinpatientswithdiabeticnephropathy.Calcium
antagonists,asshownforlacidipineintheELSAstudy[9],amlodipineinthePREVENTstudy[13],and
nifedipineGITSintheINSIGHTstudy[14],areproventodisplayantiatherogenicactivity.ForACE
inhibitorsthiseffecthasalsobeenrevealed(SECUREstudy)[15].Thecombinationamlodipine
perindoprilwaswidelyusedintheASCOTstudy,beingmoreeffectiveinloweringBPandcardiovascular
eventsthanthecombinationofabetablockerwithathiazide[18].IntheACCOMPLISHtrialthe
incidenceoftheprimaryendpoint(acompositeofseveralcardiovascularfatalandnonfatalevents)was
20%lessinpatientsonbenazeprilamlodipinecombinationthaninthegroupreceivingthebenazepril
hydrochlorothiazidecombination,withasignificantreductionalsoincausespecificeventssuchas
myocardialinfarction,althoughnotheartfailure[19].Calciumantagonists(dihydropyridines)+AT1
blockersThepresumedbeneficialeffectsofthiscombinationaregloballythesameasforthecombination
calciumantagonists+ACEinhibitors[16].Therenoprotectiveactivityindiabetic(type2)nephropathy
appearstobewellestablished[9].DihydropyridinetypecalciumantagonistsandtheAT1blockerlosartan
areknowntodisplayuricosuricactivity,whichmaybeadvantageousalsoinpatientswithgout.ACE
inhibitors+AT1blockersThiscombinationcanbeconsideredinhypertensivepatientswithdiabetic
nephropathyaswellaswithglomerulonephritis,sincebothtypesofdrugshavebeenshowntodecrease
proteinuriamorethantheindividualcomponents,sotheymaydisplayrenoprotectiveactivity.The
widespreaduseofthiscombinationhasnowbeenquestionedbytheresultsofONTARGET[2324],in
whichthecombinationoffulldosesoftelmisartanandramiprilreducedtheinitialBPvaluesslightlymore
thanthereductionseenwiththeadministrationofoneortheotherdrugalone,without,however,any
furtherreductionincardiovascularorrenalendpoints(exceptproteinuria),andindeedwithagreater
numberofrenalsideeffectsandamorefrequentdiscontinuationoftheinitialtreatment.ACEinhibitors+
imidazolinereceptoragonistsTheoreticallythiscombinationcouldbeconsideredifitweredesirableto
simultaneouslysuppresstheactivitiesofboththereninangiotensinaldos34teronesystem(RAAS)and
thesympatheticnervoussystem(SNS).ThemetabolicsyndromehasbeenproposedasatargetforSNS
suppressantdrugssuchasmoxonidineorrilmenidine,sincethissyndromeisbelievedtobepartlytheresult
ofSNShyperactivity.AT1blockers+directrenininhibitorsPreliminaryfindingsusingthedirectrenin
inhibitoraliskirenintheAVOIDtrialhavedemonstratedfurtherreductionsinproteinuriawhencombined
withvalsartan[25].TriplecombinationsAfewsuggestionshavebeenputforwardfortriplecombinations
involvingdifferentantihypertensivedrugs.Thesecombinationsareputtogetheronmerelytheoretical
grounds,virtuallywithoutformalclinicalevidence.Argumentsinfavouroftheuseofoneparticular
categoryofdrugsarethesameasthosediscussedaboveforthecomponentsofcombinationsoftwo
differentdrugs.Thefollowingdrugcombinationsareconceivable:Diuretics+betablockers+calcium
antagonistsAverypotentcombinationwhichcouldbeusedinthetreatmentofacceleratedhypertension.
Diuretics+calciumantagonists+ACEinhibitorsPotentiallybeneficialinthetreatmentofdiabetic
hypertensivepatients,ofthosewithacceleratedhypertensionorISH.AT1antagonists+calcium
antagonists+diureticsThistriplecombinationmayhelpreachthetargetBP(<130/85mmHg)in
hypertensivepatientswithtype2diabetesmellitusorwithISH.ACEinhibitors+alpha1adrenoreceptor
antagonists+imidazolineagonistsPotentiallybeneficialinthetreatmentofdiabetichypertensivepatients
orforthosewithmetabolicsyndrome,inparticularwhenbetablockersarecontraindicatedornotwell
tolerated.ACEinhibitors+Caantagonists+betablockersPotentiallybeneficialinhypertensivepatients
withcoronaryheartdisease.ConclusionsCombinationtherapyhasbecomewidelyacceptedforthe
managementofhypertensivediseaseandasubstantialfractionofpatientsisbesttreatedbytwoor
frequentlythreeantihypertensivedrugs.Tabletswithfixedcombinationoftwodrugswillfacilitatethe
therapeuticscheduleandthusimprovepatientcompliance.Useoffixeddosecombinationsoftwodrugs
candirectlyfollowinitialmonotherapywhenadditionofaseconddrugisrequiredtocontrolBP,oritcan
bethefirsttreatmentstepwhenahighcardiovascularriskmakesearlyBPcontroldesirable.Thisapproach
isnowfacilitatedbytheavailabilityofdifferentfixeddosecombinationsofthesametwodrugs,which
minimizesoneofitsinconveniences,i.e.theinabilitytoonlyincreasethedoseofonedrugbutnotthatof
theother.Thechoiceofdrugcombinationsismainlybaseduponhaemodynamicandmetaboliccriteria,
andformostcombinationsformalevidencehasnot(yet)beenputforward.DrugsPotentialuseBeta
blockers+diureticsHypertension+congestiveheartfailure(CHF)Diuretics+ACEinhibitors
Hypertension+CHF,Isolatedsystolichypertension(ISH),hypertensionintheelderlyDiuretics+AT1
blockersISH+CHF,ISHDiuretics+imidazoline(I1)receptoragonistsTobeusedwhenabblocker
(contraindications)cannotbeaddedtoadiureticDiuretics+calciumantagonists(dihydropyridines)ISH
(usuallyelderlypatients)Betablockers+ablockersAcceleratedhypertensionBetablockers+ACE
inhibitorsHypertensives:postMI(sec.prevention)CHD,CHFCaantagonist+bblockersHypertension+
CHDCaantagonist+ACEinhibitorsHypertension+nephropathy,CHDoratherosclerosisCa
antagonists+AT1blockersHypertension+nephropathy,CHDoratherosclerosisACEinhibitors+AT1
blockersHypertension+proteinuricnephropathyACEinhibitors+imidazoline(I1)receptoragonists
PatientswithactivatedRAASandSNSDiuretics+bblockers+calciumantagonistsAccelerated
hypertensionDiuretics+calciumantagonists+ACEinhibitorsAcceleratedhypertensionISH,
hypertension+diabetesmellitusDiuretics+calciumantagonists+AT1antagonistsIbid.ACEinhibitors+
a1blockers+imidazoline(I1)receptoragonistsHypertension+diabetesmellitus,metabolicsyndrome
ACEinhibitors+Caantagonists+bblockersHypertension+CHDReferences1.VanZwietenPA,
AlfoldiS,FarsangC.Interactionsbetweenantihypertensiveagentsandotherdrugs.ESHNewsletter2011;
12:No.17(revisedversion).2.TheTaskForcefortheManagementofArterialHypertensionofthe
EuropeanSocietyofHypertension(ESH)andoftheEuropeanSocietyofCardiology(ESC).2007
Guidelinesforthemanagementofarterialhypertension.JHypertens2007;25:11051187.3.TheSixth
ReportofJointNationalCommitteeonprevention,detection,evaluationandtreatmentofhighblood
pressure.ArchInternMed1997;157:24132416.4.DahlfB,LindholmLH,HanssonL,etal.Morbidity
andmortalityintheSwedishTrialinoldpatientswithhypertension(STOPHypertension).Lancet1991;
338:12811285.5.MedicalResearchCouncilWorkingParty.MRCTrialoftreatmentofmild
hypertension.BMJ1985;291:47104.6.SHEPCooperativeResearchGroup.Preventionofstrokeby
antihypertensivedrugtreatmentinolderpersonswithisolatedsystolichypertension.JAMA1991;265:
32553264.7.StaessenJA,FagardR,ThijsL,etal.Randomiseddoubleblindcomparisonofplaceboand
activetreatmentforolderpatientswithisolatedsystolichypertension.Lancet1997;350:757764.8.
MenezesFalcoL,vanZwietenPA.Currentdiagnosisandtreatmentinheartfailure.PublLidel,Lisbon
2001:207222.9.BurnierM,BrunnerHR.AngiotensinIIreceptorantagonists.Lancet2000;355,637
645.10.DahlfB,DevereuxRB,KjeldsenSE,etal;fortheLosartanInterventionforEndpointreduction
(LIFE)studygroup.CardiovascularmorbidityandmortalityintheLosartanInterventionForEndpoint
reductioninhypertensionstudy(LIFE):arandomisedtrialagainstatenolol.Lancet2002;359:9951003.
11.KjeldsenSE,DahlfB,DevereuxRB,etal;fortheLosartanInterventionforEndpointreduction
(LIFE)studygroup.Benefitsoflosartanoncardiovascularmorbidityandmortalityinpatientswithisolated
systolichypertensionandleftventricularhyperthrophy:aLIFEsubstudy.JAMA2002;288:14911498.
12.TheALLHATOfficersandCoordinatorsfortheALLHATCollaborativeResearchGroup.Major
outcomesinhighriskhypertensivepatientsrandomizedtoangiotensinconvertingenzymeinhibitoror
calciumchannelblockervs.diuretic.TheAntihypertensiveandLipidLoweringtreatmenttoprevent
HeartAttackTrial(ALLHAT).JAMA2002;288:29882997.13.PittB,ByingtonRP,FurbergCD,etal.
Effectofamlodipineontheprogressionofatherosclerosisandtheoccurrenceofclinicalevents.
ProspectiveRandomizedEvaluationoftheVascularEffectsofNorvascTrial(PREVENT).Circulation
2000;102:15031510.14.BrownMJ,PalmerC,CastaigneA,etal.Morbidityandmortalityinpatients
randomisedtodoubleblindtreatmentwithalongactingcalciumchannelblockerordiureticinthe
InternationalNifedipineGITSstudy:Interventionasagoalinhypertensiontreatment(INSIGHT).Lancet
2000;356:366372.15.LohnEM,YusufS,DzavikV,etal;fortheSECUREInvestigators.Effectsof
ramiprilandvitamineEonatherosclerosis.TheStudytoEvaluateCarotidUltrasoundchangesinpatients
treatedwithRamiprilandvitaminE(SECURE).Circulation2001;103:919925.16.FarsangC,Kawecka
JaszczK,LanganJ,etal;fortheMulticentreStudyGroup.Antihypertensiveeffectsandtolerabilityof
candesartancilexetilaloneandincombinationwithamlodipine.ClinDrugInvest2001;21:1723.17.
DahlfB,HosieJ;onbehalfoftheSwedish/UKstudygroup.Antihypertensiveefficacyandtolerabilityof
anewoncedailyfelodipinemetoprololcombinationcomparedwitheachcomponentalone.BloodPress
1993;2(Suppl1):2229.18.DahlfB,SeverPS,PoulterNR,etal;theASCOTInvestigators.Prevention
ofcardiovasculareventswithanantihypertensiveregimenofamlodipineaddingperindoprilasrequired
versusatenololaddingbendroflumethiazideasrequired,intheAngloScandinavianCardiacOutcomes
TrialBloodPressureLoweringArm(ASCOTBPLA):amulticentrerandomizedcontrolledtrial.Lancet
2005;366:895906.19.JamersonK,WeberMA,BakrisGL,etal;theACCOMPLISHTrialInvestigators.
Benazeprilplusamlodipineorhydrochlorothiazideforhypertensioninhighriskpatients.NEnglJMed
2008;359:24172428.20.LiuL,ZhangY,LiuG,etal;FEVERStudyGroup.TheFelodipineEvent
Reduction(FEVER)Study:arandomizedlongtermplacebocontrolledtrialinChinesehypertensive
patients.JHypertens2005;23:21572172.21.ZanchettiA,BondMG,HennigM,etal;European
LacidipineStudyonAtherosclerosisinvestigators.Calciumantagonistlacidipineslowsdownprogression
ofasymptomaticcarotidatherosclerosis:principalresultsoftheEuropeanLacidipineStudyon
Atherosclerosis(ELSA)arandomized,doubleblind,longtermtrial.Circulation2002;106:2422
2427.22.JuliusS,KjeldsenSE,WeberM,etal.Outcomesinhypertensivepatientsathighcardiovascular
risktreatedwithregimensbasedonvalsartanoramlodipine:theVALUErandomisedtrial.Lancet2004;
363:20222031.23.YusufS,TeoKK,PogueJ,etal;ONTARGETInvestigators,Telmisartan,ramipril,or
bothinpatientsathighriskforvascularevents.NEnglJMed2008;358:15471559.24.MannJF,
SchmiederRE,McQueenM,etal;ONTARGETInvestigators.Renaloutcomeswithtelmisartan,ramipril,
orboth,inpeopleathighvascularrisk(theONTARGETstudy):amulticentre,randomised,doubleblind,
controlledtrial.Lancet2008;372:547553.25.ParvingHH,PerssonF,LewisJB,etal:AVOIDStudy
Investigators.Aliskirencombinedwithlosartanintype2diabetesandnephropathy.NEnglJMed2008;
358:24332446.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management35THECLINICALVALUEOFAMBULATORYBLOODPRESSUREMONITORING
JeanMichelMallion1,JeanPhilippeBaguet1,GianfrancoParati2,GiuseppeMancia21Cardiology
Department,GrenobleUniversityHospital,BP217,38043Grenoblecedex09,France2Departmentof
ClinicalMedicineandPrevention,UniversityMilanoBicocca&IstitutoAuxologicoItaliano,Milano,Italy
2011;12:No.19RrevisedversionIntroductionInitiallyreservedforresearchpurposes,ambulatoryblood
pressure(BP)monitoring(ABPM)hasgraduallyenteredthestandardmedicalpracticeandisnowawidely
usedclinicaltoolbothfordiagnosticpurposesandforassessmentoftreatmentefficacy[1,2].Technical
aspectsThenumberofdevicesavailableforABPMcontinuestoincrease.Devicesbasedonauscultatory
andthosebasedonoscillometricmethodsareavailable,althoughinmostcasestheoscillometricapproach
isnowpreferred.Inordertobeacceptableforpracticaluse,adevicemusthavebeenvalidated[3]
accordingtointernationalprotocols[4,5].OneoftheseprotocolshasbeendescribedbytheWorking
GrouponABPMoftheEuropeanSocietyofHypertension[6]andhasrecentlybeenupdatedtofacilitateits
implementationindifferentlaboratories[7].AllABPMdevicesavailableforpracticaluseallowBPtobe
onlyintermittentlysampled.Differentsamplingintervalscanbeadopted,althoughitisrecommendednot
toexceed2030minutestoavoidincorrectestimatesof24hdayornighttimeBPvalues,whileintervals
nolongerthan15minutesarerequiredtoreliablyassess24hBPstandarddeviation,ameasureofBP
variability[8].Thecurrentroutineusingsamplingintervalslongeratnightthanduringtheday,toavoid
disturbanceofnightsleep,haslittlescientificbackground[9]andmayleadtoerrorsinestimatingthe
averageofnighttimeBP.Beforestartingtheambulatorymonitoringitisadvisabletoperformtwo
auscultatorymeasurementsonthecontralateralarminparallelwiththefirstautomatedreadings,aimedat
ensuringthatdifferencesdonotexceed5mmHgduetolocalmismatchbetweenarmandcuffsize,or
duetoincorrectcuffapplication.Patientsmustalsobeinstructedtolivetheirusuallifeduringthe
recording,avoidingunusualstrenuousexercise.Theyshouldalsobeinstructedtofillinadiary,by
recordingunusualeventsandquality/durationofnightsleep[10].DiagnosticuseEvidenceisavailablethat
24h,dayornighttimeaverageBPvaluescorrelatewithsubclinicalorgandamagemorecloselythan
officevalues[11].Evidenceisalsoavailablethat1)inthegeneralpopulationandinhypertensivepatients
ambulatoryBPvaluesaremorepredictiveofcardiovascularriskthanofficevalues[1215],and2)in
hypertensivepatientstheregressionofclinicallyimportantorgandamage(suchasleftventricular
hypertrophy)ismorecloselypredictedbytreatmentinducedchangesinaverageABPthaninofficeBPs
[16].ThishasjustifiedtheincreasinguseofABPMfordiagnosticpurposes[17].However,itshouldbe
keptinmindthatinthegeneralpopulationABPMvaluesaremuchlowerthantheequivalentofficevalues.
Basedoncrosssectionalpopulationstudies[18]thethresholdvaluestodiagnosehypertensionfor24h
averageBPare125/80mmHg[1]whiletheequivalentofficevaluesare140/90mmHg.Isolatedoffice
(whitecoat)hypertensionContinueduseofofficeandambulatoryBPmeasurementshasallowedthe
identificationofaconditioncharacterizedbypersistentlyelevatedofficeBPandpersistentlynormal
ambulatoryBP[19].Mostdataindicatethatthiscondition(whichoccursinabout10%[20]ofthe
population)isassociatedwithalowercardiovascularriskthantheconditioncharacterizedbybothoffice
andambulatoryBPelevation.Conflictingdataabouttheprevalenceoforgandamage,cardiovascularrisk,
andpronenesstofuturehypertensionmakeitstilluncertainwhetheritrepresentsatrulyinnocent
phenomenonascomparedtootherBPcategories[2035].Thissuggeststhatcautionshouldbeexercised
whendecidingwhetherthesepatientsshouldorshouldnotbetreated.Nondrugtreatmentshouldalwaysbe
implementedanddrugsprescribedincaseoforgandamageorforhighriskprofilepatients.Iftreatmentis
notstarted,aclosefollowupisrecommended.Maskedhypertension(reversewhitecoathypertension)
WhencomparingofficewithABPMandhomeBPmeasurement,itispossibletoidentifypatientswhose
BPvaluesarenormalintheofficeandabnormaloutsidetheoffice,aconditiontermedasmasked
hypertension[36].Intermsofprevalence,thereareimportantdifferencesaccordingtothestudied
population,withvaluesbetween10and40%.Crosssectionalstudieshaveshownthatmaskedhypertension
isassociatedwithincreasedleftventricularmassandcarotidintimamediathickness,andwithimpaired
largearterydistensibility[3740].Epidemiologicalprospectivestudiessuggestthatmaskedhypertensionis
anindependentpredictorofcardiovascularmorbidityandastrongpredictorofcardiovascularrisk[31,35,
4151].SeveralfactorscanraiseambulatoryBP,increasingthelikelihoodofhavingmasked
hypertension,eitherbecauseofstressfuleventsduringdaytimeorbecauseofdisturbanceofnightsleep,as
inthecaseofobstructivesleepapnoea[47,52].Clinicalrelevanceof24hABPprofilesandBPvariability
withinthe24hoursSeveralcomponentsofthe24hBPprofilehavebeenshowntohaveclinical
importance.ThepossibleprognosticvalueofBPincreaseinthemorning,ongoingfromsleepto
wakefulnessanddaytimeactivities,knownasmorningBPsurge,hasbeeninvestigatedinmanystudies,
basedonthereportsthatapronouncedmorningBPsurgemightpredictcardiovascularevents[53].
However,thereisnosoliddemonstrationyetoftheoccurrenceofacauseeffectrelationshipbetween
morningBPsurgeandcardiovascularevents,mostoftheavailableevidencebeingonlyinfavourofan
associationofmorningBPrisewithamorningpeakincidenceofcoronaryheartdiseaseandstroke[54
56].Indeed,otherfactors,inadditiontomorningBPrise,mightexplainthehigherrateofcardiovascular
eventsduringthistimeperiod,includingaconcomitantincreaseinplateletaggregabilityandreductionin
fibrinolyticactivity.Itseemsneverthelessadvisableforthephysiciantoensurethatantihypertensive
treatmentlowersBPalsointhemorningafterarousalwithnoescapefromthereductionseeninthe
remaining24h.NighttimeBPreduction(dipping)BPfallsatnightbutmoresoinsomesubjectsthan
inothers.Thisledtotheclassificationofhypertensivepatientsintodippersandnondippers,basedona
nocturnalBPfallofmoreorlessthan10%ofdaytimevalues,respectively[56,57].Themainlimitationsof
patientclassificationbasedonthenocturnalBPdippingratearerelatedtopoorreproducibilityofthe
magnitudeofnighttimehypotension[58](inrelationtodifferencesinsleepquality/depth)andtothefact
thatacutoffvalueforanocturnalBPfallof10%ofdaytimeBPlevelstoseparatedippersfromnon
dippers,isanarbitraryselection[18].Moreover,thelevelofnocturnalBPratherthanthedippingrate
seemstobeastrongerpredictorofoutcome[59].Indeed,severalstudieshaveshownthatnighttimeBPis
relatedtotargetorgandamageandcardiovascularrisk[6069],andsomeauthorshavereportedahigher
prognosticvalueofnocturnalvs.daytimeBP[13].Itshouldbeacknowledged,however,thatinmost
studiesdayandnightBPvaluesandtheirchangeswithtreatmenthavebeenshowntobecharacterizedbya
closerelationship[16,58,70,71].Inclinicalpracticea24hABPMshoulddefinitelyincludeBPvalues
obtainedduringthenightperiod,andtreatmentshouldensurethatbothdayandnighttimeBPlevelsare
smoothlyreduced.Specialattentionshouldbepaidtopatientsinwhomthenightisassociatedwithno
reduction(orevenanincrease)inBP(providedthatsubjectsnotsleepingatnightareexcluded)because
thissuggeststheexistenceofamarkeddegreeofvasculardamageandautonomicdysfunction,aswellasa
considerablehypertensionseverity.Thepossibilityofanobstructivesleepapnoeaconditionshouldalsobe
consideredinthesepatients[72].Inaddition,specialattentionshouldbepaidtosubjectswithavery
pronouncedreductioninnighttimeBP(>20%,socalledextremedippers)becausethismayleadtobrain
underperfusion,particularlyifafurtherBPfallisinducedbythetreatment[73].BPvariability
evidenceisavailablethatforagivenincreaseinBP,organdamageandprognosisareworsenedbyagreater
24hBPvariability[38,7477].IncreasingevidenceisaccumulatingthatBPvariabilitymightindeed
representanadditionalriskfactorontopofincreasedmeanBPlevels,althoughthesizeofsuchan
additionalcontributiontocardiovascularriskandtheimpactofatreatmentinducedreductioninBP
variabilityonpatientoutcomearestillunresolvedresearchissues[7880].Efficacyofantihypertensive
treatmentABPMhasdrasticallyimprovedtheabilitytoassesstheefficacyofantihypertensivetreatment
bothinclinicalstudiesandinmedicalpractice[8184],withresultsoftendifferentfromthoseobtainedby
focusingonclinicvisitsonly[85].Inclinicaltrialsadvantagessuchasagreaterreproducibility,thelackof
placeboeffect,andtheabsenceofanalertingdependantBPresponse[84]makeABPMtheidealapproach
toquantifytheantihypertensiveeffectofnewantihypertensivedrugs,drugcombinations,ornon
pharmacologicalmeasures.ItalsoallowsthestudyoftheextentandthedistributionoftheBPlowering
effectofdifferentantihypertensivedrugs,andacomparisonbetweendifferentdrugsand/ordifferentdoses
beingquantitativelyfacilitatedbyuseofindicessuchasthetroughtopeakratioandthesmoothness36
index[80,84,85].Tosomeextentthisisalsopossibleinthemedicalpractice,ifABPMisperformed
beforeandduringtreatment.Alimitation,however,forsuchadailyclinicalapplicationistheyet
incompleteknowledgeoftheABPvaluestobereachedbytreatmentinordertoobtainthesamedegreeof
cardiovascularprotectionofferedbyachievingtheofficeBPtargetsshownbyoutcomestudiestoensure
significantreductionincardiovascularrisk.ConclusionsABPMhasopenednewhorizonsforhypertension
research,anditsprogressivelygreater,usehashadapositiveimpactonclinicalpractice.Itsadoptioncan
thusberecommended,whenfacilitiesareavailable,inalargernumberofpatients,ascomparedtowhat
wasindicatedinpreviousrecommendations.TheusefulnessofABPMisparticularlyevidentinpatients
withconsistentdiscrepanciesbetweenclinicandhomeBPlevels,inthosewithelevatedclinicBPbutno
evidenceoforgandamage,inpatientswithhighcardiovascularriskandinthoseinwhominformationon
nighttimeBPlevelsandonthedegreeofBPfluctuationsmaybeparticularlyrelevant.However,further
researchisstillneededtocollectadditionalinformationonanumberofimportantandyetpartlyunresolved
issues,suchastheactualroleofambulatoryBPvariability,theABPtargetstobeachievedbytreatment,
theclinicalimportanceofisolatedclinicorwhitecoathypertension,andtheclinicalandpathophysiological
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haemodialysistreatment(twohours,sixtimesperweek)mayalsobeassociatedwithnormotensionwithout
medicationandwithregressionofleftventricularhypertrophy.Bilateralnephrectomymaybeconsideredin
thoserarenoncompliantindividualswithlifethreateninghypertension,whosebloodpressurecannotbe
controlledwithanyoftheabovedetaileddialysismodalities.Theclinicianmustdefinethedryweightand
goalbloodpressureforeachdialysedpatientbaseduponhisorherbestjudgment.Lifestylechangesshould
includeincreasingexercise,losingweightifoverweight,limitingalcoholintake,stoppingtheuseof
medicationsthatincreasebloodpressure,anddiscontinuationoftobaccouse(Table3)[14,15].
TREATMENTOFHYPERTENSIONINDIALYSEDPATIENTSIstvnKiss1,CsabaFarsang2,JoseL.
Rodicio31DepartmentofNephrologyHypertension,StImreTeachingHospital,Budapest,Hungary2
CardiometabolicCentre,StImreTeachingHospital,Budapest,Hungary3DepartmentofNephrology,
Hospital12deOctubre,Madrid,Spain2011;12:No.21revisedversionTable1.Aetiologyofhypertension
indialysedpatientsSodiumandvolumeexcessduetodiminishedsodiumexcretorycapacityofkidney
ActivationofthereninangiotensinaldosteronesystemIncreasedactivityofthesympatheticnervous
systemIncreasedendogenousvasoconstrictor(endothelin1,NaKATPaseinhibitors,adrenomedullin),
anddecreasedvasodilator(nitricoxide,prostaglandins)compoundsFrequentadministrationof
erythropoietinIncreasedintracellularcalciumcontent,inducedbyparathyroidhormoneexcess
HyperparathyroidismandhypercalcaemiaUseofrecombinanthumanerythropoietinCalcificationof
arterialtree,arterialstiffnessPreexistenthypertensionNocturnalhypoxaemia,frequentsleepapnoeaTable
2.AlgorithmforbloodpressurecontrolindialysispatientsEstimatedryweightDetermineHypertension
SeverityIndexInitiatenonpharmacologicaltreatmentAttaindryweightStartorincreasethedoseof
antihypertensivestomaintainbloodpressurebelow150/90mmHgIfbloodpressureisnotcontrolledor
dryweightnotattainedin30days,consider:2448hambulatorypressuremonitoring;increasingtimeof
dialysistofacilitateremovaloffluidandattainmentofdryweight;discontinuingsodiummodelling;
increasingthedoseornumberofantihypertensivesIfbloodpressureremainsuncontrolled,consider:
evaluatingforsecondaryformsofhypertension;peritonealdialysisbilateralnephrectomy(exceptional)40
PharmacologicaltreatmentofhypertensionindialysedpatientsAntihypertensivedrugtherapyisnecessary
in2530%ofpatients.Thetypeofdrugorantihypertensivecombinationdependsontheseverityof
hypertension(Table4)andcomorbidities.Tocalculateforanindividualdialysistreatment,sumthepre
dialysissystolicanddiastolicandpostdialysissystolicanddiastolicbloodpressurescores.The
hypertensionseverityindexcanrangefrom0to12.Nocturnaldosingofoncedailyantihypertensive
medicationispreferredinordertotrytominimizetheoccurenceofintradialytichypotension[16].Table5
showsthecompellingindicationsofantihypertensivedrugs,theirspecificsideeffects,andspecial
importantprecautions.AntihypertensivedrugsCalciumchannelblockersareveryeffectiveandwell
toleratedindialysispatients,eveninthosewhoarevolumeexpanded.Theyareusefulinpatientswithleft
ventricularhypertrophy,diastolicdysfunction,andstabileanginapectoris.Calciumchannelblockersdonot
requiresupplementarypostdialysisdosing.Calciumchannelblockershaveauniquefeatureamong
dialysispatientsaprospectivecohortstudyfromUSRDSshowedasignificant26%reductionin
cardiovascularmortality.Inhibitorsofthereninangiotensinsystemoughttobeconsideredasfirstline
agentsforbloodpressurecontrolinhaemodialysispatientsbecauseoftheirdocumentedbeneficialeffect
onleftventricularhypertrophy,arterialstiffness,andendothelialcellfunction[16].Angiotensinconverting
enzyme(ACE)inhibitorsareeffectiveandwelltoleratedindialysispatients.Theyareusefulinpatients
withleftventricularhypertrophy,andinthosewithheartfailureduetosystolicdysfunction.ACEinhibitors
reducemortalityinhypertensivepatientsundergoingmaintenancedialysis.Significantlylowermortality
wasobservedamongACEinhibitortreateddialysispatients(<65yearsofage).Thissurvivalbenefitwas
independentofantihypertensiveeffect.Thesedrugscanreducethesynthesis//secretionofendogenous
erythropoietinandcantriggerananaphylactoidreactioninpatientsdialysedwithAN69dialyser.Thereis
onlylimitedexperiencewithangiotensinIIreceptorblockers(ARBs)inendstagerenaldisease.Losartan
doesnotenhancetheriskofanaphylactoiddialyserreactionsthatmayoccurwiththeACEinhibitors.No
doseadjustmentisnecessaryinrenalfailureintheabsenceofvolumedepleTable4.Hypertensionseverity
index(HSI)HSIscoreSystolicbloodpressureDiastolicbloodpressure(mmHg)(mmHg)0<150<901
150159909921601791001093>179>109Table5.Useofantihypertensivedrugsinhaemodialysis
patientsDrugsCompellingindicationSpecifcsideeffectsSpecialprecautionsAngiotensinconvertingLeft
ventricularhypertrophyAnaphylacticreactionswithenzymeinhibitorsHeartfailureAN69dialysator
DiabetesmellitusDihydropyridinecalciumAssociatedcoronarychannelblockersheartdiseaseNon
dihydropyridineAssociatedcoronaryheartdiseaseAvoidcombinationwithblockerscalciumchannel
blockersBetablockersAssociatedcoronaryheartdiseaseExcessivebradycardiawithAvoidcombination
withnondihydropyridineliposolublecompoundscalciumchannelblockersCentrallyactingNonePost
haemodialysishypertensiveAvoidantiadrenergicdrugsa2reboundwithmethyldopaorI1receptor
(agonists)tion.TheKDOQIgudelinessuggestthattheseagentsarepreferredindialysispatientswith
hypertensionandsignificantresidualrenalfunction[17].Aliskirenisthefirstintheclassofdirectrenin
inhibitors,andithasnotyetbeenevaluatedinpatientsonhaemodialysis.Theuseofaldosteronantagonists
inhaemodialysispatientshasnotbeenfullyinvestigatedtodate.Theroleofendothelinantagonistsin
controllingbloodpressureinhaemodialysispatientshasnotbeentested.Betablockersareindicatedin
dialysispatientsaftermyocardialinfarction.Potentialsideeffectsincludecentralnervoussystem
depression(mainlylipidsolubledrugs),bradycardia,andheartfailure.Apreferableblockermaybe
labetalolorcarvedilol,whichhavealowerincidenceofbronchospasmandhaveaneutraleffectonplasma
lipidlevels.Atenolol,administeredthreetimesaweekpostdialysis,maybeeffective.Peripheralalpha1
adrenergicreceptorblocker(prazosin,doxazosin)wouldhelptocounteracttheincreaseinsympathetic
nerveactivity.Inlongtermtreatment,thefavourablemetaboliceffects(onlipidsandinsulinresistance)
mightbeadvantageous.Thesedrugsarepreferredinantihypertensivecombinations.Centrallyactingdrugs
(methyldopa,clonidine,guanfacine)havemoresideeffectsthanthosedescribedabove.Newerimidazoline
receptoragonists(moxonidine,rilmenidine)areconsideredtobesafeandeffective,butonlylimited
experienceisavailable.Thepharmacokineticsoffrequentlyusedantihypertensivedrugsindialysispatients
aregivenintheAppendix[18].SpecialsituationsTreatmentofrefractoryhypertensioninhypertensive
dialysispatientsUseofminoxidil(thestrongestdirectvasodilator)maybeeffectiveinreducingblood
pressure.Dialysedpatientswhoarenoncompliant,andinwhomvolumestatusandhypertensioncannotbe
adequatelycontrolled,maybenefitfromswitchingtocontinuousambulantperitonealdialysis.Treatmentof
erythropoietininducedhypertensionAnattemptshouldbemadeto1)decreasetheactualdryweight;2)
decreasethedose(ifpossible)orinterrupttreatment,andreintroducelateratlowerdosage;and3)
introduceorincreaseantihypertensivemedication,preferablycalciumchannelblockers[19].Treatmentof
hypertensionindiabeticdialysispatientsThenumberofdialysispatientswithtype2diabetesmellitusis
rapidlyincreasing,andthesepatientsaregenerallyhypertensive.Exchangeablesodiumisincreasedin
diabeticpatients,andorthostatichypotension,duetoautonomicneuropathy,anddialysishypotension,with
severesymptoms,coronaryarterydisease,andvascularatherosclerosis,arefrequent.Longerdialysis,slow
ultrafiltrationrate,haemofiltration,andglucosecontainingdialysatecanbeusedtoavoidtheriskofsevere
hypotension.ACEinhibitorsandARBsdecreasebloodpressureandmaypreventendorganvascular
diseases.Calciumchannelblockersareeffectiveinreducingbloodpressurebutmayresultinsevere
hypotensiveepisodes.Benefitfromblockadeisparticularlysignificantinpatientswithtype2diabetes
mellitusandcoronaryheartdisease.ConclusionsTheprogressofdialysistechnologyleadstobetter
tolerateddialysistreatmentandmoreadequateremovalofsodiumwateroverload.Treatmentof
hypertensionindialysispatientsstillremainsacarefulclinicaljudgment:adequateevaluationofthedry
weight,choiceofadequatetreatmenttime,andfrequency.Forthosepatientsinwhomultrafiltrationand
maintenanceofdryweightdonotadequatelycontrolhypertension,antihypertensivemedicationsare
indicated[2026].Randomizedclinicaltrialssuggestedsomebenefitfromantihypertensivetherapyamong
haemodialysispatients[27],andtreatmentwithagentstolowerbloodpressureshouldroutinelybe
consideredforindividualsundergoingdialysistoreducetheveryhighcardiovascularmorbidityand
mortalityrateinthispopulation[28].Table3.Nonpharmacologicaltreatmentofhypertensionindialysis
patientsAerobicexerciseControlofsaltandfluidintakeCessationofsmokingWeightreduction
AvoidanceofalcoholLong,slow,andmorefrequenthaemodialysistreatmentBilateralnephrectomy41
Appendix.FeaturesoffrequentlyusedantihypertensivedrugsinhaemodialysispatientsElimination,
DosingSupplementrequiredMiscellaneousmetabolismwithdialysisDiureticsThiazides/chlorthalidoneR
AvoidK+sparingRAvoidAcetazolamideRAvoidLoopagentsFurosemideR(H)Usefulinhighdoses
NoOtotoxicityandaugmentedaminoglycosidetoxicityBumetadineR(H)UsefulinhighdosesEtacrynic
acidR(H)AvoidBetablockersAcebutololH(R)2550%NoActivemetabolitesaccumulationAtenololR
2550%YesRemovedbydialysisBisoprolol25%YesBetaxolol50%YesCarvedilolUnchangedNo
LabetalolHUnchangedNoMetoprololHUnchangedNoNadololR50%YesRemovedbydialysis
PindololH(R)UnchangedNoPropranololHUnchangedNoActivemetaboliteaccumulationinterferes
withbilirubindosageSotalolR30%YesClass3antiarrhythmicpropertiesTertatololRUnchangedNo
ActivemetabolitesaccumulationTimololHUnchangedNoInactivemetabolitesaccumulationAlpha1
adrenergicblockersPrazosinH(R)UnchangedNoFirstdoseeffectDoxazosinUnchangedNoBeneficial
effectsoninsulinresistanceandonplasmalipidsUrapidilH(R)UnchangedNoInactivemetabolitesmay
accumulateAngiotensinconvertingenzymeinhibitorsAnaemia,anaphylactoidreactionsBenazeprilR(H)
50%NoNonrenalclearanceofbenazeprilateCaptoprilR2550%YesActivemetaboliteaccumulation
CilazaprilR(H)25%YesEnalaprilR(H)50%YesParentdrugaccumulationFosinoprilRandH
UnchangedNo50%hepaticeliminationLisinoprilR25%YesPerindoprilR(H)2550%YesQuinaprilR
(H)2550%NoRamiprilR(H)2550%YesTrandolaprilR(H)50%YesTrandolaprilatisfurther
metabolizedbeforeexcretionAngiotensinIIreceptorantagonistsCandesartanR(H)AvoidEprosartanH
AvoidIrbesartanHUnchangedNoLosartanR(H)UnchangedNoOlmesartanRHUnchangedNo
TelmisartanHUnchangedNoValsartanHUnchangedNoCalciumchannelblockersAmlodipineH
UnchangedNoDiltiazemHUnchangedNoRiskofconductiondisturbanceFelodipineHUnchangedNo
IsradipineHUnchangedNoLacidipineHUnchangedNoNicardipineHUnchangedNoNifedipineH
UnchangedNoNitrendipineHUnchangedNoRrenalelimination;Hhepaticelimination;NR
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Newsletter:UpdateonHypertensionManagement43HIGHBLOODPRESSURE,ALCOHOL,AND
CARDIOVASCULARRISKRamonEstruch1,AntonioCoca1,JosL.Rodicio21InstituteofInternal
Medicine,HospitalClinic(IDIBAPS),UniversityofBarcelona,Spain2FacultyofMedicine,Complutense
University,Madrid,Spain2011;12:No.22revisedversionIntroductionSeveralcrosssectionaland
prospectiveepidemiologicstudieshaveestablishedanempiricalcoholandhypertensionlink.This
observationhasbeenmadeinEuropean,NorthAmerican,Australian,andJapanesepopulationsandseems
independentfromadiposity,saltintake,education,cigarettesmoking,andotherindirectexplanations[13].
Afairyconsistentfindingisthatheavydrinking(usuallydefinedas>3drinks//day>40gof
ethanol/day)isassociatedwithincreasedbloodpressure(BP)andincidenthypertension[4].However,men
whoconsume12drinksperdayandwomenwhodrinkhalfofthisamountdonotshowsignificant
changesinBPorevensignificantreductionsinBPcomparedtoabstainers[5],suggestingthatthepressor
effectsofalcoholmayfollowaJshapecurve.Severalaspectsofthedataobtainedfromdifferentstudies
suggestacausalrelationshipbetweenhighethanolintakeandanincreaseinBP.Thus,reductionofalcohol
intakelowersBP,whereascontinuedintakeimpairsresponsetoantihypertensivetreatments[6].
Interventionstudiescarriedoutinhumansubjectsinordertoconfirmepidemiologicaldatahaveshown
inconsistentresultswitheitheranincreaseoradecreaseinBPwithalcoholadministration,evenwhen
ambulatoryBPmonitoring(ABPM)wasusedforaccuratemeasurement[7,8].Theseconflictingresults
maybeduetodifferencesinrate,dose,routeofethanoladministration,timeintervaltoBPpressure
measurement,andpsychicfactorsinthereportedstudies.However,ametaanalysisofrandomized
controlledtrials,inwhichalcoholreductionwastheonlyinterventiondifferencebetweenactiveandcontrol
treatmentgroups,showedasignificantreductioninmean(95%confidenceinterval)systolicanddiastolic
BPof3.31mmHg(2.52to4.10mmHg)and2.04mmHg(1.49to2.58mmHg),respectively.
ThesereductionsinBPwouldbeexpectedtoresultina6%reductionintheriskofcoronaryheartdisease,
anda15%reductionintheriskofstrokeandtransientischaemicattacks[9].Mechanismsofalcohol
relatedhypertensionThedifferencesobservedintheresultsofpreviousstudiessuggestthatpressoreffects
seemtobeheterogeneous.SimilartotheeffectsofsaltintakeonBP,whentheeffectsofethanolintakeon
BPareanalysed,twopopulationsmaybeencountered,onesensitivetoethanolandanotherresistanttothe
pressoreffectsofethanol.Inourexperience,halfofthenormotensiveandfourfifthsofthealcohol
dependentpatientswithhighbloodpressureshowsignificantchangesin24hmeanBPandmaybe
classifiedassensitivetoalcohol,whereastheremaindershouldbeconsideredresistanttothepressor
effectsofalcohol[10].Theresultsofthisstudyandothers[11]suggestthatgeneticfactorsmayplayarole
inthepathogenesisofethanolrelatedhypertension.Althoughthebasisoftheassociationbetweenalcohol
intakeandhypertensionhasnotyetbeenestablished,thefollowingmechanismshavebeenproposed:1)
activationofthereninangiotensinaldosteronesystem;2)adrenergicnervoussystemdischarge;3)cortisol
secretion;4)reductionofinsulinsensitivitywithimpairmentofglucosetolerance,whichmayalsofavour
fatstorageanddyslipemia;5)heartratevariability;6)directeffectsofethanolonperipheralmuscletone
viachangesincalciumorsodiumtransportintosmoothmusclecells;and7)endothelialdysfunctiondueto
ethanolthatmayinducechangesintherelaxantcapacityoftheendotheliumanddecreasethereleaseof
nitricoxide(Table1)[1215].Inrespecttothelastpoint,somestudieshavesuggestedthatpolyphenols
containedinfoods(i.e.wineandbeer)mayexertantihypertensiveeffectsandcontributetotheprevention
ofhypertensionduetotheirvasodilatationproperties[16].Someauthorshavealsosuggestedthatthe
associationofalcoholandhypertensionmaybeduetowithdrawalfromalcohol.However,inintervention
studies,nodifferencesinplasmaadrenalineornoradrenalinevalueswereobservedwhenpatientsdidordid
notreceiveethanolandalcoholwithdrawalsyndromewasexcluded.Inaddition,ifhypertensionwere
relatedtoalcoholwithdrawal,BPwouldbehigherwhenalcoholdependentpatientsgiveupalcohol.
Finally,epidemiologicalstudies[17]haverelatedchangesinBPtoobesity,cigarettesmoking,coffee,tea,
totalcholesterol,uricacid,potassium,andcalcium,andexperimentalstudieshavesuggestedthatalcohol
inducedhypertensioncouldberelatedtomagnesiumdepletion.However,ininterventionstudiesperformed
toevaluatethepressoreffectsofethanol,nosignificantdifferenceswereobservedinplasmaionicand
metabolicparametersofchronicalcoholicsbetweenthemeasurementsobtainedwhentheyreceivedethanol
andwhentheyonlyreceivedtheplacebo.Thesedatasuggestthattheshorttermeffectsofethanolarenot
relatedtoanychangeinplasmahormonesorions.ClinicalfeaturesTheclinicalrelevanceofthemagnitude
ofchangesinBPafterethanolwithdrawalshouldalsobeconsidered.Insomeinterventionstudies,the
averagechangeof24hourmeanBPwas8.4mmHginthealcoholsensitivenormotensivepatientsand
12.5mmHginthealcoholsensitivehypertensivesubjects.Inepidemiologicalstudies,reductionsofonly2
or3mmHginBPinthewholepopulationhavethesameeffectonmortalityasantihypertensive
treatment.SincethereductionsofBPobservedintheinterventionstudiesafteralcoholwithdrawalwere
betweentwotosixfoldgreaterthanthesefigures,thechangesshouldbeconsideredasclinicallyrelevant
[10].Ontheotherhand,ethanolsensitivealcoholdependentpatientshaveshownasignificantlylowerleft
ventricularejectionfractionandasignificantlygreaterleftventricularmassthanethanolresistantpatients
(Table2).Inthisrespect,onemaywonderwhethertheformergroupofalcoholdependentpatientsismore
sensitivetotheeffectsofethanolintakeonthewholecardiovascularsystemorwhetherthechanges
observedinethanolsensitivepatientsaresecondarytoarelativelyhigherBPthanethanolresistantalcohol
dependentpatients.SincenosignificantdifferenceswereobservedintheBPparameters,alcoholdependent
subjectssensitivetothepressoreffectsofethanolmayalsobemoresensitivetotheeffectsofethanolon
themyocardium[10].Thus,anechocardiographyand/orradionuclideventriculographyshouldbe
performedinallalcoholicswithethanolinducedhypertensioninordertoruleoutleftventricular
dysfunctionordilatedcardiomyopathy[18].AlcoholintakeinthemanagementofhypertensionThefirst
stepinthemanagementofhypertensioninalcoholdependentpatientsshouldbetogiveupethanol[8].In
mostofthesepatientsBPwillreducetonormalvalueswithinthefollowingdaysandtheywillnotneed
pharmacologicaltreatment.Becauseofthehighprevalenceofmyocardialdysfunctionanddilated
myocardiopathyamongchronicalcoholics,angiotensinconvertingenzymesinhibitors,angiotensinII
receptorantagonists,and/orbetablockersarecommonlyusedtotreatthesepatients.However,therapid
reductionofBPoncessationofalcoholintakemakesclosemonitoringofBPandpharmacological
treatmentnecessaryduringthefirstmonthofabstinence.Nonalcoholdependentpatientswithhypertension
shouldlimittheiralcoholconsumptiontotwoTable1.Mechanismsinvolvedinthepathogenesisofethanol
relatedhypertensionGeneticfactorsStimulationofthereninangiotensinaldosteronesystemAbnormal
sympatheticstimulationIncreasedcortisolsecretionReductionofinsulinsensitivitywithchangesin
glucosetoleranceHeartratevariabilityEffectsonperipheralmuscletoneviachangesincalciumorsodium
transportintosmoothmusclecellsEndothelialdysfunction44Alcoholandriskofcardiovasculardisease
Almostallmodernepidemiologicstudieshaveshownreducedriskofmyocardialinfarctionanddeathdue
tocoronaryheartdiseaseinmoderatedrinkerscomparedtoteetotallers[20,21].Patientswhohaveoneto
twoglassesofalcoholperdayhadfewermyocardialinfarctionsandanimprovedsurvivalcomparedto
teetotallers.Moderatealcoholconsumptionhasawiderangeofpositiveeffects:1)itimprovesinsulin
sensitivity;2)increasesHDLcholesterolandreducesatherogenicsmallsizeLDLparticles,aswellas
fastingtriglycerides;and3)itproducesbeneficialeffectsonadiponectin,Creactiveproteinandadhesion
molecules[2224].Thesebiologicalpathsofalcoholintakeexplainmorethan85%ofthereducedriskof
cardiovasculardiseaseobserved.Ontheotherhand,internationalcomparisons[25]suggestlesscoronary
arterydiseaseinwinedrinkingcountriesthaninliquordrinkingcountries.Thereisalsodatashowing
apparentcoronaryarterydiseaseprotectionsimilarinbeerdrinkerstothatseeninwinedrinkers[26].In
moderatewineandbeerdrinkersanoticeablesafemetabolic,inflammatory,andglycaemicprofilemight
balancehigherbloodpressure,leadingtoanetbenefit[27].However,protectiveeffectsofalcohol
disappearinveryheavydrinkersbecausethebeneficialincreaseinHDLcholesterolisoffsetbythe
increasesinBP[28].Thisinformationsuggeststhatlowtomoderateconsumptionofalcoholimproves
cardiovascularriskandthisbenefitexceedstheriskofhypertensionandheartfailure.However,itis
equallyimportanttorecognizetheseriousadverseeffectsduetohighalcoholingestion.Withchronichigh
dosealcoholintake,thereisadirectrelationshiptoelevatedBP,butalsoanincreaselikelihoodof
developingcongestiveheartfailure,liverdisease,andotherethanolrelateddiseases[17].Conclusions
Severalprospectivecrosssectionalandepidemiologicalstudieshaveshownahighlysignificantassociation
betweentheconsumptionofthreeormorealcoholicdrinksperdayandhypertension.Themechanismsof
ethanolinducedhypertensionhavebeenrelatedtogeneticfactors(sensitivitytothepressoreffectsof
ethanol)andchangesinsympatheticmodulation,cortisol,thereninangiotensinsystem,insulinsensitivity,
andendothelialactivity.Manypatientswithethanolinducedhypertensionalsoshowothertoxiceffectsof
alcoholonthecardiovascularsystemsuchasleftventriculardysfunctionand/ordilatedcardiomyopathy.
Thegoalinthetreatmentofethanolinducedhypertensioninchronicalcoholicsistogiveupalcohol.
However,nondependentpatientsmaylimittheirethanolintaketotwodrinksperdayinmenandonedrink
perdayinwomensinceseveralstudieshavesuggestedthatthesedosesofethanolmayexertaprotective
effectonthedevelopmentofatherosclerosisandpreventcardiovascularmorbidityandmortality.Table2.
Clinicalandlaboratorydataofthealcoholicpatientsclassifiedassensitivetothepressoreffectsofethanol
comparedtothoseclassifiedasresistant(nonsensitive)inaseriesof35normotensivechronicalcoholics
(fromref[9])SensitiveNonsensitive(n=18)(n=17)Age(y)39.87.139.58.0Dailyethanolintake
(g)2198621472TLDE(kg/kg)21.913.319.310.7SBP(mmHg)122712110MBP(mm
Hg)925917DBP(mmHg)786777Enddiastolicdiameter(mm)52.42.7*50.53.5End
systolicdiameter(mm)34.23.032.83.4Interventricularthickness(mm)10.41.4*8.20.8
Posteriorwallthickness(mm)9.81.2*8.50.7Leftventricularmass(g/m2)13223**9517
Shorteningfraction(%)34.83.835.74.7Ejectionfraction(%)52.66.1**57.84.9mcortisol
(nmol/L)451163513155ecortisol(nmol/L)206108246138PRA(pmolofangiotensinh1
ml1)0.680.990.680.66Aldosterone(ng/dL)402280460272ANP(fmol/mL)18.122.514.1
13.4Noradrenaline(pg/mL)26013724680Adrenaline(pg/mL)71366133Insulin(pmol/L)
1127112075SGOT(U/L)59.7(15357)*33.1(9101)SGPT(U/L)47.9(15128)39.3(879)
GGT(U/L)199(10885)116(21600)*p<0.05;**p<0.01;TLDEtotallifetimedoseofethanol;
SBPsystolicbloodpressure;MBPmeanbloodpressure;DBPdiastolicbloodpressure;m
morning;eevening;PRAplasmareninactivity;ANPatrialnatriureticpeptide;SGOTserum
glutamicoxaloacetictransaminase;SGPTserum glutamic pyruvic transaminase;
blood pressure remains very close and even below resting levels.
However, in some individuals there is a disproportional increase in both
systolic and diastolic blood pressure during exercise. Although a
definitive abnormal rise threshold has not yet been established, most
studies support that a systolic blood pressure > 200 mm Hg or diastolic
blood pressure > 110 mm Hg at or near peak exercise is considered an
exaggerated blood pressure response to exercise. Some studies
suggest that such a rise in exercise blood pressure is associated with
future development of hypertension [15] and predicts cardiovascular
mortality [16, 17]. There is also recent evidence to support the theory
that fitness levels may play a significant role in the exercise blood
pressure response. More specifically, moderate aerobic exercise
training may attenuate the excessive elevations of blood pressure
during physical activity. We found that higher fitness levels, as
indicated by peak exercise time, were inversely associated with blood
pressure at six minutes of exercise. We reported significantly lower
systolic and diastolic blood pressure levels at sub-maximal and
maximal workloads in hypertensive patients following 16 weeks of
aerobic training [18]. Some evidence supports the theory that an
abnormal rise in systolic blood pressure during sub-maximal levels of
exercise is associated with left ventricular hypertrophy (LVH) and may
be a better predictor of LVH than peak exercise blood pressure [19]. In
a recent study [20] we demonstrated that men and women with
normal blood pressure at rest but an abnormal rise in systolic blood
pressure during exercise of approximately 5 METs (equivalent to a brisk
walk) had a significantly higher left ventricular mass (LVM) and were
more likely to have LVH. The exercise systolic blood pressure at five
METs and the change in blood pressure from rest to a workload of five
METs were the strongest predictors of LVH. Since five METs is
equivalent to the metabolic demand of most daily activities, the
findings suggest that the impetus for increases in LVM is daily systolic
blood pressure. Furthermore, we identified that a systolic blood
pressure of 150 mm Hg at the exercise levels of five METs was the
threshold for LVH. A meta-analysis that included 54 clinical trials
comprising 2,419 participants assessed the effects of aerobic exercise
on BP. Aerobic exercise was associated with a significant reduction in
mean systolic BP by 3.8 mm Hg and diastolic BP by 2.6 mm Hg [21].
Because the BP reductions related to aerobic exercise did not
significantly differ among trials with various types, frequencies, and
intensities of exercise intervention, the result from these metaanalyses indicated that all forms of exercise seemed to be effective in
reducing BP. A prospective study among Harvard male alumni reported
that men who did not participate in vigorous exercise had a 35% higher
incidence of hypertension than those who were more active [22]. The
ARIC study pointed out that leisure time physical activity reduced the
risk of hypertension in middle-aged white men but not in black [23].
upamodestlevelofaerobicexerciseonaregularbasis,suchaswalking,jogging,orswimming.The
AmericanCollegeofSportsMedicinerecommendsthathypertensiveindividualsengageinmoderate
intensityaerobicexercisefor3060minutesonmostdaysandpreferablyeverydayoftheweek.This
exercisedurationcanalsobefulfilledbyaminimumof10minuteintermittentboutsthroughouttheday.
TheexpectedreductioninBPisapproximately510mmHg.Althoughtherecommendedmodeofexercise
isaerobic,lightresistanceexercisesarenotdiscouraged[32].However,heavyweightliftingorisometric
exercisecanhaveapressoreffectandshouldbeavoided.Ifhypertensionispoorlycontrolled,andalways
inseverehypertension,highintensityphysicalexerciseshouldbediscouragedorpostponeduntil
appropriatedrugtreatmenthasbeeninstitutedandfoundtobeeffective.Preexerciseevaluationofthe
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exerciseprogramandonthepatientssymptoms,signs,overallcardiovascularrisk,andassociatedclinical
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Management47HYPERTENSIONANDARRHYTHMIAJeanPhilippeBaguet1,SerapErdine2,Jean
MichelMallion11CardiologyDepartment,GrenobleUniversityHospital,BP217,38043Grenoblecedex
09,France2IstanbulUniversityCerrahpasaSchoolofMedicine,GztepeI.OrtaSok,34A/9Istanbul,
Turkey2011;12:No.24revisedversionIntroductionArrhythmiabothatrialandventricularisa
commoncomorbiditywithhypertension(HT).Theunderlyingmechanismsaremanyandvarious,
includingleftventricularhypertrophy(LVH),myocardialischaemia,impairedleftventricularfunction,and
leftatrialenlargement.AnyformofarrhythmiamaybeassociatedwithLVH,butventriculararrhythmiais
morecommonaswellasbeingmoredangerous.AtrialarrhythmiaPrevalenceAftersupraventricular
extrasystole,atrialfibrillation(AF)isthenextmostcommonformofarrhythmiaassociatedwithHT.The
relativeriskofdevelopingAFinHTismodestcomparedwithotherconditions,suchasheartfailureand
valvedisease.Nevertheless,HTisthemostprevalent,independent,andpotentiallymodifiableriskforAF
[1].AFismostcommonaftertheageof65andismorecommoninmenthaninwomen[2].Intherecent
RecordAFstudy,analysingthemanagementofparoxysmal/persistentAFinrecentlydiagnosedpatients,
theprevalenceofHTwas68%[3].MechanismsChangesinatrialelectricalpropertiesoccurearlyin
hypertensiveheartdisease,precedingtheappearanceofleftventricularandleftatrialenlargement[4].
Cellularmechanismsoffocalactivitymightinvolvebothtriggeredactivityandreentry[5].Moreover,AF
isperpetuatedbycontinuousconductionofseveralindependentwaveletspropagatingthroughtheatrial
musculature[5].Sympathetichyperactivity,oftenpresentinhypertensivesandparticularlyinapnoeic
subjects,representsanothermechanismfavouringoccurrenceandchronicisationofAF[6].Enlargementof
theleftatrium:Enlargementoftheleftatriumresultsinstretchingoftheatrialfibres,whichiswhatleadsto
thecreationofarrhythmogenicfoci.IntheAFFIRMstudy,ultrasoundmeasuredaleftatriumofnormal
size(diameter<40mm)inonly33%ofpatients[1].LeftatrialenlargementseemstosetinbeforeLVH.
Leftventricularhypertrophy:LVHpavesthewayforAFbyperturbingdiastolicfunctionandthereby
raisingtheleftatrialpressure[7].IntheFraminghamcohort,patientswithanelectrocardiographic
diagnosisofLVHhada3.0to3.8foldincreasedriskofdevelopingAF[8].Verdecchiaetal.foundthat,
inhypertensivesubjectswithsinusrhythmandnomajorpredisposingconditions,theriskofAFincreases
withageandleftventricularmasswhereasincreasedleftatrialsizepredisposestochronicisationofAF[9].
Geneticpredisposition:AFhasafamilialcomponent,especiallyAFofearlyonset[5,10].Abnormalblood
potassiumlevels:Bloodpotassiumimbalance,especiallyhypokalaemia(iatrogenicorsecondaryto
hyperaldosteronism)canleadtothedevelopmentofsupraventriculararrhythmia.Diagnosisandprognosis
ofatrialarrhythmiaWheneverahypertensivepatientcomplainsofpalpitations,thepossibilityof
arrhythmiasupraventricularorventricularshouldbeconsidered.AFrelatedsymptomscanbe
assessedbythenewEHRAscore[5].DefinitivediagnosisdependsonrestingECGorambulatoryheart
ratemeasurementoveraperiodof2448hours.Identifyingcausesmayrequireechocardiography(todetect
LVH,impairmentofleftventricularfunction,leftatrialenlargement,orvalvedisease)andbloodtests
(potassiumlevelsandhighsensitivityTSHtest).AFhasmanyconsequences.Themostdangerousis
systemicembolism,withstrokebeingfourtofivetimesmorecommoninpatientswithAF[11,12].Risk
stratificationforstrokeandthromboembolismcanbeassessedbyCHADS2orCHA2DS2VAScscore[5].
AFcanleadtocardiomyopathyandmayexacerbatepreexistingimpairmentofleftventricularfunction
[13].TheonsetofAFmaytriggeranepisodeofcongestiveheartfailure,especiallyiftheventricular
responseisrapidorifthereissomeunderlyingproblemwithleftventricularfunction(eithersystolicor
diastolic)[14].AFcanalsocauseepisodesofdizzinessorevensyncope.Finally,intheFraminghamstudy,
acorrelationwasobservedbetweenAFandmortalityinbothsexes,andthisindependentlyofother
variables[15].TreatmentofatrialarrhythmiaPreventingAFinhypertensivesubjectsdependson
controllingbloodpressureinordertoreducetheriskofhypertensivecardiomyopathy(oratleastmitigating
theconsequencesthereof).Antihypertensivetherapyhasbeenshowntoreversesomeofthestructural
cardiacchangescausedbyHT,includingLVHandatrialenlargement[16,17].ACEinhibitorsand
angiotensinreceptorblockersmaydirectlyreducethechanceoftherecurrenceofAF[18]butthisisstill
debated[19].Anypotassiumimbalancemustbecorrected.Moreover,antithrombotictherapyisessentialin
patientswithAF.Incontrast,thevalueofantiarrhythmicdrugsismorecontroversial.Inpractice,some
physiciansprefertoreducethearrhythmiaandthenmaintainasinusrhythm,whereasotherschooseto
workwiththeAFbycontrollingtheheartrate(tobetween60and90beatsperminute).Betablockers,
particularlysotalol,seemtobeofinterestinpatientswithhistoryofAF[19].Leftatrialcatheterablation
shouldbereservedforpatientswithAFthatremainssymptomaticdespiteoptimalmedicaltherapy,
includingrateandrhythmcontrol[5].VentriculararrhythmiaVentriculararrhythmiaisusuallytriggeredby
simpleorcomplexventricularextrasystolewhereasthemechanismwherebytachycardiaisperpetuated
moreusuallyinvolvesareentrycircuit.ArrhythmogenicfactorsLeftventricularhypertrophy:Ventricular
prematurecomplexismorecommoninhypertensivesubjectswhenthereisconcomitantLVH[20,21].The
mostdangerousformsofventriculararrhythmia(tachycardiaandventricularfibrillation)arestillrare[22].
BoththeincidenceandseriousnessoftheseformscorrelatewiththeseverityoftheLVH,asmeasuredby
ECGandultrasound[23].Asymmetricseptalandeccentrichypertrophyseemtobeassociatedmoreoften
withventriculararrhythmiathanconcentricLVH[24].ThatLVHisinvolvedinthepathogenesisof
ventriculararrhythmiaisdemonstratedbythefactthattheincidenceofthelatterdropsoncetheformerhas
beenreversed[25].Myocardialischaemia:Myocardialischaemiaisthemostcommonarrhythmogenic
factor,andthisisalsotrueinhypertensivesubjects.Thiscomorbidityincreasestheriskofsuddendeath.
Theischaemiamaybesecondarytoatherosclerosisofthemajorepicardialcoronaryarteries,ordueto
problemsinthemyocardialcapillarysystem.Inthehypertensivesubject,thereisalinkbetweenthe
frequencyandseverityofarrhythmia,andmyocardialischaemia(betheepisodessymptomaticor
subclinical)[26].Impairedleftventricularfunction:Theriskofarrhythmiainhypertensivepatientsis
likewiseexacerbatedbyimpairedleftventricularfunction(systolicordiastolic)asaresultofelectrical
asynchronism.Thisriskisfurtherincreasediftheleftventricleisenlarged.Asageneralrule,atleasttwo
oftheabovementionedriskfactors(LVH,myocardialischaemia,orimpairedventricularfunction)needto
bepresentforonsetofthemostdangerousformsofventriculararrhythmiainhypertensivesubjects.Other
factors:Circadianvariationsandsuddenincreasesinbloodpressurecantriggerarrhythmiaasaresultof
associatedchangesinpreandpostcharge[27].Similarly,thesympatheticirritabilitywhichcommonly
accompaniesHTcanleadtoventriculararrhythmia[28].Whetherornotvariationsinbloodelectrolyte
levels(notablyofpotassium)alsoconstituteanarrhythmogenicfactorismorecontroversial[22,29].
DiagnosisandprognosisofventriculararrhythmiaPositivediagnosisdependsonrestingECGand
ambulatoryheartratemeasurementoveraperiodof2448hours.AmplifiedECG(todetectlateventricular
potentials)andprogrammedventricularstimulationneednotbeperformedonasystematicbasis.
IdentifyingunderlyingmechanismswillinvolvecarryingoutexaminationstolookforLVH(byECGor
cardiacultrasound),myocardialischaemia(ECGormyocardial48ultrasoundstresstesting,myocardial
scintigraphy,Holtermonitoring),heartfailure,orsomeunderlyingmetabolicproblem.HTisassociated
withanincreasedriskofsuddendeath,essentiallyduetoventriculararrhythmia[30].InpatientswithLVH,
globalmortalityisincreasedifthereiscomplexorfrequentventricularextrasystole,evenifthisis
asymptomatic[31].TreatmentofventriculararrhythmiaIfthereisnomyocardialischaemia,onlythemore
severeformsofventriculararrhythmianeedpositivemanagement.However,ifmyocardialischaemiais
present,thisneedstobecorrectedasdofrequentventricularextrasystoles,ventriculardoublets,and
salvoes.Bloodpotassiumabnormalitiesshouldalwaysbetreated.Betablockersandamiodaronearethe
drugsofchoiceinventriculararrhythmiaalthoughcalciumchannelblockersandangiotensinconverting
enzymeinhibitorshavebeenshowntobeeffectiveagainstventriculararrhythmiabyvirtueoftheiraction
againstLVH[25,29].Spironolactonemayalsobeprescribed,notonlytoreversehypokalaemiabutalsofor
itsantifibroticactivityintheventricularmyocardium.Inpatientswitheithersevereventriculararrhythmia,
whichhasprovenrefractorytopharmacologicaltreatment,orprofoundlyimpairedventricularfunction,an
automaticimplantablecardioverterdefibrillatorshouldbeconsidered[32].ConclusionsBothventricular
andatrialformsofarrhythmiaarecommoninpatientswithHT.Theunderlyingmechanismsaremanyand
various,andthemostusefuldiagnosticinformationcomesfromambulatoryheartratemonitoring.
Arrhythmianeedstobetreatedonacasebycasebasiswithobjectivecriteriainsight.References1.The
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469481.12.WolfPA,AbbottRD,KannelWB.Atrialfibrillationasanindependentriskfactorforstroke:
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PA,DAgostinoRB,etal.Impactofatrialfibrillationontheriskofdeath:theFraminghamHeartStudy.
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Management49HYPERTENSIONANDOBSTRUCTIVESLEEPAPNOEAJeanPhilippeBaguet1,
KrzysztofNarkiewicz2,JeanLouisPpin3,PatrickLevy3,RenaudTamisier3,AnneLaureBorel3,
GianfrancoParati4,JeanMichelMallion11CardiologyDepartment,GrenobleUniversityHospital,
Grenoble,France2DepartmentofHypertensionandDiabetology,MedicalUniversityofGdansk,Gdansk,
Poland3SleepLaboratory,GrenobleUniversityHospital,Grenoble,France4DepartmentofClinical
MedicineandPrevention,UniversityofMilanoBicocca&DepartmentofCardiology,S.LucaHospital,
IstitutoAuxologicoItaliano,Milan,Italy2011;12:No.25revisedversionIntroductionMany
epidemiologicalandclinicalstudiesareinfavourofincreasedcardiovascularriskinpatientswith
obstructivesleepapnoea(OSA)[13].Severalstudieshavecontributedimportantinformationtosupport
thistheory,particularlyconcerningtheroleplayedbyOSAincardiovascularmorbidmortality,evenwhen
thenumberofnocturnalapnoeaepisodesislimited.Manypathophysiologicalmechanismsaresuggestedto
explainmorbidassociationsbetweenOSAandcardiovasculardiseases.Cardiovascularresponsesto
apnoeasareacutefollowingeachrespiratoryepisodeandchronic.Epidemiologyanddiagnosisof
OSAOSAisacommondiseaseaffectingaround5%ofthegeneralpopulation,particularlyaffectingmen
[4].Theclinicalpictureincludesfourmainsymptoms:diurnalhypersomnia,frequentnocturnalarousals
withnycturia,morningastheniawithorwithoutheadache,andseveresnoring.FactorspromotingOSAare
notonlyobesity,age,smoking,andconsumptionofalcohol,butalso,andaboveall,anomaliesoftheupper
respiratoryairwayspromotingsnoringinthesepatients.Polysomnographyisthestandardexaminationfor
diagnosisofnocturnalrespiratoryarrest.Itsimultaneouslyrecordssleep,quantifiedairflow(nasal
pressure),thoracicandabdominalrespiratorymovements,electroencephalogram,andhaemoglobinoxygen
saturation.Respiratorypolygraphywithoutsleeprecordingcanalsobeusedinestablishingadiagnosisof
OSA.Apnoeamaybeobstructive(persistentrespiratoryeffort),central(norespiratoryeffort),ormixed
(startsascentraltypeandendsasobstructivetype).Thenumberofapnoeas(airflowstopscompletely)and
hypopneas(reductionofmorethan50%ininspiratoryflowor30%linkedtomorethan3%desaturation
and/ormicroarousals)lastingmorethan10secondsperhourofsleep(apnoeahypopneaindexorAHI)can
thenbecalculated.Whenthesensitiveinstrumentsdescribedaboveareused,thethresholdof15eventsper
hourofrecordingisusuallyappliedforOSAdiagnosis.Pathophysiologicalaspectsofinteractionsbetween
OSAandthecardiovascularsystemPatientssufferingfromOSAwilldisplaypermanentoscillationsin
theirhaemodynamicparametersduringthenight.Theheartrate,bloodpressure(BP),andcardiacoutput
willthereforevaryincessantlybecauseoftherepeatedrespiratoryeventsandrapidchangesinstateof
vigilance(corticalmicroarousals)inducedbytheserespiratoryanomalies.BPfallsatthestartofeach
episodeofapnoeathengraduallyincreasestoapeakpressurejustatthemomentwhenrespirationstarts
again,withsystolicBPpossiblyincreasingby15to80mmHgduringacorticalmicroarousal.These
variationsinBPoccurundertheinfluenceoffourstimuli:O2desaturation,increaseinPaCO2,increased
respiratoryeffort,andmicroarousalattheendoftheapnoea.Respiratoryresumptionlinkedtoarousaldoes
notlastforlongwithanewepisodeofapnoeaoccurringassoonasthepatienthasgonebacktosleep.
Repetitionofthesestimulieverynightleadstochronicchangesinthecardiovascularsystemresponseand
structuralmodifications.Allthesestimuli,inparticulardesaturationreoxygenation,areasourceof
sympatheticstimulation[5].Thistypeofstimulationiswellrevealedbyplasmaorurinarycatecholamines
assayandmicroneurographydata[6,7].Moreover,OSApatientsexhibitimpairedbaroreflexsensitivityto
ahypotensivestimulus[8,9].Thisbaroreflexadaptationmayalsocontributetotheincreaseinresting
autonomictoneobservedinOSApatients.Thechronicincreaseinsympathetictone,alterationsin
baroreflexsensitivity,andassociateddeficitinvascularrelaxationleadtoelevatedperipheralvascular
resistancesinOSA[10].OthermechanismsexplainingOSArelatedhypertensionincludeabnormal
peripheralchemoreceptorfunction[11],systemicinflammation[12],oxidativestress[13],endothelial
dysfunction[14],increasedlevelsofendothelin[15],metabolicdysfunction[16],andstimulationofthe
reninangiotensinsystem[17,18].PrevalenceandcharacteristicsofhypertensioninOSAThelinks
betweenOSAandhypertensionaremorethanasimpleassociation,OSAbeingacceptedbymanyauthors,
andacknowledgedintheESHESCguidelinesforthemanagementofarterialhypertensionasacauseof
hypertension[19].Therearemanypredisposingfactorsforbothpathologies,however,particularly
overweightanditsassociatedhyperinsulinism[20].Thefirstmajorepidemiologicalstudy,performedin
1985,showedthattherelativeriskofhypertensioninsnorerscomparedwithnonsnorerswas1.94inmen
and3.19inwomen[21].Atpresent,theprevalenceofhypertensioninOSApatientsisestimatedatnearly
60%.AshasbeenwelldemonstratedbytheSleepHeartHealthStudy,thisprevalenceincreasesconstantly
withtheAHI[22].Thisdoseeffectrelationshipwasalsodetectedinanotherlargestudyinvolvingsubjects
examinedforsuspectedOSA[23].Inthislaststudy,anyincreaseinanevent(apnoeaorhypopnea)per
hourofsleepwaslinkedindependentlytoa1%riseintherelativeriskofhypertension,andany10%fallin
nocturnalO2saturationincreasestheriskofhypertensionby10%.Anotherstudy,theWisconsinSleep
CohortStudy,withsubjectsnottreatedforsleepanomalies,foundarelativeriskofhypertensionaftera4
yearfollowupof1.42foranAHI<5and2.89whentheAHIwas>15[24].Inastudyperformedon
apnoeicpatientsnotknowntobehypertensive,wefounda42%prevalenceofhypertensionbyclinical
measurementbut76%usingambulatoryBPmonitoringover24hours(ABPM)[25].InOSApatients,
daytimesystolicBPisgenerallynotdifferenttothatofcontrolsubjectswhenmatchedforageandBMI
[26].Ontheotherhand,usingofficeBPrecordingandABPMevenmore,ithasnowbeenwell
demonstratedthatOSApatientshaveahighprevalenceofisolateddiastolichypertension[25,27,28].
Takingthesedataintoaccount,andaccordingtothehighprevalenceofmaskedhypertensioninapnoeic
subjects,ABPMcouldbeproposedforOSApatientswhoseclinicalBPdoesnotdisplayanyabnormality
[29].Nearly30%ofhypertensivepatientssufferfromOSA[30,31].Thisprevalenceisevengreaterin
refractoryhypertension(about80%),particularlybeforetheageof50[3234].Theseverityofthe
hypertensionalsoseemstobeinproportiontothatoftheOSA[27].RRintervalvariabilityisdecreased
andBPvariabilityismarkedlyincreasedinpatientswithOSA[30,35].ThefallinBP(dipping),which
occursduringthenightinanormalsubject,isoftenabsentinapnoeicpatients[25,36,37].Ifthisanomaly
isobservedduringanABPManalysisinahypertensivesubject,itsuggeststhepossibilityofOSA.
DeleteriousroleoftheassociationofOSAwithhypertensionThehighprevalenceofhypertensioninOSA
andthecloserelationshipsbetweenthesetwopathologiespartlyexplainsthehighincidenceof
cardiovasculareventsinapnoeicpatients.Coronaryheartdisease,arrhythmias,cardiacconduction
disorders,andcerebrovasculareventsareoftenencounteredduringfollowupofapnoeicpatients[3845].
Therefore,itwasfoundthatwhentheAHIwasabove20,cardiovascularmortalitywasaround40%after8
yearsinmen[46].Apartfromthesecardiovascularevents,OSAisamajorsourceofsocialhandicap
becauseofthesnoringandnonrecuperativeaspectofthesleepobtained.AdiagnosisofOSA,suggested
byaspecificquestionnaire(theEpworthSleepinessScaleortheBerlinquestionnaire)[47,48],confirmed
bypolysomnographyorrespiratorypolygraphy,isthereforeanessentialstepbecausetreatingthis
pathologyseemstoreducetheriskoflatercardiovascularcomplications.Leftventricularhypertrophyand
diastolicfunctioninOSALeftventricularhypertrophy(LVH)seemstobemorecommonincasesofOSA,
evenaftertakingtheBPintoaccount[49,50].ThefrequencyofoccurrenceofLVHriseswithseverityof
OSA[51].ThegreaterprevalenceofLVHinapnoeicpatientsappearstoberelatedtopostloadelevation
duringapnoeaepisodesandsympathetichyperstimulation[51].However,thesedatashouldbeviewedwith
cautionbecauseofthedifficultyinobtainingreliablemeasurementsofleftventricularmassinOSA
patients,whoareoftenoverweight.LVHexplainssomeofthefunctionalanomaliesoftheleftventricle
observedinapnoeicpatients.Thus,diastolicdysfunctionisfrequentduringOSAandislinkedtoseverity
ofrespiratoryevents[52].EffectsofOSAtreatmentonBPThefirsttreatmentforOSAwastracheotomy,
whichhadabeneficialeffectonBPvaluesandcardiovascularmorbimortality[53].Today,therapeutic
strategiesforOSAincludesleepposturalchanges,avoidingsleepingontheback,weightloss,avoidanceof
alcoholandsedativehypnotics,mandibularadvancingdevices,andupperairwaysurgicalprocedures.The
mostwidelyusedtreatmentconsistsofcontinuouspositiveairwaypressure(CPAP)administeredduring
thenight.CPAPtreatmentpreventsairwaycollapseduringinspiratoryefforts.Effectivelongterm
treatmentofOSAbyCPAPhasbeenshowntodecreasesympatheticactivity,improvebaroreflexcontrolof
heartrate[54,55],andimproveBPcontrol.SeveralstudieshavedemonstratedthatCPAPcanreducethe
BPofapnoeicpatients,especiallydiastolic50andnocturnalBP.However,themajorityofthesestudies
includedlessthan50subjectsandmanyofthemwereneitherrandomisednorcontrolled.Threemeta
analysesusing19randomizedcontrolledtrialswerepublishedin2007[5658].ThemeanBPreduction
withactivetreatmentvs.placebowasabout2mmHg.ParametersthatarepositivelyassociatedwithaBP
reductionunderCPAPtreatmentweresevere,untreated,orrefractoryhypertension,severeOSA,and
compliancewithCPAP>3hourspernight.ThefallinBPwithCPAPisparalleltothatobtainedfor
plasmaandurinarynorepinephrine[59].Themechanismsuggestedexplainingtheefficacyofthistreatment
isthereductioninnocturnalBPpeaksandmicroarousalsbyCPAP.Concerningmedication,hypertension
inOSApatientsseemstobesensitivetobetablockers[60].Morerecently,wedemonstratedthanvalsartan
inducedafourfoldhigherdecreaseinmean24hourBPthanCPAPtreatmentinuntreatedhypertensive
patientswithOSA[61].Insummary,treatmentofOSAwithnasalCPAPnormalizesthenocturnalBP
profilebyeliminatingthelargeBPswingsassociatedwithOSA[55,62],buthaslittleeffectonmean24
hourordaytimeBP[63].Thisfindingcarriesthreemajorimplications:1)thedecreaseinBPassociated
withOSAtreatment,albeitsmall,cansignificantlycontributetoreducecardiovascularrisk[64];2)
hypertensivepatientswithOSAusuallyneedpharmacologicaltreatmentinadditiontoCPAPtonormalize
BP[61];and3)inordertoproperlyassesstheeffectsofOSAonBP,conventionalclinicmeasurementsare
notenoughandshouldbecombinedwithhome[65,66]andambulatoryBPmonitoring.Indeed,
ambulatorybloodpressuremonitoring(ABPM)isthemethodwhichappearsmostusefulintheassessment
ofBPinOSApatientssinceitallowsthedetectionofmaskedhypertensionandassessmentoftheBP
profileduringbothwakefulnessandsleep[67].However,ABPMisnotroutinelyperformedinmany
centres.OptimisationofBPmeasurementsintheofficeorathomeisalsoaveryimportantissueinthe
diagnosisandtreatmentofhypertension,asunderlinedbyguidelinesissuedbytheEuropeanSocietyof
Hypertension(ESH)[66,68].Finally,OSAcanbeassociatedwithresistanthypertension,i.e.aconditionin
whichnormalizationofBPisnotachievedundertreatmentwith3antihypertensivedrugs[33];inthese
patients,CPAPtreatmentcanhelptoachieveBPcontrol[69].ConclusionsOSAisapathologywhichis
bothcommonandunderestimated,andwhichcannotbesummedupasasimpleassociationofsnoringand
obesity.Itsprognosisiscloselylinkedtotheoccurrenceofcardiovascularincidents.Thecausallink
betweencardiovasculareventsandOSAisonlyformallyestablishedforhypertension.Therearemany
pathophysiologicalmechanismsthatmayexplainthemorbidassociationbetweenOSAandhypertension,
withsympathetichyperactivityinthelead.OSAmustbesuggestedinprincipleforanyhypertensive
patient,particularlyifthehypertensionisrefractorytotreatment,predominantlydiastolic,orlinkedtoa
nondipperprofile.ThebeneficialeffectoftreatingOSAwithCPAPwithrespecttoBPseemstobe
established.BPshouldbemeasurednotonlyintheclinic,butalsoindailylifeconditions.HomeBP
monitoring,andinparticularABPM(whichallowsBPtobemonitoredalsoatnight),shouldbe
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patientswithobstructivesleepapneahypopnea:ametaanalysisofrandomizedcontrolledtrials.Lung
2007;185:6772.58.BazzanoLA,KhanZ,ReynoldsK,HeJ.Effectofnocturnalnasalcontinuous
positiveairwaypressureonbloodpressureinobstructivesleepapnea.Hypertension2007;50:417423.59.
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Chest2001;120:887893.60.KraicziH,HednerJ,PekerY,GroteL.Comparisonofatenolol,amlodipine,
enalapril,hydrochlorothiazideandlosartanforantihypertensive treatment in patients with
obstructive sleep apnea. Am J Respir Crit Care Med 2000; 161: 1423
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continuous positive airway pressure and valsartan in hypertensive
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62. Bonsignore MR, Parati G, Insalaco G, et al. Baroreflex control of
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patientswithcoronaryorcerebralvasculardisease[24].Furthermore,costcalculationsshouldbemadeto
seewhetherthecostsofsuchanapproachwouldoutweighthebenefitsofcontrollingthegreatlyincreased
riskinthesepatients.Conclusion(Table1)InPADpatientswithhypertensionthetotalCVriskis
substantiallyincreased.Alleffortsshouldbemadetocontrolbloodpressuretoatleast140/90mmHgor
evenslightlylower,asindiabeticpatients.ThisReferences1.DeBuyzereML,ClementDL.Management
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patientswithcerebrovascularorperipheralarterialdiseasecomparedtocoronaryarterydisease.JIntern
Med2010: 267: 621633. can be achieved by all antihypertensive drugs;
only ACE inhibitors seem to have, besides their blood pressure lowering
properties, a slightly more favourable effect on claudication distance
and risk. The most important action in PAD patients will aim at
decreasing total CV risk; this can be achieved by adding to the
antihypertensive treatment antiplatelet drugs, ACE inhibitors, and
diabetes [2], but it may take 1015 years for the increased risk to
manifest itself and this is not seen in relatively short-term clinical trials.
In view of the predicted increase in the number of diabetic patients
during the coming decades [8], the choice of treatment strategy of
hypertensive subjects may become of increasing importance. As the
duration of adverse drug effects on metabolism is important, it is very
likely that it is more important to take these effects into consideration
for the middle-aged patient with newly discovered hypertension than
for the elderly patient for whom the short-term benefits of blood
pressure control clearly outweigh the adverse effects on metabolism.
New-onset diabetes in large hypertension trials The effects of different
antihypertensive regimens on new-onset diabetes as demonstrated by
some major hypertension trials are shown in Table 1. The difference in
risk reduction between conventional and newer therapies ranges from
0% to 34% (87% when including the small ALPINE study [9]). However,
different criteria have been used for diagnosing diabetes. Thus the
1985 WHO criteria [10] were used in the CAPPP study [11], the 1999
WHO criteria [12] in the VALUE study [7], and both WHO criteria in the
LIFE study [13, 14], whereas new antidiabetic medication, increased
glycated haemoglobin (HbA1c), and self-reported diabetes were the
criteria in the HOPE study [15]. The study design varies between the
trials, and not all the studies were double blind. The CAPPP [11],
NORDIL [16], and STOP-2 [17] studies used an open-label design with
blinded end-point assessment (PROBE), and this can lead to detection
bias; for example, diabetes is more actively sought in thiazide or beta-blocker arms. There are some randomised placebo-controlled trials,
not all of them antihypertensive (CHARM [18], EWPHE [19], HOPE [15],
SCOPE [20], SHEP [21], and SOLVD [22]) reporting new-onset diabetes,
but it is unclear whether this is due to the antihypertensive effect per
se or to specific drug effects. It is also difficult to draw conclusions from
the results of other trials comparing two or more antihypertensive
agents because the observed effects may represent a detrimental
effect of one agent in contrast to a beneficial effect of the other. For
example, the results from INSIGHT [6] and LIFE [13, 14] might reflect
the adverse metabolic effects of thiazide diuretics or beta-blockers
rather than the beneficial effects of calcium channel blocker or ARB
therapy. In the HOPE [15] and PEACE trials [23] the results were post
hoc analysis. This raises the possibility of publication bias, because
positive results are more likely to be reported than negative results.
Furthermore, there is a possibility of detection bias, because if an endpoint is not pre-planned, the studies are not always adequately
powered to prove significance. New- -onset diabetes was not always a
pre-specified primary end point, but the incidence of type 2 diabetes
was a predefined secondary end point in nine of the studies: ALPINE
[9], CAPPP [11], CHARM [18], INSIGHT [6], LIFE [13, 14], NORDIL [16],
SCOPE [20], STOP-2 [17], and VALUE [7]. The effects of different
angiotensinII.Furthermore,thehypokalaemiceffectofdiureticsmaybluntthereleaseofinsulinfromthe
pancreas.ThiswasoriginallyproposedbyConntoexplaintheapparentdiabeticstatefoundinprimary
aldosteronism[29].Preventinghypokalaemiawithpotassiumsupplementationattenuatesthiazideinduced
glucoseintolerance,andthecombinationofadiureticandangiotensinconvertingenzymeinhibitormay
conferalesserriskofnewonsetdiabetes[30].BetareceptorblockersInaprospectivestudyof12,550
adultsbyGressetal.[31],betablockersincreasedtheriskofsubsequentdiabetesby28%among
hypertensivepatientscomparedtohypertensivepatientsnotreceivinganyantihypertensivetherapy,witha
hazardratioof1.28(95%confidenceinterval:1.041.57).Themechanismmayincludeweightgain,
alterationsininsulinclearanceandreducedfirstphaseinsulinsecretion,and,probablymostimportantly,
reducedperipheralbloodflowasaresultofincreasedperipheralvascularresistance[32].Summaryof
findingsintrialsThemajorityofhypertensivepatientsrequiremultiplepharmaceuticalpreparationsforlife
topreventcardiovascularrisk.Datafromcohortandrandomisedtrialssuggestthattheincidenceoftype2
diabetesmellitusisunchangedorincreasedbythiazidesandbetablockersinadosedependentway,while
itappearstobeunchangedordecreasedbyACEIs,CCBs,orARBs[4,28,31].Ametaanalysisofseven
studiesin58,010individualsbyOpieetal.[33]showedthatthenewtherapies,namelyACEIs,ARBs,
andCCBs,provokelessnewdiabetesthantheconventionaloldtherapies(diureticsandbetablockers).
ACEIsandARBsdecreasednewdiabetesby20%(p<0.001)whereasCCBsdecreasednewdiabetesby
16%(p<0.001).Conclusions1)Thedevelopmentofhyperglycaemiainpatientswithhypertensioncould
eitherreflectmetabolicabnormalitiesassociatedwithelevatedbloodpressureperseortheinfluenceof
antihypertensivedrugs.2)Hyperglycaemiaisaprovenriskfactorforbothmacrovascularand
microvasculardiseaseandshouldthereforebetakenseriously.3)Someantihypertensivedrugsseemto
furtherincreasetheriskofhyperglycaemiabyimpairinginsulinsensitivityand/orinsulinsecretion.
Examplesofsuchdrugsarebetareceptorblockersandhighdosethiazidediuretics,especiallywhenusedin
combination.Calciumantagonistsaremostlyneutral.4)ACEinhibitorsorangiotensinreceptorblockers
(ARB),ontheotherhand,mayimproveinsulinsensitivityanddecreasetheriskofnewonsetdiabetes.5)
Theriskassociatedwithhyperglycaemiaislikelytoincreasewiththedurationoftreatment.Thechoiceof
antihypertensivedrugtreatmentinthisperspectiveshouldthereforebeamatterofgreaterrelevanceforthe
middleagedthanfortheelderlypatientwithashorterremaininglifeexpectancy.6)Blockadeoftherenin
angiotensinsystemseemstobeanappropriatechoiceasoneofthepartnerdrugsinofferingcombination
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inCommunitiesStudy.NEnglJMed2000;342:905912.32.JacobS,RettK,HenriksenEJ.
Antihypertensivetherapyandinsulinsensitivity:dowehavetoredefinetheroleofbetablockingagents?
AmJHypertens1998;11:12581265.33.OpieLH,SchallR.Oldantihypertensivesandnewdiabetes.J
Hypertens2004;22:14531458.EuropeanSocietyofHypertensionScientificNewsletter:Updateon
HypertensionManagement55TREATMENTOFHYPERTENSIVEURGENCIESANDEMERGENCIES
EnricoAgabitiRosei1,MassimoSalvetti1,CsabaFarsang21DepartmentofInternalMedicine,
UniversityofBrescia,Italy21stDepartmentofInternalMedicine,St.EmericHospital,Budapest,Hungary
2011;12:No.28revisedversionHypertensiveemergenciescanbedefinedassevereelevationsofblood
pressure(BP)inthepresenceofacutetargetorgandamage.Acutecoronarysyndromes,dissectingaortic
aneurisms,acutepulmonaryoedema,hypertensiveencephalopathy,acutecerebralinfarction,intracerebral
haemorrhage,oracutearterialbleedingoreclampsiarepresentclinicalconditionsinwhichanimmediate
bloodpressurereductionisneededtopreventtheprogressionoftargetorgandamage(TOD)(Table1).
HypertensiveurgenciesarecharacterisedbysevereelevationsinBP(>180/120mmHg)withoutevidence
ofacuteTOD.InhypertensiveurgenciesBPcanusuallybereducedintheemergencydepartment(ED)by
orallyadministereddrugswithouthospitaladmissionandwithambulatoryfollowup[1].Initialevaluation
Appropriatetriageofpatientsisacrucialpartoftheinitialevaluation.Afteracompletehistory(with
particularattentionpaidtopreexistinghypertensionandTOD)andanaccuratephysicalexamination
(includingfundoscopicexamination),selectedlaboratorystudiessuchasurinalysis,creatinine,urea,
electrolytes,andafullbloodcountshouldbeperformed.Whenasecondaryformofhypertensionis
suspectedasampleforplasmareninactivity,aldosterone,andcatecholaminesshouldalsobedrawn.Itis
advisabletoobtainineachpatientanelectrocardiogramandachestradiogram(Table2).Bloodpressure
shouldbemeasuredaccordingtocurrentGuidelines,bothinsittingandstandingpositions[2].A
significantdifferenceinBPbetweenthetwoarmsshouldraisethesuspicionofaorticdissection.TheED
bloodpressureshouldthenbestrictlymonitored.TreatmentofhypertensiveemergenciesPatientsshouldbe
admittedtoanintensivecareunitforclinicalsurveillanceandcontinuousBPmonitoring.Aggressive
treatmentwithparenteraldrugsisthepreferredapproach;inthemajorityofcases,however,theinitialgoal
shouldbeapartialreduction(andnotnormalisation)ofBP,withareductioninBPofnomorethan20
25%withinthefirstminutesanduptooneortwohours,withpossiblecautiousfurtherdecreasesin
subsequenthours[3,4].InmosthypertensiveemergenciesarapidloweringofBPisbeneficial,withthe
exceptionofcerebrovascularaccidents,inwhichitisadvisabletotakeamorecautiousapproach[58].An
excessivereductionofBPvaluesispotentiallydangerous,possiblyleadingtoischaemiccomplications
suchasacutemyocardialinfarctionandstroke.Severalparenteralagentsareavailableforthetreatmentof
hypertensiveemergencies(Table3);thechoiceoffirstlineantihypertensiveagentsshouldbetailoredto
thepatientsclinicalstatus.Nitroprussideisahighlyeffectiveshortactingarteriolarandvenousdilator,
whichcanbeusedinmosthypertensiveemergencies.Inpatientswithprimaryintracerebralhaemorrhage
cautionisneededbecauseofthepotentialantiplateleteffectandintracranialpressureincrease.Theriskof
cyanatetoxicityisgreaterwhentheTable2.DiagnosticworkupRepeatedbloodpressuremeasurements
(firstmeasurementsatbotharms)Clinicalhistoryandphysicalexamination:cardiovascularCNS
fundusoculiSelectedlaboratorystudies:urinalysis,creatinine,urea,electrolytes,andafullbloodcount
whenasecondaryformofhypertensionissuspected,asampleforplasmareninactivity,aldosterone,and
eventuallycatecholaminesshouldalsobedrawnElectrocardiographyChestXraysFurtherinvestigations
(accordingtotheclinicalpresentation):echocardiography(TT,TE)brainCTscanorMRIabdominal
ultrasonographythoracoabdominalCTscanorMRIvascularultrasoundTable3.Drugsfor
hypertensiveemergenciesDrugDoseOnsetDurationAdverseeffectsSodiumnitroprussiate0.2510
mg/kg/minImmediate12minHypotension,vomiting,cyanatetoxicityLabetalol2080mgbolus12
mg/mininfusion510min26hNausea,vomiting,heartblock,bronchospasmGlyceryltrinitrate5100
mg/min13min515minHeadache,vomitingEnalaprilat1.255.00mgbolus15min46hHypotension,
renalfailure,angioedemaFurosemide4060mg5min2hHypotensionFenoldopam0.10.6mg/kg/min
510min1015minHypotension,headacheNicardipine210mg/h510min24hReflextachycardia,
flushingHydralazine1020mgbolus10min26hReflextachycardiaPhentolamine510mg/min12
min35minReflextachycardiaUrapidil2550mgbolus34min812hSedationTable1.Hypertensive
emergenciesHypertensiveencephalopathySeverehypertensionassociatedtoacutetargetorgandamage:
acutecoronarysyndromespulmonaryoedemaacuteaorticdissectionintracerebralhaemorrhage,
subarachnoidhaemorrhageacutebraininfarctionacuteorrapidlyprogressingrenalfailureSevere
hypertensionafterthrombolysisforischaemicstrokePheochromocytomacrisisGuillainBarrsyndrome
SpinalcordinjuryDrugsrelatedhypertension(sympathomimetics,cocaine,phencyclidine,
phenylpropanolamine,lysergicaciddiethylamide,cyclosporine,antihypertensivetreatmentwithdrawal,
interactionwithMAOinhibitors)EclampsiaPostoperativebleedingPostcoronaryarterybypass
hypertension56drugisusedforlongperiods(days)orinpatientswithhepaticorrenaldysfunction.With
nitroprusside,BPshouldbecontinuouslymonitoredintraarterially;hypotensioncan,however,bemanaged
inmostcasesbydiscontinuingtheinfusion.Nitroglycerinisavenousand,toalesserdegree,arteriolar
dilator,particularlyindicatedinacutecoronarysyndromesandpulmonaryoedema.Labetalolisanalpha
andbetaadrenergicblocker,whichcanbegivenasanintravenousbolusorinfusion;itishighlyeffective
andisindicatedinmosthypertensiveemergencies,inparticularinaorticdissectionandinacutecoronary
syndromes.Itmaybegivenalsoaftercocaineoramphetamineuse,whichmayinducetransientbut
significanthypertensionleadingtostrokeand/orseriouscardiacdamage.Urapidil,analphablockerwith
additionalactionsinthecentralnervoussystem(itactivates5HT1Areceptors),hasalsobeenfound
effectivesinceitinducesvasodilatationwithouttachycardia.Finally,itmustberememberedthat
furosemidecanbeparticularlyindicatedwhenvolumeoverloadispresent,asinleftventricularfailure.In
thepresenceofvolumedepletion,incontrast,diureticscouldcauseadditionalreflexvasoconstrictionand
shouldthereforebeavoided.SpecifichypertensiveemergenciesInpatientswithacutecoronarysyndromes
asevereelevationofBPvaluesisnotuncommon;ontheotherhand,myocardialischaemiamayalsobe
inducedbyacuteelevationsinBPinpatientswithouthaemodynamicallyrelevantcoronaryarterydisease
throughanincreaseinleftventricularwallstressandmyocardialoxygenconsumption.Inthissetting
intravenousvasodilators,suchasnitroglycerinandnitroprusside,shouldbetheinitialdrugs,incombination
withabetablocker(labetalol,metoprolol,esmolol,oratenolol),whichmayfurtherdecreaseBPandreduce
heartrateand,consequently,myocardialoxygenconsumption.Inthepresenceofacuteleftventricular
failureBPshouldberapidlycontrolled.Thepreferreddrugsareintravenousnitroglycerinornitroprusside
incombinationwithloopsdiureticsforvolumeoverloadcontrol.Inpatientswithaorticdissectionand
hypertensionBPcontroliscrucial.ThetreatmentshouldbestartedimmediatelyandsystolicBPrapidly
reducedtolessthan100mmHg;theidealdrugshouldnotonlyallowthereductionofBPbutalsoreduce
heartrateandcardiaccontractilitywiththeaimofreducingstressontheaorticwall.Thiscanbeachieved
withacombinationofabetablockerandavasodilator,suchasnitroprussideornitroglycerin,administered
intravenously.Pheochromocytomacrisescanbemanagedwithanintravenousalphablockersuchas
phentolamine,followedbyconcomitantinfusionofabetablocker;nitroprussidemayalsobeadded.Beta
blockersshouldalwaysbeassociatedwithalphablockersinpatientswithpheochromocytomasince
inhibitionofbetareceptorinducedvasodilationmayleadtoafurtherincreaseinBPvaluesinthepresence
ofalphaadrenergicvasoconstriction.Simultaneousalphaandbetablockademayalsobeachievedwith
monotherapywithlabetalol.Inpatientswithacutestroketheuseofantihypertensivetherapyisstill
controversial.Autoregulationofbloodflowisimpairedinischaemicareasofthebrain,andBPreduction
mayfurtherreduceflowintheischaemicpenumbraandfurtherexpandthesizeoftheinfarction.Itseems
reasonabletorecommendtheinstitutionofantihypertensivetreatmentonlyinthepresenceofBPvalues
above220/120mmHg(ormeanBP>140mmHg)inischaemicstrokeandtoobtainaninitialreductionof
BPvaluesofabout1015%.Treatmentmaybeinitiatedwithintravenouslabetalol,and,ifneeded,with
nitroprussideornitroglycerin.InpatientswithacutestroketreatedwiththrombolysisBPshouldbekept
below185/110mmHg.Inprimaryintracerebralhaemorrhage,treatmentshouldbestartedifBPvaluesare
greaterthan180/105mmHg[58].Forlessmarkedelevationsofbloodpressuretheavailabledatadonot
supporttheinitiationofantihypertensivetreatmentintheearlyphasesofstroke.Infact,afterthepromising
resultsoftheACCESSstudy(342patientswithacutestroke)[9],morerecently,theSCASTstudy[10]
showednoevidenceofabeneficialeffectofcarefulbloodpressureloweringtreatmentwithanangiotensin
receptorblockerinmorethan2000patientswithacuteischaemic(85%)orhaemorrhagic(14%)strokeand
ameanbloodpressureof171/90mmHg.Theseresultsarefurtherreinforcedbythoseofametaanalysis
performedbythesameauthors,includingmorethan3600patients,whichconfirmedthelackofbenefitof
BPloweringinacutestrokeandmildtomoderateelevationsinBP.Forhaemorrhagicstroke,inthe
recentlypublishedINTERACTstudy[11],inwhich404patientswithintracerebralhaemorrhageand
systolicBPbetween150and220mmHg,underwentearlyintensiveBPloweringtreatment,asignificant
reductioninhaematomagrowthover72hourswasobservedinactivelytreatedpatients.Theongoingmain
study(INTERACT2)willassesstheeffectofearlyintensiveBPloweringonfunctionaloutcomeona
largersampleofpatients(2800).Therefore,whileawaitingtheresultsoftheongoingstudies,routineBP
loweringintheacutephaseofstrokeinpatientswithmildtomoderateelevationsinbloodpressuredoes
notappearadvisable.Acutepostoperativehypertensionisnotuncommon,particularlyaftercardiothoracic,
vascular,headandneck,andneurosurgicalprocedures.Formostnoncardiactypesofsurgerythereisno
agreementonBPthresholdsfortreatment,andthepatientsbaselineBP,typeofsurgicalprocedure,and
associatedclinicalconditionsshouldbetakenintoaccountinpatientmanagement.Itseemsreasonableto
maintainbloodpressurewithin20%ofpreoperativearterialpressure.Forcardiothoracicsurgerythereis
moreevidenceofanincreasedriskassociatedwithapostoperativeincreaseinBPvalues,whichshouldbe
keptbelow140//90mmHg[12,13].Labetalol(andotherbetablockers),nitroprusside,nitroglycerin,or
fenoldopamshouldbethepreferredintravenousdrugsforBPcontrol.Treatmentofhypertensiveurgencies
InthemajorityofpatientswithseverehypertensionnosignsofacuteTODareusuallyobserved.Inthese
patientsBPshouldbeloweredgraduallyoveraperiodof2448hours;thiscanoftenbeachievedbyorally
administereddrugswithouthospitaladmissionandwithcloseambulatoryfollowup.Clinicalsurveillance
isadvisableduringthefirstfewhoursafterdrugadministration.Bloodpressureloweringshouldbe
gradual:thereisnoprovenbenefitfromarapidreductioninBPinasymptomaticpatientswhohaveno
evidenceofacuteTOD,andaprecipitousfallinBPcoulddomoreharmthangood.InTable4
recommendedoralagentsforhypertensiveurgenciesarereported.Aninitialapproachwithacombination
ofantihypertensivedrugsincreasesthelikelihoodofeffectiveBPreduction.ThedegreeofBPreduction
inducedbysublingualnifedipinecanneitherbepredictednorcontrolledandthispreparationisnot
recommended[14].ConclusionsInthepresenceofsevereelevationsofBPapromptandaccurateinitial
workupiscrucialfortheidentificationofacuteTOD.TreatmentshouldbestartedpromptlyintheEDwith
parenteralororaldrugsaccordingtothefindingsoftheinitialevaluation.Bloodpressureshouldberapidly
reducedbutaprecipitousfallinBPshouldbeavoidedand,inthemajorityofcases,reductionratherthan
normalisationofbloodpressureshouldbetheinitialgoaloftreatment.Table4.Drugsforhypertensive
urgenciesDrugDoseTimetopeakHalflifeSideeffectsCaptopril12.525mgp.o.1560min1.9hRenal
failureinpatientswithrenalarterystenosisLabetalol200400mgp.o.20120min2.58hBronchospasm,
depressionofmyocardialcontractility,AVblock,nausea,elevationofliverenzymesFurosemide2550
mgp.o.12h0.51.1hVolumedepletionAmlodipine510mgp.o.16h3050hHeadache,tachycardia,
flushing,peripheraloedemaFelodipine510mgp.o.25h1116hHeadache,tachycardia,flushing,
peripheraloedemaIsradipine510mgp.o.11.5h816hHeadache,tachycardia,flushing,peripheral
oedemaPrazosin12mgp.o.12h24hSyncope(firstdose),palpitations,tachycardia,orthostatic
hypotensionReferences1.VaughanCJ,DelantyN.Hypertensiveemergencies.Lancet2000;356:411
417.2.ManciaG,DeBackerG,DominiczakA,etal.2007ESHESCPracticeGuidelinesforthe
ManagementofArterialHypertension:ESHESCTaskForceontheManagementofArterial
Hypertension.JHypertens2007;25:17511762.3.VaronJ,MarikPE.Clinicalreview:Themanagement
ofhypertensivecrises.CriticalCare2003;7:374384.4.ElliottWJ.ManagementofHypertension
Emergencies.CurrHypertensRep2003;5:486492.5.InternationalSocietyofHypertensionWriting
Group.InternationalSocietyofHypertension(ISH)WritingGroup:statementonthemanagementofblood
pressureinacutestroke.JHypertens2003;21:665672.6.BrottT,BogousslavskyJ.Drugtherapy:
treatmentofacuteischemicstroke.NEnglJMed2000;343:710722.7.GoldsteinLB.Bloodpressure
managementinpatientswithacuteischemicstroke.Hypertension2004;43:137141.8.QureshiAI.Acute
hypertensiveresponseinpatientswithstroke:pathophysiologyandmanagement.Circulation2008;118:
176187.9.SchraderJ,LudersS,KulschewskiA,etal;onbehalfoftheACCESSStudyGroup.The
ACCESSstudy:evaluationofAcuteCandesartanCilexetilTherapyinStrokeSurvivors.Stroke2003;34:
1699703.10.SandsetEC,BathPMW,BoysenG;onbehalfoftheSCASTStudyGroup.Theangiotensin
receptorblockercandesartanfortreatmentofacutestroke(SCAST):arandomised,placebocontrolled,
doubleblindtrial.Lancet2011;377:741750.11.AndersonCS,HuangY,WangJG,etal;forthe
INTERACTInvestigators.Intensivebloodpressurereductioninacutecerebralhaemorrhagetrial
(INTERACT):arandomisedpilottrial.LancetNeurol2008;7:391399.12.HowellSJ,SearJW,FoexP.
Hypertension,hypertensiveheartdiseaseandperioperativecardiacrisk.BrJAnaesth2004;61:1661
1675.13.HaasCE,LeblancJM.Acutepostoperativehypertension:areviewoftherapeuticoptions.AmJ
HealthSystPharm2004;61:16611675.14.GrossmanE,MesserliFH,GrodzickiT,KoweyP.Shoulda
moratoriumbeplacedonsublingualnifedipinecapsulesgivenforhypertensiveemergenciesand
pseudoemergencies?JAMA1996;276:13281331.EuropeanSocietyofHypertensionScientific
Newsletter:UpdateonHypertensionManagement57TREATMENTOFHIGHBLOODPRESSUREIN
THEELDERLYSverreE.Kjeldsen1,AudE.Stenehjem1,IngridOs1,ThomasHedner2,GordonT.
McInnes31OsloUniversityHospital,Ullevaal,Oslo,Norway2SahlgrenskaUniversityHospital,
Gteborg,Sweden3WesternInfirmary,UniversityofGlasgow,UK2011;12:No.29revisedversion
EpidemiologyandpathophysiologyinelderlyandoldpatientsHypertensionintheelderly(thoseoverthe
ageof65years)isanincreasingpublichealthconcern[1].Raisedbloodpressure,especiallysystolic
pressure,confersasignificantcardiovascularriskandshouldbeactivelytreatedinelderlypatients.Evenin
theveryold(thoseabovetheageof80years),hypertensionisadominantriskfactor;treatmentprolongs
lifeandpreventsstrokeandheartfailure.Theprevalenceofhypertensionapproachesorevenexceeds50%
inpeopleaged70andabove[2].Mostelderlypeoplewithhypertensionhaveisolatedsystolic
hypertension,definedassystolicpressuregreaterthan140mmHganddiastolicpressurelessthan90mm
Hg[3,4].Systolichypertensionisamorepotentriskfactorthanincreasesindiastolicpressure.Sluggish
baroreceptorfunctionandreducedcardiovascularsensitivitytocatecholaminesmaketheelderlymore
sensitivetonaturalordruginducedfallsinbloodpressure.Diagnosticworkupofhypertensioninthe
elderlyandtargetorgandamageTheremaybediagnosticproblemsintheelderlyandveryoldpeople.
Pseudohypertensionshouldbesuspectedinolderpatientswho,despitehighbloodpressure
measurements,haveminimalvasculardamageintheretinaandwhoexperienceinordinatepostural
dizzinessdespitecautioustherapy.Thisisaconditioninwhichthereisamajordiscrepancybetweenintra
arterialandarmcuffbloodpressures,suchthatcuffpressuresarefalselyhigh[5,6].Bloodpressure
readingsarefarmorevariableintheelderly,somorereadingsshouldbetakeninitiallythanforpatientsin
thegeneralpopulation.Bloodpressureshouldbemeasuredinboththesittingandstandingpositionssince
thereisahighfrequency(asmuchas30%)ofa20mmHgorgreaterfallinbloodpressureinpatientswith
asystolicpressureover160mmHg.Inthesecircumstancesstandingbloodpressureshouldbeusedto
guidetreatmentdecisions.Sideeffectslikedizzinessandlightheadednessshouldalerttheinvestigatorof
possibleovertreatment.Prevalenceofclinicallysignificantsecondaryhypertensionislow(probablyinthe
15%range).Ambulatoryandhomebloodpressure(ABPandHBP)Thelastguidelinesforthe
managementofhypertensionprovidedetailedsuggestionsregardinghowandwhentouseABPmonitoring
[7].ABPhasbeenfoundtobeasignificantpredictorofcardiovascularmorbidity,independentofoffice
bloodpressureandotherriskfactorsinelderlysubjectsandthosewithisolatedsystolichypertension[8,9].
Thewhitecoatphenomenon,thedifferencebetweenofficebloodpressureandABP,maybemore
pronouncedintheelderly[10].Thereversedwhitecoatphenomenon,whenABPishigherthanoffice
bloodpressure,hasalsobeenrevealedinasubstantialportionofolderhypertensives[11].However,the
reproducibilityandthereforetheclinicalutilityofthewhitecoateffecthavebeenquestioned[12].Inmost
people,bloodpressurefallsatnight.Thenocturnaldipislessmarkedwithincreasingage[1214]and
disappearsincentenarians[13].ThereisapaucityofdataonHBPinelderlysubjects.IntheOhasama
study,HBPhadgreaterpredictivepowerformortalityandstrokethanscreeningbloodpressure[15],
suggestingthepotentialusefulnessofHBPmeasurements.However,physicalandintellectuallimitations,
whicharemoreevidentinelderlysubjects,maycurtailmoreextensiveuseofHBPmonitoring[7].Total
cardiovascularriskandwhentostartdrugtreatmentforhypertensionintheelderlyThesamegeneralrules
applytothewholehypertensivepopulation[1620].Calculationoftotalcardiovascularriskusingmethods
suchasthoseproposedbythe2003EuropeanSocietyofHypertensionEuropeanSocietyofCardiology
Guidelines[21]isrecommended.TheHYVETstudyshowedthatreducingsystolicBPfromapproximately
170to140mmHginpatientsabovetheageof80yearsreducesmortality,stroke,andheartfailure[22].
Treatmentofhypertensioninveryoldpatientsshouldberestrictedtothosewhoareotherwiserelativelyfit
andwithatleastgradeIIhypertension[22].PlacebocontrolledtrialsThe2003EuropeanSocietyof
HypertensionEuropeanSocietyofCardiologyGuidelines[21]forthemanagementofarterialhypertension
concludedthatrandomisedcontrolledtrialsleavelittledoubtthatelderlypatientsbenefitfrom
antihypertensivetreatmentintermsofreducedcardiovascularmorbidityandmortality,irrespectiveof
whethertheyhavesystolicdiastolicorisolatedsystolichypertension.Benefitsinelderlypatients[2225]
havebeenshownwithrepresentativeagentsfromseveralclassessuchasdiuretics,betablockers,calcium
antagonists,angiotensinconvertingenzyme(ACE)inhibitors,andangiotensinreceptorblockers.Several
studies[23,2628]haveshownmajorbenefitsfromtreatingelderlypatientswithisolatedsystolic
hypertension.ComparativetrialsThefirstfivelargecomparativetrialscomprisingabout58,000
hypertensivepatientsshowednodifferenceintheprimarycardiovascularendpointwhennewerdrugs
werecomparedwitholderdrugs.Theimpressionwasthusthatthemostimportantaspectofmanagement
istolowerbloodpressurewithacombinationofwelltolerateddrugs[2935].Severalrecentcomparative
trialshaveincludedpopulationswithmeanages>65years.TheLIFEstudy[35]showedaclearbenefitof
theangiotensinreceptorblockerlosartanoverthebetablockeratenololinpatientswithleftventricular
hypertrophy;thiazidewasusedsimilarlyasaddontreatmentinbotharms.Thelosartanbenefitswere
particularlyexpressedintwoprespecifiedsubgroupsofpatients:thosewithdiabetes[36]andthosewith
isolatedsystolichypertension[37].IntheSCOPEstudy[38]theangiotensinreceptorblockercandesartan
wasassociatedwithfewerstrokes,butalsolowerbloodpressure[38].TheSHELLStudy[39]showedno
differenceinoutcomebetweencalciumantagonistsanddiureticsinpatientswithisolatedsystolic
hypertension.IntheVALUEtrial[40]theangiotensinreceptorblockervalsartanandthecalcium
antagonistamlodipinepreventedtheprimarycardiacendpointtothesameextent,althoughbloodpressure
remainedhigheronvalsartan.TheVALUEfindings[41]stronglysuggestthatbloodpressureshouldbe
controlledtoalevelbelow140/90mmHgwithin36monthstopreventneworworseningcardiovascular
disease.TheASCOTstudy[42]showedthattreatmentwiththecombinationofamlodipineplustheACE
inhibitorperindoprilwasassociatedwithreducedmortalityandfewercardiovascularendpointsthanwas
treatmentwithatenololcombinedwithbendroflumethiazide,butthebloodpressurewasslightlyhigherin
thelattertreatmentarm.However,intheACCOMPLISHtrialafixedamlodipineACEIcombinationwas
superiortodiureticACEIinreductionofendpointsirrespectiveofagedespitelittlebloodpressure
differencebetweenthetreatmentarms[43].Targetbloodpressureandthebenefitsofacetylsalicylicacid
andstatinasaddontherapyTheHypertensionOptimalTreatment(HOT)study[44]aimedtostudythe
relationshipbetweenthreelevelsoftargetdiastolicbloodpressure(90,85,and80mmHg)and
cardiovascularmorbidityandmortalityinhypertensivepatients,andtoexaminetheeffectson
cardiovascularmorbidityandmortalityofalowdose(75mgdaily)ofacetylsalicylicacid.Felodipinewas
givenasbaselinetherapywiththeadditionofotheragents.TheHOTstudycomprisedalargegroupof
elderlypatients(>65years)[45].Thesesubjects(n=5987)averaged70.6+3.9yearsofage,54%were
womenandtheirbloodpressureswere17515/1054mmHgatrandomisation.Intensiveloweringof
bloodpressurewasassociatedwithalowrateofcardiovasculareventswithoutdifferencesfortheblood
pressuretargetgroups.Acetylsalicylicacidsignificantlyreducedmajorcardiovasculareventswiththe
greatestbenefitseeninallmyocardialinfarction.Therewasnoeffectontheincidenceofstrokeorfatal
bleeds,butnonfatalmajor58bleedsweretwiceascommon.Likewise,theeffectofatorvastatinwasat
leastasstrongintheelderlypatientsasintheyoungerpatientsinthelipidloweringarmoftheASCOT
study[46].SummaryThereislittledoubtfromrandomisedcontrolledtrialsthatelderlypatientsbenefit
fromantihypertensivetreatmentintermsofreducedcardiovascularmorbidityandmortality,whetherthey
havesystolicdiastolicorisolatedsystolichypertension.Thelargerrandomisedcontrolledtrialsof
antihypertensivetreatmentversusplaceboornotreatmentinelderlypatientswithsystolicdiastolic
hypertensionusedadiureticorabetablockerasfirstlinetherapy.Intrialsonisolatedsystolic
hypertension,firstlinedrugsconsistedofadiureticoradihydropyridinecalciumchannelblocker.Inall
thesetrialsactivetherapywassuperiortoplaceboornotreatment.Otherdrugclasseshaveonlybeenused
incomparativetrials.Benefithasbeenshowninolderpatientsforatleastonerepresentativeagentof
severaldrugclasses,includingdiuretics,betablockers,calciumchannelblockers,convertingenzyme
inhibitors,andangiotensinreceptorantagonists.Initiationofantihypertensivetreatmentinelderlypatients
shouldfollowthegeneralguidelines.Manypatientswillhaveotherriskfactors,targetorgandamage,and
associatedcardiovascularconditions,towhichthechoiceofthefirstdrugshouldbetailored.Furthermore,
manypatientswillneedtwoormoredrugstocontrolbloodpressure,particularlysinceitisoftendifficult
tolowersystolicpressuretobelow140mmHg.References1.DyerAR,StamlerJ,ShekelleRB,
SchoenbergerJA,FarinaroE.Hypertensionintheelderly.MedClinNorthAm1997;61:513529.2.
HarrisT,CookEF,KannelWB,SchatzkinA,GoldmanL.Bloodpressureexperienceandriskof
cardiovasculardiseaseintheelderly.Hypertension1985;7:118124.3.VokonasPS,KannelWB,Cupples
LA.Epidemiologyandriskofhypertensionintheelderly:theFraminghamStudy.JHypertens1988;6
(Suppl1):S3S9.4.ChaundhrySI,KrumholzHM,FoodyJM.Systolichypertensioninolderpersons.
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Hypertens1993;11:16.6.NationalHighBloodPressureEducationProgramWorkingGroup.Reportof
hypertensionintheelderly.Hypertension1994;23:275285.7.OBrienE,AsmarR,BeilinL,etal.
EuropeanSocietyofHypertensionrecommendationsforconventional,ambulatoryandhomeblood
pressuremeasurement.JHypertens2003;21:821848.8.BjrklundK,LindL,ZetheliusB,BerglundL,
LithellH.Prognosticsignificanceof24hambulatorybloodpressurecharacteristicsforcardiovascular
morbidityinapopulationofelderlymen.JHypertens2004;22:16911697.9.StaessenJ,LutgardeT,
FagardR,etal.Predicting cardiovascular risk using conventional vs
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Dahlf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular
events with an antihypertensive regimen of amlodipine adding
perindopril as required versus atenolol adding bendroflumethiazide as
required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised
controlled trial. Lancet 2005; 366: 895906. 43. Jamerson K, Weber MA,
Bakris GL, et al; for the ACCPLISH Trial Investigators. Benazepril plus
amlodipine or hydrochlorothiazide for hypertension in high-risk
patients. NEJM 2008: 359: 24172428. 44. Hansson L, Zanchetti A,
Carruthers SG, et al. Effects of intensive blood pressure lowering and
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351: 17551762. 45. Kjeldsen SE, Kolloch RE, Leonetti G, et al.
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for the ASCOT Investigators. Prevention of coronary and stroke events
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Society of Hypertension Scientific Newsletter: Update on Hypertension
Management 59 HYPERTENSION AND HEART FAILURE Enrico Agabiti
Rosei1 , Maria Lorenza Muiesan1 , Wolfgang Kiowski2 1 Clinica Medica,
University Hospital, Brescia, Italy 2 Cardiovascular Center and
Foundation Zrich, Klinik Im Park, Zrich, Switzerland 2011; 12: No. 30
revised version Epidemiology At the present time, a persistent increase
in morbidity and mortality associated with CHF has been observed and
heart failure remains a common cause of premature death [1].
Hypertension is the most important modifiable risk factor for heart
failure [2] and it increases the risk for heart failure in all age groups. It
has been calculated that in subjects aged 40 years or older with
increased blood pressure ( 140 and/or 90 mm Hg) the lifetime risk of
developing HF is double compared with those subjects with BP lower
than 140/90 mm Hg. For CHF occurring in the absence of myocardial
infarction it has been calculated that lifetime risk is 1 in 9 for men and
1 in 6 for women, which indicates the risk of CHF that is largely
attributable to hypertension. In the Framingham Study update in 2003
only 25% of patients with heart failure suffered a myocardial infarction
and about 75% of patients had a history of arterial hypertension; a
significant association was observed between systolic and/or pulse
pressure and incidence of HF [3]. Night-time blood pressure appears to
convey additional risk information about congestive heart failure
beyond office blood pressure measurements and other established risk
factors, as shown in a cohort of uncomplicated elderly men in Sweden
(BNP).TheincreaseinLVstressactivatesthetranscriptionandreleaseofBNPthatcanbemeasuredinthe
plasmaofpatientswithsystolicand/ordiastolicdysfunction;theelevationinplasmaBNPlevelscannot,
however,discriminatesystolicfromdiastolicdysfunction.TreatmentMostoftheearlierrandomised
clinicaltrialsevaluatingtheefficacyofantihypertensivedrugshavebeenassociatedwithasignificant
preventionofsystoliccardiacfailure,increasingpatientssurvival[15].Theefficacyofantihypertensive
therapysupportstheimportantcontributionofpersistentlyelevatedbloodpressuretoonsetandprogression
ofCHF[16].IntheUKPDSstudyasignificantreductioninheartfailureratewasassociatedwiththe
progressivedecreaseofbloodpressure(12%decreaseintheincidenceofheartfailurefor10mmHg
decreaseofsystolicbloodpressure)[17].However,themetaanalysisoftheresultsofmajorinterventional
randomizedtrialsconductedinhypertensivepatientshaveshownthatthereductionintheincidenceofCHF
isrelatednotonlytothedegreeofbloodpressurereduction,butalsototheclassofdrugused[18].
DiureticsandbetablockerswerecomparabletoACEinhibitorsinpreventingthedevelopmentofheart
failure,anddiuretics,betablockers,andACEinhibitorsweremoreeffectivethancalciumantagonists[18].
AngiotensinIIreceptorblockers(ARBs)havebeendemonstratedtobemoreeffectivethandiuretics,beta
blockers,andcalciumantagonistsinreducingtheincidenceofheartfailureinhypertensivediabetic
patientswithrenaldisease(RENAAL,IDNT)orLVH(LIFE)[19](Table2).Table1.Characteristicsof
patientswithsystolicordiastolicheartfailureCharacteristicDiastolicheartfailureSystolicheartfailure
AgeFrequentlyelderlyAllages,typically5070yrSexFrequentlyfemaleMoreoftenmaleLeft
ventricularPreservedornormal,Depressedejectionfractionapproximately40%approximately40%or
higherorlowerLeftventricularUsuallynormal,oftenwithUsuallycavitysizeconcentricleftventricular
dilatedhypertrophyLeftventricularUsuallypresentSometimespresenthypertrophyonelectrocardiogram
ChestradiographyCongestionwithCongestionandorwithout cardiomegaly cardiomegaly
Gallop rhythm present Fourth heart sound Third heart sound 60 On the
other hand, in the ALLHAT study [20], symptoms of heart failure
increased in patients randomized to treatment with the angiotensinconverting enzyme (ACE) inhibitor or with the calcium-antagonist,
possibly because previous therapy including a diuretic was withdrawn
at inclusion; in addition, despite significant differences in the incidence
of heart failure, heart failure mortality did not differ among treatment
arms with different antihypertensive drugs. In the VALUE study [21]
heart failure incidence was significantly lower in patients receiving
valsartan in respect to those treated with amlodipine only after three
years of treatment. In hypertensive patients with coronary artery
disease, the control of blood pressure seems to be particularly relevant
in the prevention of heart failure. The ACTION study [22] has shown
that nifedipine GITS may reduce the number of new- -onset heart
failure in all patients (29%) and to a greater extent in the subgroup of
hypertensives (38%). More recently BP reduction with an ACE inhibitor
and diuretic combination was associated with a striking reduction in
heart failure incidence as compared to placebo in very elderly (> 80
years of age) patients with hypertension [23]. The goal of
antihypertensive treatment for the prevention of heart failure should
be the control of blood pressure, but also the regression of left
ventricular hypertrophy, of coronary epicardial artery atherosclerosis
and of small vessel structural alterations, in addition to the decrease of
ventricular fibrosis. ACE inhibitors and angiotensin II receptor blockers
(ARBs) seem more effective in favouring the regression of LVH and of
small vessel structural changes. They may also have a favourable
effect in the reversal of myocardial fibrosis [24]. Only a few studies
Med2008;359:24562467.28.ChobanianAV,BakrisGL,BlackHR,etal.TheSeventhReportofthe
JointNationalCommitteeonPrevention,Detection,Evaluation,andTreatmentofHighBloodPressure:the
JNC7Report.JAMA2003;289:25602572.29.ZanchettiA,CifkovaR,FagardR,etal.2003European
SocietyofHypertensionEuropeanSocietyofCardiologyguidelinesforthemanagementofarterial
hypertension.JHypertens2003;21:10111053.30.ManciaG,DeBackerG,DominiczakA,etal.2007
ESHESCPracticeGuidelinesfortheManagementofArterialHypertension:ESHESCTaskForceonthe
ManagementofArterialHypertension.JHypertens2007;25:17511762.EuropeanSocietyof
HypertensionScientificNewsletter:UpdateonHypertensionManagement61HYPERTENSIONAND
MACROVASCULARDISEASEStphaneLaurent,MD,PhDDepartmentofPharmacology,Pompidou
Hospital,InsermU652andUniversityParisDescartes,France2011;12:No.31revisedversionArterial
stiffnessandwavereflectionarenowwellacceptedasthemostimportantdeterminantsofincreasing
systolicandpulsepressuresinageingsocieties,andthusaffordamajorcontributiontostrokeand
myocardialinfarction.Amajorreasonformeasuringarterialstiffnessandcentralbloodpressurein
hypertensivepatientscomesfromthedemonstrationthatarterialstiffnessandcentralBPhaveapredictive
valueforCVevents.Anexpertconsensusdocumenthasreviewedthemethodologicalagreementsfor
measuringarterialstiffness,centralBP,andwavereflections[1].Thisnewsletterwillnotaddresstheissue
ofintimamediathickness(NewsletterNo.15,revisedversion)andendothelialdysfunction.Methodsof
measurementLargearterydamageinhypertensioncanbenoninvasivelyassessedthroughthe
measurementofarterialstiffness,centralBP,andcentralaugmentationindex(AIx)(Table1).Incontrastto
systemicarterialstiffness,whichcanonlybeestimatedfrommodelsofthecirculation,regionalandlocal
arterialstiffnesscanbemeasureddirectly,andnoninvasively,atvarioussitesalongthearterialtree.The
measurementofpulsewavevelocity(PWV)isgenerallyacceptedasthemostsimple,noninvasive,robust,
andreproduciblemethodwithwhichtodeterminearterialstiffness[1].CarotidfemoralPWVisadirect
measurementofaorticstiffness,anditcorrespondstothewidelyacceptedpropagativemodelofthearterial
system.Measuredalongtheaorticandaortoiliacpathway,itisthemostclinicallyrelevantsincetheaorta
anditsfirstbranchesarewhattheleftventricleseesandarethusresponsibleformostofthe
pathophysiologicaleffectsofarterialstiffness.PWVisusuallymeasuredusingthefoottofootvelocity
method[1,2].Localarterialstiffnessofsuperficialarteriescanbedeterminedusingultrasounddevices[3].
Carotidstiffnessmaybeofparticularinterestsinceinthatarteryatherosclerosisisfrequent.Amajor
advantageisthatlocalarterialstiffnessisdirectlydeterminedfromthechangeinlocalpressuredrivingthe
changeinvolume,i.e.withoutusinganymodelofthecirculation.However,becauseitrequiresahigh
degreeoftechnicalexpertise,andtakeslongerthanmeasuringPWV,localmeasurementofarterialstiffness
isonlyreallyindicatedformechanisticanalysesinpathophysiology,pharmacology,andtherapeutics,
ratherthanforroutineuse[1].Arterialpressurewaveformshouldbeanalysedatthecentrallevel,i.e.the
ascendingaorta,sinceitrepresentsthetrueloadimposedontheleftventricleandcentrallargearterywalls.
Aorticpressurewaveformcanbeestimatedeitherfromtheradialarterywaveform,usingatransfer
function[4],orfromthecommoncarotidwaveform,usingapplanationtonometry[5].Thearterialpressure
waveformisacompositeoftheforwardpressurewavecreatedbyventricularcontractionandareflected
wave.Inthecaseofstiffarteries,PWVrisesandthereflectedwavearrivesbackatthecentralarteries
earlier,addingtotheforwardwaveandaugmentingthesystolicpressure.Thisphenomenoncanbe
quantifiedthroughtheaugmentationindex(AIx)definedasthedifferencebetweenthesecondandfirst
systolicpeaksexpressedasapercentageofthepulsepressure[4,5].PathophysiologyofCVeventsA
generallyacceptedmechanisticviewisthatanincreaseinarterialstiffnesscausesaprematurereturnof
reflectedwavesinlatesystole,increasingcentralPP,andthusSBP.SBPincreasestheloadontheleft
ventricle,increasingmyocardialoxygendemand[6].Inaddition,arterialstiffnessisassociatedwith
increasedsympatheticnerveactivity[7]andleftventricularhypertrophy.TheincreaseincentralPPandthe
decreaseindiastolicBPmaydirectlycausesubendocardialischaemia[6].Anincreasedarterialstiffness
canincreasetheriskofstrokethroughseveralmechanisms,includinganincreaseincentralPP,influencing
arterialremodellingbothatthesiteoftheextracranialandintracranialarteries,increasingcarotidwall
thickness,andthedevelopmentofstenosisandplaques,thelikelihoodofplaquerupture,andthe
prevalenceandseverityofcerebralwhitematterlesions[8].Finally,coronaryheartdiseaseandheart
failure,whicharefavouredbyhighPPandarterialstiffness,arealsoriskfactorsforstroke.Predictive
valueofarterialstiffnessandcentralBPInthelate1990s,someepidemiologicalstudies[911]showed
thataorticstiffnesshadanindependentpredictivevalueforallcauseandCVmortality.Currently,asmany
as19studiessomeofthemincludedinarecentmetaanalysis[12]consistentlyshowedthe
independentpredictivevalueofaorticstiffnessforfatalandnonfatalCVeventsinvariouspopulations
(Table2).AorticstiffnesscanthusbeconsideredasanintermediateendpointforCVevents.The
independentpredictivevalueofaorticstiffnesshasbeendemonstratedafteradjustmenttoclassical
cardiovascularriskfactors,includingbrachialPP.Thisindicatesthataorticstiffnesshasabetterpredictive
valuethaneachoftheclassicalriskfactors.Althoughtherelationshipbetweenaorticstiffnessandeventsis
continuous,athreshold>12m/shasbeensuggestedasaconservativeestimateofsignificantalterationsof
aorticfunctioninmiddleagehypertensives,andwasincludedinthe2007ESHGuidelinesforthe
managementofhypertension[13].HighaorticPWVmaythusrepresenttargetorgandamage,whichneeds
tobedetectedduringestimationofCVriskinhypertensives.Intheearly2000ssomeepidemiological
studies[14,15]showedthatcentralAIxandPP,directlymeasuredbycarotidtonometry[14,15],were
independentpredictorsofallcauseandCVmortalityinESRDpatients.Arecentmetaanalysis[16]
confirmedthesefindingsinseveralpopulations.However,centralBPhasalessindependentpredictive
valuethanaorticstiffnessforCVevents,eitherinESRD,hypertensives,elderly,orgeneralpopulations.
Also,theadditivepredictivevalueofcentralBPbeyondbrachialBPwasnotsignificantinmoststudies
[17].Thus,the2007ESHGuidelinesfortheManagementofHypertension[13]andtheirreappraisal[18]
consideredthatmoreinvestigationwasnecessarybeforerecommendingtheroutineclinicaluseofcentral
BP.Nevertheless,themeasurementofcentralBPandAixisofgreatinterestformechanisticanalysesin
pathophysiology,pharmacology,andtherapeutics.ClinicalapplicationNonpharmacologicaltreatments
whichareabletoreducearterialstiffnessand/orcentralPPandAIxincludeanumberofpossible
interventions,fromexercisetrainingtodietarychanges[1].Antihypertensivetreatmentsareabletoreduce
arterialstiffnessmainlythroughtheloweringofmeanBP,thusreducingtheloadonthearterialwall[1].
FewstudieshaveclearlydemonstratedthatarterialstiffnesscanbeloweredbeyondBPreduction.The
reductioninwavereflections,throughperipheralvasodilatation,associatedwiththereductioninaortic
stiffness,representsameanstolowercentralPPand/orAIx.CentralPPand/orAIxarebestloweredby
ACEinhibitors,AT1blockers,andcalciumchannelblockers(CCB),andtoalesserdegreebydiureticsand
vasodilatingbetaTable1.Methodsformeasuringarterialstiffnessinclinicalinvestigation(adaptedfrom
ref[1])ParameterPredictiveDegreeofvaluefortechnicalCVeventsexpertise1.CarotidfemoralPWV+
+++GoldstandardforarterialstiffnessSpeedoftravelofthepulsealonganarterialsegment(L/Dtinm/s)
2.Centralpulsewaveanalysis+++CarotidandaorticpressurewavesCentralpulsepressure(PP)andSBP
Centralaugmentationindex(AIx)3.Localarterialstiffness++++Carotiddistensibility62Table2.
Nineteenlongitudinalstudiesreportingtheindependentpredictivevalueofaorticstiffnessforallcauseand
CVmortalityandCVevents(adaptedfromref[1]and[12])Measurementsite,refEventsFollowup
(years)Typeofpatient(number)Meanageatentry(years)Blacheretal,1999CVmortality6.0ESRD
(241)51Laurentetal,2001CVmortality9.3Hypertension(1,980)50Meaumeetal,2001CVmortality
2.5Elderly(>70)(141)87Shojietal,2001CVmortality5.2ESRD(265)55Boutouyrieetal,2002CHD
events5.7Hypertension(1,045)51Cruickshanketal,2002Allcausemortality10.7IGT(571)51Laurent
etal,2003Fatalstrokes7.9Hypertension(1,715)51Pannieretal,2005CVmortality5.8ESRD(305)53
SuttonTyrrelletal,2005CVmortalityandevents4.6Elderly(2,488)74Shokawaetal,2005CV
mortality10Generalpop.(492)64Hansenetal,2006CVmortality9.4Generalpop.(1,678)55Mattace
Rasoetal,2006CVmt,CHD4.1Elderly(2,835)72Choietal,2007CVmortalityandevents2.6Chest
painpatients(497)58Zoungasetal,2007CVmortalityandevents3.6ESRD(207)55Teraietal,2008
CVmortalityandevents4.8Hypertension(676)62Andersonetal,2009Allcausemortality19.6General
pop.(174)60Mitchelletal,2010CVevents7.8Generalpop.(2,232)63Wangetal,2010Allcauseand
CVmt15Generalpop.(1,272)52Maldonadoetal,2011CVmortalityandevents1.7Generalpop.(2,200)
46CHDcoronaryheartdisease;ESRDendstagerenaldisease;IGTimpairedglucosetolerance
blockers.Bycontrast,nonvasodilatingbetablockersareeitherineffectiveorincreasecentralBPand/or
AIx[19].ThreeRCTscomparingcombinationtherapiesshowthatcentralBPand/orAIxarebestlowered
byacombinationofanRASblockerandaCCB[2022].ConclusionThesedatahighlighttheimportance
ofarterialstiffnessandcentralBPforpredictingCVoutcomes.ArterialstiffeningandcentralBPalso
providedirectevidenceoftargetorgandamage,whichisofmajorimportanceindeterminingtheoverall
CVriskofthehypertensivepatient.Indeed,measurementofaorticstiffnessandcentralBPmayavoid
patientsbeingmistakenlyclassifiedasatlowormoderateriskwhentheyactuallyhaveanabnormallyhigh
aorticstiffnessorcentralBPplacingthemwithinahigherriskgroup.Severalissuesremaintobe
addressed.Amongthem,itiscrucialtodeterminewhetherareductioninarterialstiffnessisadesirable
therapeuticgoalintermsofhardclinicalendpointssuchasmorbidityandmortality.Althoughthishasbeen
doneinpatientswithESRD[23],itremainstobeshowninapopulationofhypertensivepatientsatlower
CVrisk.Inaddition,itisimportanttodemonstratewhetheratherapeuticstrategyaimingatnormalizing
arterialstiffnessandcentralBPprovestobemoreeffectiveinpreventingCVeventsthanusualcare.
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SocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement63SEXUAL
DYSFUNCTIONINHYPERTENSIONAthanasiosJ.Manolis1,MichaelDoumas2,MargusViigimaa3,
KrzysztofNarkiewicz41CardiologyDept.,AsklepeionVoulaHospital,Athens,Greece2Internal
MedicineDept.,AristotleUniversity,Thessaloniki,Greece3CardiologyDept.,NorthEstoniaMedical
Centre,Tallinn,Estonia4Dept.ofHypertensionandDiabetology,MedicalUniversityofGdansk,Gdansk,
Poland2011;12:No.32revisedversionIntroductionPreviouslyencounteredasanunspokenreality,
sexualdysfunctionisnowacknowledgedasaclinicalconditionthatimpairspeoplesgeneralhealthand
wellbeingandhasamajorimpactonthequalityoflifeofbothpatientsandtheirpartners[1].Itisthusnot
surprisingthatsexualdysfunctionrepresentsarealtherapeuticchallengetophysiciansofmanyspecialties.
Erectiledysfunctionhasbeendefinedasthepersistentinabilitytoattainand/ormaintainpenileerection
sufficientforsexualintercourse[2].Femalesexualdysfunctionisdescribed,inamorecomplexway,asa
persistentorrecurringdecreaseinsexualdesireorinsexualarousal,thedifficultyortheinabilityto
achieveanorgasm,orthefeelingofpainduringsexualintercourse,whichmirrorsthemultifoldaspectsof
womensexuality[3].Sexualdysfunctionandcardiovasculardisease:whatisnew?Notlongsinceerectile
dysfunctionwasfirstprojectedasanearlydiagnosticwindowofcoronaryheartdisease,accumulating
evidenceisnowavailablethatsustainsandreinforcesthisargument.Valuabledatahavebeenderivedfrom
prospectivestudies;erectiledysfunctionwasidentifiedasanindependentpredictorofcardiovascular
eventsoveralongtermfollowup(9years),withahazardratioof1.45thatwasfoundtobeequaltoor
greaterthantraditionalriskfactorslikehyperlipidaemia,smoking,orpositivefamilyhistoryofmyocardial
infarction[4].Inanotherstudythemeanintervalbetweenthepresenceoferectiledysfunctionandtheonset
ofevidentcoronaryarterydiseasewasestimatedin39months[5].AdditionalprospectivedataintypeII
diabeticpatientsestablisherectiledysfunctionasanindependentstrongpredictoroffuturecardiovascular
events,evenafteradjustmentforotherknowntraditionalriskfactors.Thiswasconfirmedinagroupof
diabeticpatientswithnoclinicalevidenceofcardiovasculardisease,withahazardratioof1.58[6],aswell
asindiabeticpatientswithangiographicallydocumentedsilentcoronaryarterydisease,whoweretwiceas
likelytoexhibitmajoradversecardiaceventsunderthepresenceoferectiledysfunction[7].Similarly,the
recentlypublishedsubstudyoftheONTARGETTRANSCENDtrialsdemonstratedthaterectile
dysfunctionpredictedcardiovasculareventsinhighriskpatientsaswell[8].Itappears,therefore,thatour
knowledgeabouttheinterfacebetweenerectiledysfunctionandcardiovasculardiseasehasmovedonestep
forward;currentdatastronglypointtowardsabilateraldirectioninthecausativelinkbetweenthesetwo
clinicalentities.Nonetheless,inpatientswithoutsubsistentcardiovasculardisease,thepredictivevalueof
erectiledysfunctionforcardiovasculardiseasebeyondtraditionalriskfactorswasrecentlydisproven[9].
Furtherresearchisrequiredtoestablishornegatetheroleofbotherectileandfemalesexualdysfunctionas
independentandpotentpredictorsofcardiovasculardisease.Sexualactivityisaformofexercisethatcan
sometimesbeintense.Arecentmetaanalysisrevealedanalmost3foldincreasedrelativeriskforMI
duringorimmediatelyaftersexualintercourse[10].Itshouldbenoticedhoweverthattheabsoluteriskis
low(23per10,000personyearswithonehourofsexualactivityperweek).Therefore,lowriskpatients
maysafelyproceedwithsexualintercourse,whilesexualactivityshouldbedeferredinhighriskpatients
untilappropriatecardiologicevaluation[11].Sexualdysfunction:definingtheextentoftheproblem
Despitetheaccumulationofmultipleepidemiologicalstudies,theexactprevalenceofsexualdysfunctionin
thegeneralpopulationremainsunclarified.Theprevalenceoferectiledysfunctionvariesaccordingto
differentreportsandrangesfrom753%,with1520%beingthemostprobableestimation[12].Data
regardingfemalesexualdysfunctionarescarce,butitemergesthat,althoughunderstudied,itismore
commonlyencounteredthanerectiledysfunction(43%vs.31%intheUSAin1999)[13].Thedisparityof
availabledatareflectsthedifferencesinthestudypopulationswithregardtoage,selectioncriteria,and
culturalhabits,incombinationwiththevariantandofteninvalidatedassessmentmethodologies;yetit
highlightsthatsexualdysfunctioniscommonlyencounteredinthegeneralpopulationandmayeven
representamajorburdeninspecificgroupsofpatients.Sexualdysfunctioninhypertensivepatients
Currentlyconsideredadiseaseofvascularorigin[14],erectiledysfunctionhasbeenrepeatedlyfoundtobe
higheramonghypertensivecomparedtonormotensivesubjects(i.e.45.8%vs.18.9%inSpain,35.2%vs.
14.1%inGreece).Similarly,accumulatingevidenceshowsthathypertensivewomenexhibitahigher
prevalenceofsexualdysfunctioncomparedtonormotensives(42.1%vs.19.4%accordingtoonestudy,
oddsratio3.2)[15].Durationandseverityofhypertensionwerepositivelycorrelatedwiththedegreeof
sexualdysfunction[16].Obstructivesleepapnoeathatisfrequentlyaccompaniedbyhypertensioncouldbe
consideredasanadditionalcontributingfactor,sincesexualdysfunctionishighlyprevalentinsuchpatients
[17].SexualdysfunctionincardiovasculardiseaseRemarkably,severaltraditionalcardiovascularrisk
factors(hypertension,diabetesmellitus,hyperlipidaemia,smoking)constituteriskfactorsforerectile
dysfunctionaswell[18,19].Sincepatientswithcardiovasculardiseaseexhibitincreasedprevalenceof
thesecomorbidities,theysubsequentlypresentincreasedfrequencyofsexualdysfunction.Indeed,
prevalenceoferectiledysfunctioninpatientswithcoronaryarterydiseaseisovertlyhigherthaninthe
generalpopulation,withestimationsrangingfrom4975%[20,21].(Patho)physiologicalpathwaysin
hypertensionleadingtosexualdysfunctionPenileerectionrepresentsaneurovascularpathwayinwhich
psychologicalandhormonalfactorsplayapivotalrole.Inerectiledysfunction,bloodflowofthepenile
vasculatureisimpairedincorrespondencetothesystemicstructuralchangescausedbyhypertension,with
stenoticlesionssecondarytoatherosclerosiscomprisingthecommonbackground.Elevatedbloodpressure
levelsinduceendothelialdysfunction,activatethereninangiotensinsystem,andimpairtheneurogenicand
smoothmuscleinducedrelaxationinresponsetonitricoxide.Thecombinationoftheaforementioned
structuralandfunctionalabnormalitiestriggeredbyincreasedbloodpressurerendershypertensionakey
promoteroferectiledysfunction.Althoughdataregardingthepathophysiologyoffemalesexual
dysfunctionaresignificantlylimited,itappearsthathypertensionexertssimilareffectsonthesexual
functioningofbothsexes.EffectsofantihypertensivedrugtherapyonsexualfunctionTheprevalent
perceptionthatantihypertensivetreatmentisdetrimentaltosexualfunctioningmaydramaticallyextenuate
patientsadherence,exposingthemtotherisksofalltheshortandlongtermnegativeconsequencesof
hypertension.However,thesuperiorityorinferiorityofeachclassofantihypertensivedrugsregarding
sexualfunctionisdifficulttodeterminebeyonddoubtsincetheincidenceofsexualdysfunctionmustbeco
estimatedwithseveralfactorsotherthanantihypertensivetreatment,suchashypertensioncharacteristics,
personalcharacteristics,existingcomorbiditiesandcoadministereddrugs.Sofar,outcomesfromrelevant
studiessuggesttheclassificationofantihypertensivetreatmentto:drugsnegativelyaffectingerectile
function,includingcentralacting,diuretics,andbblockers,withtheonlypossibleexceptionbeing
nebivolol[2227];drugsthatappeartoexertaneutraleffectonerectiledysfunction,includingcalcium
antagonistsandangiotensinconvertingenzyme(ACE)inhibitors[28,29];anddrugsthatseemtoimprove
erectiledysfunction,withangiotensinreceptorblockers(ARBs)beingrecommendedasfirstlinetreatment
inpatients64withpreexistingsexualdysfunctionorassubstitutiontherapyinpatientswith
antihypertensivedruginducederectiledysfunction[30].Ofnote,thequantityandqualityofavailabledata
doesnotallowtheextractionofdefiniteconclusions,particularlyinregardtothenewergeneration
antihypertensiveagents.Indeed,thebeneficialeffectofARBsonerectiledysfunctionwasrecently
questionedbytheoutcomesofthesubstudyoftheONTARGETTRANSCENDtrials,inwhichARB
administrationneithersignificantlyimprovednorimpairederectiledysfunction[8].However,extrapolation
oftheseresultsshouldbecircumspect,takingintoconsiderationthefactthatARBswereaddedontopof
previousmultidrugtherapyinhighriskpatients.Inaddition,thereisalackofsolidevidenceregardingthe
newestmedicationofthereninangiotensinaxis,therenininhibitoraliskiren;dataregardingcombination
therapyareinconclusive,andthefieldisstillunclearwhenitcomestofemalesexualdysfunction.Since
extractionofconclusionsisinsecureintheabsenceofsounddata,headingtowardsthedirectionoflarge
randomized,doubleblind,prospectivetrialsexaminingeffectsofdifferentantihypertensivedrugson
sexualdysfunctionemergesasextremelyimportant.Sexualdysfunctionandhypertension:amutualtarget
forPDE5inhibitors?Despitetheinitialcircumspectionregardingadministrationofphosphodiesterase
(PDE)5inhibitorsinhypertensivesubjects,awealthofclinicaldataconvincinglyproclaimsthatits
concomitantusewithallclassesofantihypertensivedrugsisnotonlysafe,butprovidesadditionalbenefits
beyondtreatmentoferectiledysfunction[31].Precautionsneedtobetakenwithalphablockersduetothe
riskofmarkedhypotension;therefore,initiationoftreatmentwithhalfdosesofeitherdrugis
recommended.TheadditionofaPDE5inhibitorinhypertensiveswitherectiledysfunctionenhancesthe
possibilityofinitiationratherthandiscontinuation,andadditionratherthanrejectionofantihypertensive
medication[32].Indeed,adherencetoantihypertensivetherapyissignificantlyimproved,with36%of
noncompliantpatientsbecomingadherentafteradministrationofPDE5inhibitorsinonereport[33].PDE
5inhibitorsexhibitadegreeofsystemicvasorelaxingactivity,whichaccountsforusuallysmall,clinically
insignificantbloodpressurereductionsbothinnormotensiveandhypertensiveindividuals[3436].
AlthoughtheinitialconceptindevelopingPDE5inhibitorswastowardsthemanagementof
cardiovasculardisease,thispotentialwasleftasidethereafter.However,anew,longactingPDE5inhibitor
wasrecentlyadministeredasanantihypertensiveagentandachievedasustained,moderatebloodpressure
decreasewithagoodsafetyandtolerabilityprofile[37].Interestingly,additionofaPDE5inhibitorin
resistanthypertensivepatients,aloneorincombinationwithanitrate,providedanadditionalclinically
significantBPreductionwithoutsignificantadverseeffects[38].Thesmallnumberofparticipants,
however,andthepotentialrisksofthiscombinationprohibittheextractionofsafeconclusions.Concluding
remarksSexualdysfunctionisfrequentlyencounteredinhypertensivepatients,eitherasaresultofpenile
atheroscleroticdiseaseduetohighbloodpressurelevels,orcausedbycertainantihypertensivedrugs,ora
combinationofbothfactors.Sexualdysfunctionrequiresspecialinterestbyhypertensionspecialists,
cardiologists,internists,andprimarycarephysiciansbecause:sexualdysfunctionmaybeusedasan
earlydiagnosticindicatorforasymptomaticcoronaryarterydisease,providingauniqueopportunityfor
timelyrecognitionofcardiovasculardisease;sexualdysfunctionaffectspatientsandtheirsexual
partnersqualityoflife.Managementoferectiledysfunctionnotonlyimprovesqualityoflifebutgreatly
increasesadherencetoantihypertensivemedication.AWorkingGrouponSexualDysfunctionhasrecently
beenformedbytheEuropeanSocietyofHypertensionaimingtoimprovethedetectionandmanagementof
sexualdysfunctionbyallcliniciansdealingwithhypertensivepatients.Inaddition,theWorkingGroup
aimstosensitizeotherspecialties(Urologists,Gynaecologists,andPsychiatrists)thatsexualdysfunction
maybethefirstsignofcardiovasculardiseaseandrequirescardiologicevaluation.References1.Wagner
G,FuglMeyerKS,FuglMeyerAR.Impactoferectiledysfunctiononqualityoflife:patientandpartner
perspectives.IntJImpRes2000;12(Suppl4):S144S146.2.NIHConsensusConference.NIHConsensus
DevelopmentPanelonImpotence.JAMA1993;270:8390.3.BachmanGA,AvciD.Evaluationand
managementoffemalesexualdysfunction.Endocrinologist2004;14:337345.4.ThompsonIM,Tangen
CM,GoodmanPJ,etal.Erectiledysfunctionandsubsequentcardiovasculardisease.JAMA2005;294:
29963002.5.MontorsiF,BrigantiA,SaloniaA,etal.Erectiledysfunctionprevalence,timeofonsetand
associationwithriskfactorsin300consecutivepatientswithacutechestpainandangiographically
documentedcoronaryarterydisease.EurUrol2003;44:360364.6.MaRC,SoWY,YangX,etal.
Erectiledysfunctionpredictscoronaryheartdiseaseintype2diabetes.JAmCollCardiol2008;51:2045
2050.7.GazzarusoC,SolerteSB,PujiaA,etal.Erectiledysfunctionasapredictorofcardiovascular
eventsanddeathindiabeticpatientswithangiographicallyprovenasymptomaticcoronaryarterydisease:a
potentialprotectiveroleforstatinsand5phosphodiesteraseinhibitors.JAmCollCardiol2008;51:2040
2044.8.BhmM,BaumhkelM,TeoK,etal;ONTARGET/TRANSCENDErectileDysfunction
SubstudyInvestigators.ErectileDysfunctionpredictscardiovasculareventsinhighriskpatientsreceiving
telmisartan,ramipril,orboth:theOngoingTelmisartanAloneandincombinationwithRamiprilGlobal
EndpointTrial/TelmisartanRandomizedAssessmeNTStudyinACEiNtolerantsubjectswith
cardiovascularDisease(ONTARGET/TRANCEND)Trials.Circulation2010;121:14391446.9.Araujo
AB,HallSA,GanzP,etal.Doeserectiledysfunctioncontributetocardiovasculardiseaseriskprediction
beyondtheFraminghamriskscore?JAmCollCardiol2010;55:350356.10.DahabrehIJ,PaulusJK.
Associationofepisodicphysicalandsexualactivitywithtriggeringofacutecardiacevents:systematic
reviewandmetaanalysis.JAMA2011;305:12251233.11.KostisJB,JacksonG,RosenR,etal.
Sexualdysfunctionandcardiacrisk(theSecondPrincetonConsensusConference).AmJCardiol2005;96:
313321.12.ViigimaaM,DoumasM,VlachopoulosC,etal.;fortheESHWorkingGrouponSexual
Dysfunction.Hypertensionandsexualdysfunction:timetoact.JHypertens2011;29:403407.13.
ManolisA,DoumasM.Sexualdysfunction:theprimaballerinaofhypertensionrelatedqualityoflife
complications.JHypertens2008;26:20742084.14.AzadzoiKM.Vasculogenicerectiledysfunction:
beyondthehaemodynamicchanges.BJUInt2006;97:1116.15.DoumasM,TsiodrasS,TsakirisA,etal.
Femalesexualdysfunctioninessentialhypertension:acommonproblembeinguncovered.JHypertens
2006;24:23872392.16.DoumasM,TsakirisA,DoumaS,etal.Factorsaffectingtheincreased
prevalenceoferectiledysfunctioninhypertensivecomparedtonormotensiveindividuals.JAndrol2005;
27:469477.17.GoncalvesM,GuilleminaultC,RamosE,PalhaA,PaivaT.Erectiledysfunction,
obstructivesleepapneasyndromeandnasalCPAPtreatment.SleepMed2005;6:333339.18.JacksonG.
Erectiledysfunctionandcardiovasculardisease.IntJClinPract1999;53:363368.19.FungMM,
BettencourtR,BarrettConnorE.Heartdiseaseriskfactorspredicterectiledysfunction25yearslater:the
RanchoBermardoStudy.JAmCollCardiol2004;43:14051411.20.KlonerRA,MullinSH,ShookT,et
al.Erectiledysfunctioninthecardiacpatient:howcommonandshouldwetreat?JUrol2003;170:S46
S50.21.SolomonH,ManJW,WierzbickiAS,JacksonG.Relationoferectiledysfunctiontoangiographic
coronaryarterydisease.AmJCardiol2003;91:230231.22.WassertheilSmollerS,BlaufoxMD,
ObermanA,etal.Effectofantihypertensivesonsexualfunctionandqualityoflife:theTAIMStudy.Ann
InternMed1991;114:613620.23.FogariR,PretiP,DerosaG,etal.Effectofantihypertensivetreatment
withvalsartanoratenololonsexualactivityandplasmatestosteroneinhypertensivemen.EurJClin
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treatedwithvalsartanorcarvedilol:acrossoverstudy.AmJHypertens2001;14:2731.25.KoDT,
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hypertensivemen.ClinExpPharmacolPhysiol2007;34:327331.28.KronerBA,MulliganT,Briggs
GC.Effectoffrequentlyprescribedcardiovascularmedicationsonsexualfunction:apilotstudy.Ann
Pharmacother1993;27:13291332.29.OmvikP,ThaulowE,HerlandOB,etal.Doubleblind,parallel,
comparativestudyonqualityoflifeduringtreatmentwithamlodipineorenalaprilinmildormoderate
hypertensivepatients:amulticentrestudy.JHypertens1993;11:103113.30.DoumasM,DoumaS.The
effectofantihypertensivedrugsonerectilefunction:aproposedmanagementalgorithm.JClinHypertens
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antihypertensivetherapies.AmJCardiol2003;92(Suppl):47M57M.36.VanAhlenH,WahleK,Kupper
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EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement65
DISCOVERINGTHEGENETICDETERMINANTSOFHYPERTENSIONSandoshPadmanabhan1,
OlleMelander2,ClaireHastie1,AnnaF.Dominiczak11InstituteofCardiovascularandMedical
Sciences,UniversityofGlasgow,Glasgow,UnitedKingdom2UniversityHospitalMalm,Lund
University,Malm,Sweden2011;12:No.33revisedversionHypertension(HTN)andbloodpressure(BP)
areexamplesofcomplex(polygenic)traitsinfluencedbymultiplegeneticandenvironmentalfactors.The
determinationofthegeneticvariantsinvolvedinHTNshouldprovidenewinsightintothedisease
susceptibility,progression,andseverity,leadingtonovel pharmaceutical targets, with the
effects in families with Mendelian forms of HTN and hypotension [7, 8].
The genetic dissection of BP and HTN has, however, been one of the
most challenging of all the polygenic traits. We outline the successes
and limitations of current approaches and the prospects and obstacles
to future progress in blood pressure genetics. Gene mapping studies in
hypertension There are three key characteristics of a genetic variant
that determine its impact on the phenotype studied: 1) the frequency
of the variant; 2) the effect size of the variant on the phenotype, and
3) the number of genetic variants acting on the phenotype. Monogenic
HTN syndromes are due to rare variants with large effect sizes [7, 8],
and these account for less than 1% of human HTN. The high
prevalence of essential HTN and the continuous nature of the BP
phenotype suggest that these traits cannot be explained by rare
variants harbouring large effect-sizes. The common disease, common
variant hypothesis (CD:CV) is the model invoked to explain how genes
influence common traits like BP or HTN [9, 10]. This model proposes
using an evolutionary framework that common disease is due to allelic
variants with a frequency greater than 5% in the general population
and a small individual effect size. Linkage and candidate gene studies
Initial systematic approaches to identifying genes for BP/HTN were
linkage and candidate gene studies. Linkage mapping is a method of
studying genetic markers of known chromosomal location that are coinherited with the disease in related individuals. Association mapping,
commonly used in candidate gene studies, is based on linkage
disequilibrium (LD). LD is the non-random association of alleles at two
or more loci on a chromosome and results in the greater co-occurrence
of two genetic markers in a population than would be expected for
independent markers. In practical terms, LD results in single nucleotide
polymorphisms (SNPs) that are in close proximity and travel together in
a block when passed from parent to child, allowing one SNP in a block
to serve as a surrogate for the other SNPs in the block, thus obviating
the need for testing all the SNPs individually. A new mutation that
arises within a block travels along with the members of the block for
hundreds of generations. In short, linkage measures the cosegregation
between a genetic marker and a disease affection status in a pedigree,
due to meiotic recombination events in the last 23 generations [9];
while LD measures cosegregation in a population (a very large
pedigree extending back to the founders) resulting from much earlier
ancestral meiotic recombination events [10]. Linkage analysis, while
powerful for finding Mendelian disease genes, showed modest to
minimal success in the mapping of complex traits [1114]. The key
limitations of linkage studies are relatively low analytical power
(especially for detecting common alleles that have low penetrance), a
lack of positional resolution, multiple pleiotropic variants of low
penetrance, epistasis, poor replication, ethnic diversity of human
populations, phenotypic heterogeneity, and the inability to control for
variants that influence BP/HTN and can explain the remaining missing
heritability. Another type of genetic variation overlooked in all
association studies are structural variations, specifically submicroscopic rearrangements between 500 bp 66 and 5Mb in size,
commonly called copy number variation (CNV). Early studies looking at
the association of CNVs in HTN have not been promising [37]. Future
The next phase in the genetic dissection of blood pressure related
traits will include larger meta-analysis of BP as quantitative traits and
BP extremes. Next generation sequencing technologies will allow
identification of both rare and common DNA sequence variants and
enable a complete analysis of all risk variants. While these strategies
will uncover additional BP/HTN genetic variants, it is unclear if these
would explain the entire heritability of the traits. Other equally
important strategies include analysis of intermediate phenotypes such
as sodium homeostasis, endothelial function, and the sympathetic
nervous system, gene-environment interactions, and gene gene
interactions, which will help to understand the physiological link
between gene variants and phenotype. Table 1. Genome-wide
association studies: replicated findings for BP and HTN Chr SNP Position
Ethnicity N Phenotype Risk allele Risk allele frequency OR or b p
Nearest gene Ref 1 rs17367504 11,785,365 E 34,433 SBP G 0.14 0.85
2 1013 MTHFR, CLCN6, NPPA, NPPB, AGTRAP [28, 32] 2 rs6749447
168,749,632 E 542 SBP G 0.28 1.90 8 105 STK39 [23] 3 rs9815354
41,887,655 E 29,136 DBP A 0.17 0.49 3 109 ULK4 [28, 32] 4
rs16998073 81,403,365 E 34,433 DBP T 0.21 0.50 1 1021 FGF5,
PRDM8, C4orf22 [28, 32] 4 rs991316 100,541,468 AA 1017 SBP T 0.45
1.62 5 106 ADH7 [24] 10 rs11014166 18,748,804 E 29,136 DBP A
0.66 0.37 1 108 CACNB2 [28, 32] 10 rs1530440 63,194,597 E
34,433 DBP T 0.19 0.39 1 109 C10orf107, TMEM26, RTKN2,
RHOBTB1, ARID5B, CYP17A1 [28, 32] 10 rs1004467 104,584,497 E
29,136 SBP A 0.90 1.05 1 1010 TMEM26, RTKN2, RHOBTB1, ARID5B,
CYP17A1 [28, 32] 10 rs11191548 104,836,168 E 34,433 SBP T 0.91
1.16 3 107 CYP17A1, AS3MT, CNNM2, NT5C2 [28, 32] 11 rs381815
16,858,844 E 29,136 SBP T 0.26 0.65 2 109 PLEKHA7 [28, 32] 12
rs17249754 88,584 EA 8,842 SBP, DBP A 0.37 1.06 9 107 ATP2B1
[27] 12 rs2681472 88,533,090 E 29,136 SBP, DBP, HTN A 0.83 0.50 2
109 ATP2B1 [28, 32] 12 rs2681492 88,537,220 E 29,136 SBP, DBP,
HTN T 0.80 0.85 4 1011 ATP2B1 [28, 32] 12 rs3184504 110,368,991
E 29,136 SBP, DBP T 0.49 0.48 3 1014 ATXN2, SH2B3 [28, 32] 12
rs653178 110,492,139 E 34,433 DBP T 0.53 0.46 3 1018 ATXN2,
SH2B3 [28, 32] 12 rs2384550 113,837,114 E 29,136 DBP A 0.35 0.43 4
108 TBX3, TBX5 [28, 32] 15 rs1550576 56,000,706 AA 1,017 SBP C
0.86 1.92 3 106 ALDH1A2 [24] 15 rs1378942 72,865,396 E 34,433
DBP C 0.36 0.43 1 1023 CSK, CYP1A1, CYP1A2, LMAN1L, CPLX3,
ARID3B, ULK3 [28, 32] 15 rs6495122 72,912,698 E 29,136 DBP A 0.42
0.40 2 1010 CSK, CYP1A1, CYP1A2, LMAN1L, CPLX3, ARID3B, ULK3
Impairedmicrovasculardilatationandcapillaryrarefactioninyoungadultswithapredispositiontohigh
bloodpressure.JClinInvest1997;99:18731879.25.HeFJ,MareiniakM,MarkanduND,AntoniosTF,
MacGregorGA.Effectofmodestsaltreductiononskincapillaryrarefactioninwhite,black,andAsian
individualswithmildhypertension.Hypertension2010;56:253259.26.FeihlF,LiaudetL,WaeberB,
LvyBI.Hypertension:adiseaseofthemicrocirculation?Hypertension2006;48:10121017.European
SocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement69Cardiovascular
disease(CVD)remainstheleadingcauseofdeathindevelopedcountries[1].Hypertensionand
dyslipidaemiaaretwomajorCVDriskfactorshighlyprevalenteitheraloneorincombination[2].
HypertensionoftenclusterswithotherCVDriskfactorsassociatedwithamarkedlyincreasedriskofCV
events.TheinteractionamongCVDriskfactorsissuchthattheprobabilityofaCVeventisfrequently
greaterinpatientswithonlymoderateBPandcholesterolabnormalitiesinthepresenceofadditionalrisk
factorsthaninpatientswithisolatedmarkedelevationofBPorcholesterollevelsalone[3].Inaddition,the
majorityofCVeventsinthepopulationoccuramongindividualswithmodestlevelsofseveralriskfactors
ratherthanamongthoserarepersonswithextremevaluesofjustoneriskfactor.Amajoraimoftreating
hypertensionisamaximaldecreaseinlongtermtotalCVrisk.Thiscanonlybeachievedbytreatmentof
allreversibleriskfactorsandassociatedconditionsinadditiontotreatmentofraisedBPperse.Lipid
abnormalitiesandhypertensionThereisevidencethatnormotensivesubjectswithhypercholesterolaemia
haveanexcessiveBPresponsetoamentalarithmeticstresstest[4].Furthermore,upto40%ofpatients
withessentialhypertensionandmanypatientswithborderlinehypertensionalreadyhavelipid
abnormalities.AnanalysisofthePhysiciansHealthStudyprospectivelyexamineddatafrom3110
participantswhowerefreeofhypertension,CVD,andcanceratbaseline[5].Overanaverageof14years
offollowup,approximatelyonethirdofthemendevelopedhypertension.Elevatedlevelsoftotal
cholesterol,nonHDLcholesterol,andthetotalcholesterol/HDLcholesterolratiowereindependently
associatedwithanincreasedriskofhypertensioninmiddleagedandoldermen.Furthermore,higherlevels
ofcholesterolwereassociatedwithahigherriskofhypertension.Geneticstudiesinhumansandinanimal
modelssuggestthatapredispositiontothedevelopmentofbothhypertensionanddyslipidaemiamayresult
fromtheinheritanceofsharedgeneticfactors.EffectofstatinsonBPinclinicalstudiesInadditiontotheir
beneficialeffectsonlipids,statinsmayreducesystolic,diastolic,andmeanarterialBPinnormotensive,
hypercholesterolaemic[6]menandkidneytransplantpatients[7].Theseeffectswereindependentoftheir
lipidactions.ThecapacityofstatinstolowerBPhasbeenreportedtobesuperiortothatofotherlipid
loweringdrugs.IntheBrisighelaHeartStudy[8]atotalof1356hypercholesterolaemicindividualswere
randomlytreatedwithalowfatdiet,cholestyramine,gemfibrozil,orsimvastatinforfiveyears.Participants
weredividedatbaselineintofourquartilesbaseduponsystolicBP.AsignificantdecreaseinBPwas
observedinthetwoupperquartilesofsystolicBP,andwasgreaterinsubjectstreatedwithlipidlowering
drugs.Inparticular,theBPreductionwasgreaterinpatientstreatedwithastatin,despiteacomparative
reductioninLDLcholesterol(reductionof13%inbothsystolicanddiastolicBPatthehighestquartiles
afterfiveyearsoftreatmentwithastatinascomparedwith10%aftertreatmentwithnonstatindrugs).The
BPloweringeffectofstatinsisnotconsistent.Milionisetal.[9]summarized,inanelaboratereviewofthe
availabledataregardingtheBPloweringeffectofstatins,theeffectofstatintreatmentonBP.Thisreview
includedstudieswithinabroadspectrumofpatients(normotensives,hypertensives,individualswith
normallipidsanddyslipidaemia,diabeticpatients)publishedupto2005.TheeffectonBPvariedfrom
neutraltomostfavourable(DsystolicBP813mmHg;DdiastolicBP57.8mmHg).Ametaanalysisof
allstudiespublishedupto2005andreportingBPdataduringtreatmentwithstatinsincluded20
randomisedcontrolledtrials(828patients)[10].Thedurationofthestudiesrangedfrom1to12months.
SystolicBPwassignificantlylowerinpatientsonstatinsthaninthoseonplacebooracomparativelipid
loweringdrug(meandifference:1.9mmHg;95%CI:3.8to0.1).Theeffectwasgreaterwhenthe
analysiswasrestrictedtostudieswithabaselinesystolicBP>130mmHg(DsystolicBP4.0mmHg;
95%CI:5.8to2.2).TherewasatrendtowardlowerdiastolicBPinpatientsreceivingstatintherapy
comparedwithcontrols:0.9mmHg(95%CI:2.0to0.2)overall,and1.2mmHg(95%CI:2.6to0.1)
instudieswithabaselinediastolicBP>80mmHg.TheCaliforniaSanDiegoStatinStudy,arandomised,
doubleblind,placebocontrolledtrialwith973patientsallocatedequallytosimvastatin(20mg),
pravastatin(40mg),orplaceboforsixmonths,showedamodestbutsignificantBPreduction(2.42.8mm
HgforbothSBPandDBP)withbothstatins[11].Becausethiseffectwasseeninpatientsnotreceiving
antihypertensivetreatment(mostpatientswerenormotensive),theseresultsarecompatiblewiththeabove
possibilitythatstatinsexertasmallBPloweringeffectthatcanbedetectedonlywhentheyaregivenalone.
Bycontrast,intherecentlypublishedPHYLLIS(randomised,placebocontrolled,doubleblind)trial
including508patientswithmildhypertensionandhypercholesterolaemia,administrationofastatin
(pravastatin40mgoncedaily)inhypertensivepatientswithBPeffectivelyreducedbyconcomitant
antihypertensivetreatmentdidnothaveanadditionalBPloweringeffect[12].Thestrengthsofthisstudy
werea2.6yearfollowupandambulatoryBPmonitoringinadditiontoclinicBPmeasurement.Reduction
inBPduetostatintherapy:pathophysiologicalmechanismsStatinsinduceconsistentandpredictable
reductionsincirculatingLDLcholesterolandtriglycerides,andhaveasmalleffectonHDLcholesterol.
Inaddition,theseagentsexhibitancillaryactionswhichhavebeenattributedtoreductionsinisoprenoid
cholesterolintermediatesandreductionsindolichols,geranylgeranoicacid,andfarsenylfarsenoicacid.It
canbehypothesisedthattheseactionsmayprovideapleiotropicmechanismbywhichstatinsexertactions
onBPaswellastargetorgandamageassociatedwithhypertension.Statinsimproveendothelialfunctionby
increasingthebioavailabilityofNO,promotingreendothelialisation,reducingoxidativestress,and
inhibitinginflammatoryresponses[13].IncreasedangiotensinIIsensitivitypredisposestohypertensionand
plaqueinstability.IthasbeenreportedthattheincreasedsensitivitytoangiotensinIIinhealthyyoung
subjectswithisolatedhypercholesterolaemiacanbepartlyrestoredbytherapytoreducethelevelsofLDL
cholesterolusingstatins.ThereisevidencethatstatinsdownregulateAT1receptorexpression[14].There
isalsosomeevidencethatstatinsmayreducethelevelsofcirculatingaldosterone[15].Renalfunction,
hypertension,lipids,andstatinsRecentclinicaltrialshavedemonstratedthataggressivetreatmentwith
statinsimprovesserumcreatinine,glomerularfiltrationrate,anduratelevels[16,17].Thiseffectis
probablyanotherconsequenceofimprovedbloodflowfollowingtreatmentwithstatins.Theeffectofstatin
useonthedevelopmentofrenaldysfunctionwasexaminedin197,551patients(DepartmentofVeterans
Affairs,VeteransIntegratedServiceNetwork[18]).Theoddsfordevelopingrenaldysfunctionwere
decreasedby13%instatinusers.Thebeneficialeffectofstatinsinpreventingthedevelopmentofrenal
dysfunctionseemstobeindependentoftheirlipidloweringeffect.StatinsandBP:implicationsoflarge
clinicaloutcometrialsTreatmentofhypertensionisassociatedwithareductioninstrokeand,toalesser
extent,coronaryevents.Itisalsowellknownthatelevatedserumtotalcholesterolsignificantlyincreases
CHDrisk.Therefore,itislogicalthatcoexistingvascularriskfactors,includingabnormallipidprofiles,
shouldbeanintegralpartofhypertensionmanagement.Statinswereprescribedforalongtimetovarious
subgroupsinlargelandmarkprimaryandsecondarypreventiontrials.TheoverallbenefitinCVDrisk
reductionwassimilaramonghypertensiveandSTATINSANDHYPERTENSIONRenataCfkov1,2,3,
PeterM.Nilsson41CentreforCardiovascularPrevention,ThomayerUniversityHospitalandCharles
UniversityMedicalSchoolI,2DepartmentofMedicineII,CharlesUniversityMedicalSchoolI,3
DepartmentofPreventiveCardiology,InstituteforClinicalandExperimentalMedicine,Prague,Czech
Republic4DepartmentofClinicalSciences,LundUniversity,UniversityHospital,Malm,Sweden2011;
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MF.EffectsofcholesterolreductiononBPresponsetomentalstressinpatientswithhighcholesterol.Am
JHypertens1997;10:592599.5.HalperinRO,SessoHD,MaJ,etal.Dyslipidemiaandtheriskof
incidenthypertensioninmen.Hypertension2006;47:4550.6.TerzolliL,MircoliL,RacoR,FerrariAU.
LoweringofelevatedambulatorybloodpressurebyHMGCoAreductaseinhibitors.JCardiovasc
Pharmacol2005;46:310315.7.PrasadGV,AhmedA,NashMM,ZaltzmanJS.Bloodpressurereduction
withHMGCoAreductaseinhibitorsinrenaltransplantrecipients.KidneyInt2003;63:360364.8.
BorghiC,DormiA,VeronesiM,etal.;fortheBrisighellaHeartStudyWorkingParty:associationwith
differentlipidloweringtreatmentstrategiesandbloodpressurecontrolintheBrisighellaHeartStudy.Am
HeartJ2004;148:285292.9.MilionisHJ,LiberopoulousEN,ElisafMS,MikhailidisDP.Analysisof
antihypertensiveeffectsofstatins.CurrHypertensRep2007;9:175183.10.StrazzulloP,KerrySM,
BarbatoA,etal.Dostatinsreducebloodpressure?Ametaanalysisofrandomized,controlledtrials.
Hypertension2007;49:792798.11.GolombBA,DimsdaleJE,WhiteHL,RitchieJB,CriquiMH.
Reductioninbloodpressurewithstatins:resultsfromtheUCSDStatinStudy,arandomizedtrial.Arch
InternMed2008;168:721727.12.ManciaG,ParatiG,ReveraM,etal.Statins,antihypertensive
treatment,andbloodpressurecontrolinclinicandover24hours:evidencefromPHYLLISrandomized
doubleblindtrial.BMJ2010;340:c1197.13.WolfrumS,JensenKS,LiaoJK.Endotheliumdependent
effectsofstatins.ArteriosclerThrombVascBiol2003;23:729736.14.WassmannS,FaulA,HennenB,
etal.Rapideffectof3hydroxy3methylglutarylcoenzymeAreductaseinhibitiononcoronaryendothelial
function.CircRes2003;93:e98e103.15.IdeH,FujiyaS,AanumaY,AgishiY.Effectsofsimvastatin,
anHMGCoAreductaseinhibitor,onplasmalipidsandsteroidhormones.ClinTher1990;12:410420.
16.CollinsR,ArmitageJ,ParishS,etal.;fortheHeartProtectionStudyCollaborativeGroup:MRC/BHF
HeartProtectionStudyofcholesterolloweringwithsimvastatinin5963peoplewithdiabetes:a
randomisedplacebocontrolledtrial.Lancet2003;361:20052016.17.AthyrosVG,ElisafM,
PapageorgiouAA,etal.;fortheGREACEStudyCollaborativegroup:effectsofstatinsversusuntreated
dyslipidemiaonserumuricacidlevelsinpatientswithcoronaryheartdisease:asubgroupanalysisofthe
GREekAtorvastatinandCoronaryheartdiseaseEvaluation(GREACE)study.AmJKidneyDis2004;
43:589599.18.SukhijaR,BursacZ,KakarP,etal.Effectsofstatinsonthedevelopmentofrenal
dysfunction.AmJCardiol2008;101:975979.19.AmarencoP,TonkinAM.Statinsforstroke
prevention:disappointmentandhope.Circulation2004;109:III44III49.20.TheALLHATOfficersand
CoordinatorsfortheALLHATCollaborativeResearchGroup.Majoroutcomesinmoderately
hypercholesterolemic,hypertensivepatientsrandomizedtopravastatinvsusualcare.TheAntihypertensive
andLipidLoweringTreatmenttoPreventHeartAttackTrial(ALLHAT).JAMA2002;288:29983007.
21.SeverPS,DahlofB,PoulterNR,etal;fortheASCOTInvestigators.Preventionofcoronaryandstroke
eventswithatorvastatininhypertensivepatientswhohaveaverageorlowerthanaveragecholesterol
concentrations,intheAngloScandinavianCardiacOutcomesTrialLipidLoweringArm(ASCOTLLA):a
multicentrerandomisedcontrolledtrial.Lancet2003;361:11491158.22.DahlofB,SeverPS,Poulter
NR,etal.;fortheASCOTInvestigators.Preventionofcardiovasculareventswithanantihypertensive
regimenofamlodipineaddingperindoprilasrequiredversusatenololaddingbendroflumethiazideas
required,intheAngloScandinavianCardiacOutcomesTrialBloodPressureLoweringArm(ASCOT
BPLA):amulticenterrandomisedcontrolledtrial.Lancet2005;366:895906.23.SeverP,DahlfB,
PoulterN,etal.;onbehalfoftheASCOTSteeringCommitteeMembers.Potentialsynergybetweenlipid
loweringandbloodpressureloweringintheAngloScandinavianCardiacOutcomesTrial.EurHeartJ
2006;27:29822988.24.MesserliFH,PintoL,TangSSK,etal.Impactofsystemichypertensiononthe
cardiovascularbenefitsofstatintherapyametaanalysis.AmJCardiol2008;101:319325.25.
ChapmanRH,BennerJS,PetrillaAA,etal.Predictorsofadherencewithantihypertensiveandlipid
loweringtherapy.ArchInternMed2005;165:11471152.26.FlackJM,VictorR,WatsonK,etal.
Improvedattainmentofbloodpressureandcholesterolgoalsusingsinglepillamlodipine/atorvastatinin
AfricanAmericans:theCAPABLEtrial.MayoClinProc2008;83:3545.27.ManciaG,DeBackerG,
DominiczakA,etal.2007Guidelinesforthemanagementofarterialhypertension.JHypertens2007;25:
11051187.normotensiveindividuals.Althoughasizeablenumberofhypertensivesubjectswereincluded
amongthesestudies,therearenodataastowhetherstatintreatmentproducedanysignificantBP
reductions.However,weshouldkeepinmindthat:1)theeffectofstatintreatmentonBPwasnotincluded
inthestudydesign;and2)theinclusionoflargenumbersofnormotensiveparticipantscouldhave
attenuatedanybeneficialeffectonBP,whichcouldhavealsobeenmaskedby3)theuseofspecific
antihypertensivetherapy.Onlystatinswithintheclassoflipidloweringagentshavebeenshowntoinduce
aconsistent2025%reductionintheriskofstrokeortransientischaemicattacks[19].Thebenefitof
loweringbothBPandcholesterolwasevaluatedintwolargescaletrials:ALLHAT[20]andASCOTLLA
[21].ApartofALLHATwasdesignedtodeterminewhetherpravastatincomparedwithusualcarewould
reduceallcausemortalityin10,355patientswithhypertensionandmoderatehypercholesterolaemia,plus
atleastoneadditionalCHDriskfactor[20].Atfouryearstotalcholesterolwasreducedby17.2%with
pravastatinvs.7.6%withusualcare.Allcausemortalitywassimilarinthetwogroups,andCHDevent
rateswerenotdifferentbetweenthetwogroups;sixyearCHDeventrateswere9.3%(pravastatin)and
10.4%(usualcare).Theseresultscouldbeattributedtothesmalldifferenceintotalcholesterol(9.6%)and
LDLcholesterol(16.7%)betweenpravastatinandusualcarecomparedwithotherstatintrials.Adherence
tothetreatmentassigneddeclinedovertime.Forthoseassignedtopravastatin,adherencedroppedfrom
87.2%atyear2to80%atyear4,and77%atyear6,althoughthenumberofparticipantswassmall.Onthe
otherhand,intheusualcaregroup,crossoverstostatintreatmentincreasedfrom8%atyear2to17%by
year4.Thisincreasecontinuedatyear6,butthenumberofparticipantswassmall.IntheASCOTBPLA
trial[22],19,342menandwomenwithhypertensionandatleastthreeotherCVriskfactorswere
randomisedtoamlodipine(510mg/d)perindopril(48mg/d)ortoatenolol(50100mg/d)
bendroflumethiazide(1.252.5mg/d).Atotalof10,305ofthesepatientswithnormalorslightlyelevated
totalcholesterolwererandomisedtoatorvastatin10mg/dorplacebo[21].Theatorvastatinarmwas
stoppedprematurelyat3.3yearsduetoasignificantreductionintheprimaryendpoint(36%;p=0.0005).
Thebenefitofatorvastatintreatmentwasapparentwithinthefirstyearoftreatment.Fatal/nonfatalstroke
andtotalCV/coronaryeventswerealsoreducedwithatorvastatin.Atoneyear,atorvastatinreducedtotal
cholesterolby24%andLDLcholesterolby35%.However,intheperiodbetween6weeksand18months,
asignificant1.1/0.7mmHgdifferenceinBPwasseeninfavourofatorvastatinregardlessoftitrationof
dosesandnumbersofdrugs.Overall,amlodipineperindopriltherapywassuperiortoatenolol
bendroflumethiazidetherapy[22],andafurtheranalysisofearlymonotherapydatacomparingamlodipine
withatenololsuggestedapositiveinteractionbetweenatorvastatinandamlodipine[23].Thelatestmeta
analysissofaroflargeclinicaltrials,includingonlythosewithmorethan1000patientsfollowedformore
than2years,hasbeenpublishedbyMesserlietal.[24].BesidesASCOTLLAandALLHATLLT,12
trialsenrolling69,284patientsmettheinclusioncriteria.Overall,inthese12trials,statintherapydecreased
cardiacdeathby24%(RR0.76;95%CI0.710.82).TherewasnoevidenceofadifferenceinRRestimates
forhypertensiveandnormotensivepatients.Inconclusion,statintherapyeffectivelydecreasedCV
morbidityandmortalitytothesameextentinhypertensiveandnormotensivepatients.Compliancewith
antihypertensiveandlipidloweringtreatmentThecriticalissueofanylongtermmedicationisadherence,
whichvariesaccordingtodiagnosis.Thecompliancerateforantihypertensivemedication,asreportedby
theUSNationalCouncilonPatientInformationandEducation,is53%.Inaretrospectivecohortstudy
[25],adherencetomedicationwasanalysedin8406enroleesinaUSmanagedcareplanwhichinitiated
treatmentwithantihypertensiveandlipidloweringdrugswithina90dayperiod.Adherenceto
concomitantantihypertensiveandlipidloweringtherapywaspoor,withonly35.9%ofpatientsadherentto
bothmedicationsat6months.Asinglepillcontaininganantihypertensiveandlipidloweringcompound
mayincreasepatientadherencetothesemedicationsandthusimprovethesimultaneousmanagementof
hypertensionanddyslipidaemia,whichmayalsoimproveclinicaloutcome[26].ConclusionsThe2007
ESH/ESCguidelinesforthemanagementofarterialhypertension[27]recommendconsideringlipid
loweringagentsinallhypertensivepatientswithestablishedcardiovasculardiseaseorwithType2
diabetes,aimingatserumtotalandLDLcholesterollevelsof<4.5mmol/l(175mg/dl)and<2.5mmol/l
(100mg/dl),respectively,orlower,ifpossible.InviewoftheresultsoftheASCOTtrial[21],itseems
reasonabletoconsiderstatintherapyinhypertensivepatientsagedlessthan80yearswhohavean
estimated10yearriskofcardiovasculardisease20%orofcardiovasculardeath(basedontheSCORE
model)of5%ormore.TargetlevelsshouldbeserumtotalcholesterolandLDLcholesterollevelsof<5
mmol/l(190mg/dl)and<3mmol/l(115mg/dl),respectively.EuropeanSocietyofHypertensionScientific
Newsletter:UpdateonHypertensionManagement71IntroductionThedetectionofsmallamountsof
urinaryalbuminexcretion(UAE),aconditionknownasmicroalbuminuria,byusingsensitive
immunologicalmethodswasinitiallyusedintheevaluationandmanagementofrenaldamageindiabetes.
Inthelastfewyears,however,ithasreceivedincreasedattentionasaprognosticmarkerforcardiovascular
and/orrenalriskinnondiabeticsubjects[111].Consequently,microalbuminuriaassessmentisnow
recommendedinariskstratificationstrategyforhypertensionmanagement[12]sinceitspresenceindicates
earlyorgandamageandaclusteringofcardiovascularriskfactors.AstheESH/ESCguidelinesindicate,
microalbuminuriaisareliableprognosticmarker,whichiswidelyavailableandatlowcost[12].Moreover,
recentdataindicatesthatmicroalbuminuriaispotentiallyanintermediateendpointduringantihypertensive
treatment[11,13].DefinitionandprevalenceMicroalbuminuriahasbeendefinedasaUAEhigherthanthe
thresholdvalueobtainedfromstudiesassessingtheriskfordevelopingnephropathyindiabetes(UAE
30300mg/24hor20200mg/min).Thealbumin/creatinineratiofromspoturine,preferablyfromthe
firstvoidedinthemorning(30300mg/g),isequivalenttothevaluesduringa24hoururinecollection
[14].Onthebasisofthisthresholdtheprevalenceofmicroalbuminuriainhypertensiondependsonthe
characteristicsofthepatientsincluded,thelowestinPrimaryCaresettings(around1012%)andthe
highestinreferralHypertensionClinics(upto30%).AtthetimeofassessingUAEtwoaspectsneedtobe
considered:reproducibilityandcircadianvariability.Sincealargeintraindividualvariabilityexists,atleast
twoUAEassessmentsneedtobecollected.IfdiscrepanciesbetweentheUAEvaluesexist,athirdsample
shouldberequested.ThereisfrequentlyareductionofUAEatnighttoaround20%ofthatexcretedduring
daytimeactivity.Consequently,thefirstvoidedurineanalysedshowstheUAEvaluesattheirlowest.
Recentlytheinformationcollectedfromprognosticstudies(seebelow)haschallengedtheconceptofusing
microalbuminuriaasaqualitativeparameter,andhasindicatedthatquantitativevaluesshouldbe
considered[14].Likewise,theprognosticvaluehasastronginteractionwiththeestimatedglomerular
filtrationrate(eGFR);therefore,ariskchartwithbothUAEandeGFRhasrecentlybeenproposed(Figure
1)[15].MechanismsofmicroalbuminuriaMicroalbuminuriainessentialhypertensivepatientsisthe
consequenceofanincreasedtransglomerularpassageofalbuminratherthantheresultofadecreaseinthe
proximaltubulereabsorptionofalbumin.Itmayresultfromhaemodynamicmediatedmechanismsand/or
functionalorstructuralimpairmentoftheglomerularbarrier[16].Asregardsthehaemodynamics,
hyperfiltration,withtheconsequentincrementinglomerularpressure,isofparticularimportance.Itis
probablymediatedbyabnormaltransmissionofsystemichypertensiontotheglomerulusthrougha
disturbanceinglomerularautoregulationand/orfromprogressivelossoffunctioningnephrons.Ofthenon
haemodynamics,functionalabnormalitiesoftheglomerularbasalmembranehavebeenclaimed,although
someevidencehasbeenagainstthisinhypertension.Morewidelyaccepted,however,isthat
microalbuminuriareflectsthekidneyexpressionofamoregeneralisedstateofendothelialdysfunction.
FactorsrelatedtomicroalbuminuriaFactorsrelatedtothepresenceofmicroalbuminuriainessential
hypertensionhavebeenanalysedincrosssectionalaswellasinafewprospectivestudies(reviewedin
[17]).Fromthesestudiesitseemsthatthesignificanceofmicroalbuminuriainessentialhypertensionis
muchbroaderthanexpected,andseveralfactorsmayinfluencethepresenceofmicroalbuminuria.Both
crosssectionalandfollowupstudieshaveindicatedthatbothBPvaluesandhyperinsulinaemiaarethe
mainfactorsassociatedwiththerisk.Microalbuminuriamaybetheconsequenceofadoubleproduct,
whichistimeofhypertensionperbloodpressure(BP)value.Ifthepatienthasinsulinresistance,
microalbuminuriacanbepresentevenwhenthedoubleproductoftimeandpressureissmall.Bycontrast,
subjectswithoutinsulinresistanceneedalengthoftimeand/orhighbloodpressurevaluestodevelop
microalbuminuria.Overandabovethesescenarios,thedevelopmentofnephrosclerosis,lessprevalentin
noninsulinresistance,addsanewcomponenttotheriskofhavingmicroalbuminuria.Incrosssectional
studies,microalbuminuriahasbeenrelatedtoBPvaluesandtohyperinsulinaemiaasanexpressionof
insulinresistance.TheimportanceofBPvaluesandalterationsinthecarbohydratemetabolismhasbeen
corroboratedbyasmallnumberoffollowupstudies.Bloodpressurevaluesachievedovertimeand
changesinfastingglucosewerethemostimportantfactors,notonlyfordevelopingnewonset
microalbuminuriabutalsoinreducingurinaryalbuminexcretionduringantihypertensivetreatment.The
influenceofglomerularfiltrationrate(GFR)onthemicroalbuminuriaofhypertensionmeritsacomment.
TheprevalenceofmicroalbuminuriaincreasesastheGFRdecreases,althoughnotalwaysinparallel.
Moreover,whenGFRis<60ml/min/1.73m2,theprobabilityofUAEnormalisationduring
antihypertensivetreatmentisclearlyreduced[18].Otherpotentialfactorsassociatedwiththepresenceof
microalbuminuriaaresaltsensitivity,overactivityofthereninangiotensinsystem,inflammation,genetics,
obesity,andsmoking.PrognosticvalueThepotentialprognosticvalueofmicroalbuminuriato
cardiovasculardiseasehasbeenassessedamongdiabeticsandnondiabeticsinthegeneralpopulation,
postmenopausalwomen,andhighcardiovascularriskpatients.InallofthesethehighestUAEvalues
observedatthebeginningofeachstudywerefollowedbyanincreaseinmorbidityandmortality
cardiovascularrisk.TheUAEthresholdvaluepointingtoanincrementofriskwaslargelybelowtheUAE
valueof30mg/24hours,regardlessofthepopulationstudied,andtherelationshipbetweenUAEandrisk
wascontinuousatbelow30mg/24hours.AkeypointinconsideringUAEasanintermediateobjective
arisesfromthedemonstrationthatareductioninurinaryproteinsisfollowedbyasignificantreductionin
cardiovascularand/orrenalevents[19].TheLosartanInterventionForEndpointreductioninhypertension
(LIFE)hasamplydemonstratedthattherateoftheprimarycompositecardiovascularendpointof
cardiovasculardeath,fatalornonfatalstroke,andfatalornonfatalmyocardialinfarctionincreases4fold
to5foldfromthelowesttothehighestdecileofthealbumin/creatinineratio.Schraderetal.[13]observed
thatnormalizationofUAEduringtreatmentwasassociatedwithatrendtowardsfewercardiovascular
eventsascomparedwithpersistingmicroalbuminuria.Conversely,newMICROALBUMINURIAIN
ESSENTIALHYPERTENSIONJosepRedon1,FernandoMartinez1,JoseM.Pascual21Hypertension
Clinic,InternalMedicine,HospitalClnico,UniversityofValencia,Valencia,Spain2HypertensionClinic,
InternalMedicine,HospitalofSagunto,Sagunto,CIBERofObesityandNutrition,CarlosIIIInstituteof
Health,Spain2011;12:No.36revisedversionFigure1.Riskcategoriesforkidneyandmortalityoutcomes
byGFRandalbuminuriaorproteinuriastage[15]72References1.MogensenCE.Microalbuminuria
predictsclinicalproteinuriaandearlymortalityinmaturityonsetdiabetes.NEnglJMed1984;310:356
360.2.YudkinJS,ForrestRD,JacksonCA.Microalbuminuriaasapredictorofvasculardiseaseinnon
diabeticsubjects.Islingtondiabetessurvey.Lancet1988;2:530533.3.DamsgaardEM,FrolandA,
JorgensenOD,MogensenCE.Microalbuminuriaaspredictorofincreasedmortalityinelderlypeople.Br
MedJ1990;300:297300.4.HaffnerSM,SternMP,KozlowskiMK,etal.Microalbuminuria:apotential
markerforincreasedcardiovascularfactorsinnondiabeticsubjects?Atherosclerosis1990;10:727731.5.
BigazziR,BianchiS,BaldariD,CampeseVM.Microalbuminuriapredictscardiovasculareventsandrenal
insufficiencyinpatientswithessentialhypertension.JHypertens1998;16:13251333.6.BorchJohnsen
K,FeldtRasmussenB,StrandgaardS,SchrollM,JensenJS.Urinaryalbuminexcretion. An
disease: a step forward. Ann Intern Med. 2011; 154: 6567. 16.
Mountokalakis TD. The renal consequences of hypertension. Kidney Int
1997; 51: 16391653. 17. Redon J, Pascual JM. Development of
microalbuminuria in essential hypertension. Curr Hypertens Rep 2006;
8: 171177. 18. Pascual JM, Rodilla E, Miralles A, Gonzalez C, Redon J.
Determinants of urinary albumin excretion reduction in essential
hypertension: a long-term follow-up study. J Hypertens 2006; 24: 2277
2284. 19. Ibsen H, Olsen MH, Wachtell K, et al. Reduction in
albuminuria translates to reduction in cardiovascular events in
hypertensive patients: a LIFE study. Hypertension 2005; 45: 198202.
20. Schmieder (data on file) 21. Haller H, Ito S, Izzo JL Jr, et al.;
ROADMAP Trial Investigators. Olmesartan for the delay or prevention of
microalbuminuria in type 2 diabetes. N Engl J Med. 2011; 364: 907
917. 23. Redon J. Antihypertensive treatment: should it be titrated to
blood pressure reduction or to target organ damage regression? Curr
Opin Nephrol Hypertens 2005; 14: 448452. 24. Redon J, Ruilope LM.
Microalbuminuria as an intermediate endpoint in hypertension.
Evidence is coming. J Hypertens 2004; 22: 16891691. 25. Sinzinger H,
Kritz H, Furberg CD. Atorvastatin reduces microalbuminuria in patients
with familial hypercholesterolemia and normal glucose tolerance. Med
Sci Monit 2003; 9: PI88PI92. ly developed proteinuria was associated
with a trend towards increasing events. Recently data coming from the
ONTARGET study, confirm that a 50% per cent or more increment or
reduction in UAE is followed by an increase or decrease of CV and renal
events, respectively [20]. In contrast, in normoalbuminuric patients
with type 2 diabetes, the reduction in new occurrence of
microalbuminuria was not followed for a reduction in CV events
although the study was unpowered for CV events [21]. Future studies
with appropriate design and analysis are required to give credence to
microalbuminuria as an intermediate objective [22]. Recommendation
for UAE assessment Microalbuminuria assessment is now
recommended at the initial evaluation of a patient with hypertension.
Two first-morning voided urine samples should be tested for the
albumin/creatinine ratio. No recommendation exists, however,
concerning when UAE measurement should be repeated, if it is
considered as an intermediate objective. If so, the proposed algorithm
is presented in Figure 2. Treatment of hypertension with
microalbuminuria Blood pressure reduction is the most important
determinant of diminishing UAE during antihypertensive treatment.
Reninangiotensin system blockers are superior to other
antihypertensive agents in reducing UAE in subjects, mainly those in
the high range of BP. If such treatment reduces BP enough to achieve
BP goals, differences in the UAE reduction among antihypertensive
classes become smaller, or no differences are observed at all [23, 24].
The role of additional interventions for BP reduction needs to be
considered. Statins (agents with ancillary properties beyond their lipid-
lowtomoderatephysicalactivity(intensity<
power [24, 26]. Cornelissen et al. [27] compared the effect of training
at lower and higher intensity on blood pressure in 55-year-old
sedentary men and women, by use of a randomized cross-over design
comprising three 10-week periods. In the first and third period,
participants exercised at, respectively, lower or higher intensity (33%
or 66% of heart rate reserve) in random order, with a sedentary period
in between. Training programmes comprised walking, jogging, cycling,
and stepping, were identical except for intensity, and were performed
three times for one hour per week. Thirty-nine (18 men) of 48
randomized participants completed the study; age averaged 59 years.
The change of aerobic power from baseline to the end of each period
was more pronounced (p < 0.05) with higher intensity (+3.70 ml*kg
1*min1, p < 0.001) than with lower intensity training (+2.31 ml*kg
1*min1, < 0.001). Systolic blood pressure at rest and during
submaximal exercise were reduced with both intensities (p < 0.01) by
about 5 to 6 mm Hg, without significant differences in blood pressure
reduction between intensities. In conclusion, endurance training for
three times one hour per week at lower intensity increases fitness
levels, but to a lesser extent than does higher intensity training, and
lower and higher intensity training reduce office and exercise systolic
blood pressure to a similar extent. Static exercise Blood pressure
increases during acute static exercise, and the increase is more
pronounced than with dynamic exercise, particularly with heavy static
exercise at an intensity of > 4050% of maximal voluntary contraction.
In a meta-analysis of randomized controlled trials, resistance training
at moderate intensity was found to decrease blood pressure by 3.5/3.2
mm Hg [28]. The meta-analysis included nine studies designed to
increase muscular strength, power and/or endurance, and all but one
study involved dynamic rather than purely static exercise. In fact, few
sports are characterized by purely static efforts. However, only three
trials in the meta-analysis reported on patients with hypertension. In
the meantime the number of studies has substantially increased, and
the blood pressure lowering effect of resistance training has recently
been confirmed in a meta-analysis of 26 randomized controlled trials
[29]. HYPERTENSION IN ATHLETES Robert H. Fagard, MD, PhD
Hypertension and Cardiovascular Rehabilitation Unit, Department of
Cardiovascular Diseases, Faculty of Medicine, University of Leuven, KU
Leuven, Leuven, Belgium 2011; 12: No. 37 revised version Table 1.
Indications for exercise testing for sports participation in patients with
hypertension Demands of exercise Risk category Static and/or dynamic
Low or moderate High or very high Light (< 40% of max) No No
Moderate (4059% of max) No Yes High ( 60% of max) Yes Yes In
case of an associated clinical condition, the recommendations for the
specific condition should be observed 74 References 1. Celis H, Fagard
RH. White-coat hypertension: A clinical review. Eur J Intern Med 2004;
15: 348357. 2. Kouidi E, Fahadidou A, Tassoulas E, et al. White-coat
Cardiovasc Prev Rehab 2005; 12: 326331. 19. Pescatello LS, Franklin
B, Fagard R, et al. American College of Sports Medicine Position Stand:
Exercise and Hypertension. Med Sci Sports Exerc 2004; 36: 533553.
20. Fagard RH, Pardaens K, Staessen JA, et al. Should exercise blood
pressure be measured in clinical practice? J Hypertens 1998; 16: 1215
1217. 21. Fagard R, Amery A. Physical exercise in hypertension. In:
Hypertension: Pathophysiology, diagnosis and management. Brenner LJ
(ed). 2nd edition. Raven Press, New York 1995: 26692681. 22. Fagard
R, Grassi G. Blood pressure response to acute physical and mental
stress. In: Manual of Hypertension of the European Society of
Hypertension. Mancia G, Grassi G, Kjeldsen SE. (eds). Informa
Healthcare, London 2008: 184189. 23. Fagard RH, Cornelissen V.
Physical activity, Exercise, Fitness and Blood Pressure. In: Handbook of
Hypertension: Principles and Practice. Battagay E, Lip GYH, Bakris GL
(eds). Taylor &Francis,BocaRaton2005:195206.24.FagardRH.Exercisecharacteristicsandthe
bloodpressureresponsetodynamicphysicaltraining.MedSciSportsExerc2001;33(Suppl):S484S492.
25.WheltonSP,ChinA,XinX,etal.Effectsofaerobicexerciseonbloodpressure:ametaanalysisof
randomised,controlledtrials.AnnInternMed2002;136:493503.26.CornelissenVA,FagardRH.
Effectsofendurancetrainingonbloodpressure,bloodpressureregulatingmechanismsandcardiovascular
riskfactors.Hypertension2005;46:667675.27.CornelissenVA,HolvoetP,ArnoutJ,etal.Influenceof
exerciseatlowerandhigherintensityonbloodpressureandcardiovascularriskfactorsatolderage.J
Hypertens2009;27:753762.28.CornelissenVA,FagardRH.Effectofresistancetrainingonresting
bloodpressure:ametaanalysisofrandomizedcontrolledtrials.JHypertens2005:23:251259.29.
CornelissenV,FagardRH,VanheesL.Theimpactofdynamicresistancetrainingonbloodpressureand
othercardiovascularriskfactors:ametaanalysisofrandomizedcontrolledtrials.Presentedatthe20th
EuropeanMeetingonHypertension,Oslo,Norway,June20,2010.30.FagardRH.Athleteswithsystemic
hypertension.CardiolClin2007;25:441448.31.ManciaG,LaurentS,AgabitiRoseiE,etal.
ReappraisalofEuropeanguidelinesonhypertensionmanagement:aEuropeanSocietyofHypertension
TaskForcedocument.JHypertens2009;27:21212158.32.VanBaakMA.Hypertension,betaadrenergic
blockingagentsandexercise.IntJSportsMed1994;15:112115.33.VanheesL,DefoorJGM,Schepers
D,etal.Effectsofbisoprololandatenololonenduranceexercisecapacityinhealthymen.JHypertens
2000;18:3543.34.VanBortelLM,vanBaakMA.Exercisetolerancewithnebivololandatenolol.
CardiovascularDrugsTher1992;6:239247.35.VanheesL,FagardR,LijnenP,etal.Effectof
antihypertensivemedicationonenduranceexercisecapacityinhypertensivesportsmen.JHypertens1991;
9:10631068.RecommendationsGeneralrecommendationsAthleteswithhypertensionshouldbetreated
accordingtothegeneralguidelinesforthemanagementofhypertension[3,18,30].Appropriatenon
pharmacologicalmeasuresshouldbeconsideredinallpatients.Antihypertensivedrugtherapyshouldbe
startedpromptlyinpatientsathighorveryhighaddedriskforcardiovascularcomplications.Inpatientsat
lowormoderateaddedrisk,drugtreatmentisonlyinitiatedwhenhypertensionwouldpersistafterseveral
monthsorweeks,respectively,despiteappropriatelifestylechanges.Thegoalofantihypertensivetherapy
istoreducebloodpressuretoatleastbelow140/90mmHgandtolowervaluesiftoleratedinall
hypertensivepatients,andtobelow130/80mmHgindiabeticsandotherhighorveryhighriskconditions,
althoughthelatterlowerthresholdhasrecentlybeendebatedbecauseoflackofhardevidence[31].Current
evidenceindicatesthatpatientswithwhitecoathypertensiondonothavetobetreatedwith
antihypertensivedrugs,unlesstheyareathighorveryhighrisk,butregularfollowupandnon
pharmacologicalmeasuresarerecommended[3].Also,subjectswithnormalbloodpressureatrestand
exaggeratedbloodpressureresponsetoexerciseshouldbefollowedupmoreclosely.Choiceofdrugs
Severaldrugclassescanbeconsideredfortheinitiationofantihypertensivetherapy:diuretics;beta
blockers;calciumchannelblockers;angiotensinconvertingenzymeinhibitors;andangiotensinIIreceptor
blockers[3].However,diureticsandbetablockersarenotrecommendedforfirstlinetreatmentinpatients
engagedincompetitiveorhighintensityenduranceexercise[18,21,30).Diureticsimpairexercise
performanceandcapacityinthefirstweeksoftreatmentthroughareductioninplasmavolume,but
exercisetoleranceappearstoberestoredduringlongertermtreatment;nevertheless,diureticsmaycause
electrolyteandfluiddisturbances,whicharenotdesirableintheenduranceathlete.Betablockersreduce
maximalaerobicpowerbyonaverage7%asaresultofthereductioninmaximalheartrate,whichisnot
fullycompensatedbyincreasesofmaximalstrokevolume,peripheraloxygenextraction,orboth.
Furthermore,thetimethatsubmaximalexercisecanbesustainedisreducedby~20%bycardioselective
betablockersandby~40%bynonselectivebetablockers,mostlikelyasaresultofimpairedlipolysis[21,
32,33].Thereareindicationsthatthebetablockernebivololmaynotimpairexerciseperformance[34].In
addition,diureticsandbetablockersareonthedopinglistforsomesports,inwhichweightlossorcontrol
oftremorareofparamountimportance.Diureticsarealsobannedbecausetheymaybeusedtoconcealthe
useofotherdopingagents,suchasanabolicsteroids,bydilutingtheurinesamples.Thehypertensive
athletewhohastouseadiureticand/orabetablockerfortherapeuticpurposesshouldfollowthe
InternationalStandardforTherapeuticUseExceptionsoftheWorldAntiDopingAgency(WADA).
Calciumchannelblockersandblockersofthereninangiotensinsystemarecurrentlythedrugsofchoicefor
thehypertensiveenduranceathlete[21,35]andmaybecombinedincaseofinsufficientbloodpressure
control.However,thecombinationofanangiotensinconvertingenzymeinhibitorandanangiotensinII
receptorblockeriscurrentlynotadvocatedforthetreatmentofhypertension.Ifathirddrugisrequired,a
lowdosethiazidelikediuretic,possiblyincombinationwithapotassiumsparingagent,isrecommended.
Thereisnounequivocalevidencethatantihypertensiveagentswouldimpairperformanceinresistance
sports.RecommendationsforsportsparticipationRecommendationsforparticipationincompetitivesports
inathleteswithhypertensionarebasedontheresultsoftheevaluationandontheriskstratificationand
withtheunderstandingthatthegeneralrecommendationsforthemanagementofhypertensionare
observed,asdescribedabove,andprovidedthattheclinicalconditionisstable.Table2summarizesthe
recommendationswithregardtocompetitivesportsparticipation[17,18].Thesamerecommendationsmay
applytopatientswhoaimtoengageinhardorveryhardleisuretimesportsactivitiesinorderto
substantiallyenhanceperformance.However,mostrecreationalphysicalactivitiesareperformedatlowto
moderateintensity.Dynamicsportsactivitiesaretobepreferred,butalsolowtomoderateresistance
trainingisnotharmfulandmayevencontributetobloodpressurecontrol[28,29].Incaseofcardiovascular
orrenalcomplications,therecommendationsarebasedontheassociatedclinicalconditions.Finally,all
patientsshouldbefollowedupatregularintervals,dependingontheseverityofhypertensionandthe
categoryofrisk.Inaddition,allexercisingpatientsshouldbeadvisedonexerciserelatedwarning
symptoms,suchaschestpainordiscomfort,abnormaldyspnoea,dizziness,ormalaise,whichwould
necessitateconsultingaqualifiedphysician.SummaryHypertensionisrareintheyoungbutitsprevalence
increaseswithage.Theoverallriskofthehypertensionpatientdoesnotonlydependonbloodpressurebut
alsoonthepresenceofothercardiovascularriskfactors,targetorgandamage,andassociatedclinical
conditions.Therecommendationsforpreparticipationscreening,sportsparticipation,andfollowupdepend
onthecardiovascularriskprofileoftheindividualathlete.Whenantihypertensivetreatmentisrequired,
calciumchannelblockersandblockersofthereninangiotensinsystemarecurrentlythedrugsofchoicein
theexercisingpatient.Table2.Recommendationforstrenuousleisuretimephysicalactivityand
competitivesportsparticipationinathleteswithsystemichypertensionaccordingtothecardiovascularrisk
profileRiskcategoryEvaluationCriteriaforeligibilityRecommendationsFollowupLowaddedrisk
History,PE,ECG,ET,echoWellcontrolledBPAllsportsYearlyModerateHistory,PE,ECG,ET,echo
WellcontrolledBPandriskfactorsAllsports,withexclusionofhighstatic,Yearlyaddedriskhigh
dynamicsports(IIIC)HighHistory,PE,ECG,ET,echoWellcontrolledBPandriskfactorsAllsports,
withexclusionYearlyaddedriskofhighstaticsports(IIIAC)VeryhighHistory,PE,ECG,ET,echo
WellcontrolledBPandriskfactors;Onlylowmoderatedynamic,6monthsaddedrisknoassociated
clinicalconditionslowstaticsports(IAB)BPbloodpressure;PEphysicalexamination,including
repeatedbloodpressuremeasurementsaccordingtoguidelines;ECG12leadelectrocardiography;ET
exercisetesting;echoechocardiographyatrestEuropeanSocietyofHypertensionScientific
Newsletter:UpdateonHypertensionManagement75ConceptanddefinitionArterialhypertensionisoften
partofaconstellationofanthropometricandmetabolicabnormalitiesthatincludeabdominalobesity,
characteristicdyslipidaemiawithlowhighdensitylipoproteincholesterolandhightriglycerides,glucose
intolerance,insulinresistance(IR),andhyperuricaemia.Thesefeaturesoccursimultaneouslytoahigher
degreethanwouldbeexpectedbychancealone,supportingtheexistenceofadiscretedisorder,socalled
metabolicsyndrome(MS)orcardiometabolicsyndrome.MSiscurrentlyconsideredtoconferanincreased
riskofcardiovascular(CV)eventsattributable,inpart,totheindividualriskfactorswhichconcurin
definingitand,inpart,toaclusterofotherfactorssuchashyperuricaemia,aproinflammatorystate,
impairedfibrinolysis,andoxidativestress,whichusuallygoalongwithit.MSisextremelycommon
worldwideandcanbefoundinapproximatelyonethirdofpatientswithessentialhypertension,inwhomit
considerablyincreasestheriskofCVandrenalevents.ThecriteriaemployedtoidentifyMShavechanged
overtheyears[1](Table1).AfterthemoremechanisticWorldHealthOrganizationandEuropeanGroup
forInsulinResistancedefinitions,theAdultTreatmentPanelIII(ATPIII),oneoftheMSdefinitions
presentedin2001,wasmoreclinicallyoriented.Recently,theInternationalDiabetesFederationdefinition
aimedatconsideringresearchneedsbutalsoatofferinganaccessiblediagnostictoolsuitablefor
worldwideuse.Themostimportantnewelement,comparedtootherdefinitions,isthatcentralobesityand
insulinresistanceareregardedasthemostimportantcausativefactors.Thelastofthedefinitionswas
releasedbytheAmericanHeartAssociation/NationalHeartBloodandLungInstitute(AHA/NHBLI).It
hasgivensupporttotheATPIIIcriteria,exceptforareductioninthethresholdoftheimpairedfasting
glucosecomponentfrom6.1to5.6mmol/l(110to100mg/dl)inlinewiththerecentmodificationproposed
bytheAmericanDiabetesAssociation[2].AlthoughthecausesandmechanismsofMSmayindeedbe
diversified,whichiswhatthetermsyndromeimplies,thereisevidencethattheoverallCVrisk
accompanyingthisconditionmaybegreaterthanthesumofitsidentifiablecomponents.Furthermore,
thesecomponentsareoftendefinedbyvaluesthatarelowerthanarethosemeetingthedefinitionofrisk
factorsgivenbymanyguidelines,whichconsequentlymayfailtodetectthepresenceofahighCVriskin
someindividualswithMS.Finally,thesimpleandeasyidentificationofMSfavourstheuseofthis
approachinclinicalpractice,whichresistsuseofmorecomplexchartsfortotalCVriskquantification,
ultimatelyhelpingimplementationofCVprevention.MechanismsofhypertensioninMSMechanisms
involvedinMSareobesity,IR,andaconstellationofindependentfactorswhichincludemoleculesof
hepatic,vascular,andimmunologicoriginwithproinflammatoryproperties[3].Skeletalmuscleandthe
liver,notadiposetissue,arethetwokeyinsulinresponsetissuesinvolvedinmaintainingglucosebalance,
althoughabnormalinsulinactionintheadipocytesalsoplaysaroleindevelopmentofthesyndrome.At
eachofthesekeypoints,IRandobesity/proinflammatorymolecules,thereareinteractionsof
demographics,lifestyle,geneticfactors,andenvironmentalfoetalprogramming.Superimposinguponthese
areinfectionsand//orchronicexposuretocertaindrugswhichcanalsomaketheircontribution.Theseall
interacttocreatethefinalindividualphenotype.Likewise,theyinteractleadingtochangesinblood
pressureregulatorymechanisms.HypertensionisfrequentinMS,andbloodpressureabnormalityiseven
morefrequent,withvaluesinthehighnormalrange,representingoneofthefivecomponentsthatleadto
theidentificationofthiscondition.InthePAMELApopulationstudy,forexample,abloodpressureinthe
highnormalorhypertensionrangewasfoundinmorethan80%oftheindividualswithMS,followed,ina
decreasingorderofprevalence,byvisceralobesity,lipidabnormalities,andimpairedfastingglucose[4].
ThehighprevalenceofBPabnormalitiesinMSexplainstheveryfrequentoccurrenceofsubclinicalorgan
damageofthetypethatisfrequentlyassociatedwith,andisdependenton,bloodpressureelevation,such
asleftventricularhypertrophy,arterialstiffening,orincreasedurinaryproteinexcretion.Someofthese
typesoforgandamage,however,alsoshowanincreasedprevalenceinindividualswhohaveMSwithouta
bloodpressureelevation,suggestingthatothercomponentsofthisconditionplayaroleindependentlyof
BP.Ingeneral,theMScomponentsarecharacterizedbyahighdegreeofinteraction,onecontributingto
theestablishmentoftheabnormalityoftheotherandviceversa.Ithasbeenrecognizedformanyyears,for
example,thatthetwomaincomponentsofMS,obesityandIR,mayplayanimportantroleintheincrement
ofbloodpressureandthedevelopmentofhypertension.Factorscommonlyassociatedwith,andpartly
dependenton,obesityandIR,suchasoveractivityofthesympatheticnervoussystem[5,6],stimulationof
thereninangiotensinaldosteronesystem[7],abnormalrenalsodiumhandling[8],andendothelial
dysfunction[9],needtobeconsidered.RecentlytheroleofvitaminDmetabolism[10]andapotential
geneticcontributionhasbeenemphasized[11].Severalcrosssectionalandprospectivestudieshaveshown
anassociationbetweenlowvitaminDstatus,asindicatedbyconcentrationsofserum25hydroxyvitaminD
andincreasedprevalenceoftheMSandindividualCVDriskfactors.Theseepidemiologicalobservations
aresupportedbymechanisticstudies,butexperimentaldataarelimitedandnointerventionstudiesexistto
confirmthehypothesis,whichcanbebiasedbytheassociationofadiposityandageingwithlowvitaminD
levels[12].Finally,anassociationbetweenthealleleTofSNPrs17055869nearthealpha1A
adrenoreceptorgeneandmetabolicsyndromeandthesympatheticoveractivityhasbeendescribed[11].MS
andhypertensioninducedorgandamageMetabolicsyndromehasbeenassociatedwithahigherprevalence
ofearlysignsofsubclinicalcardiovascularandrenaldamage[1].Severalstudieshavedemonstratedthat
MSisassociatedwithahighprevalenceofleftventricularhypertrophy(LVH)throughoutawideage
spectrum.Moreover,thenumberofMScomponentshasbeendirectlylinkedtotheriskofhavingEKGand
echocardiographicLVH.TheeffectofMSonLVstructurehasbeenreportedtobemorepronouncedin
womenthaninmen,andhasbeenshowntobepartlyindependentoftheeffectofhaemodynamicandnon
haemodynamicdeterminantsofLVmass,includingbloodpressurevaluesover24hours.Atrial
enlargement,aprognosticfactorforthedevelopmentofatrialfibrillationandstroke,hasalsobeen
associatedwithoverweight,highfastingglucose,andMS,independentlyofLVmassandgeometry.An
increaseintheprevalenceofabnormalurinaryalbuminexcretionhasbeenobservedamonghypertensives
withMS,ascomparedtothosewithoutMS,andindeedmicroalbuminuriahasbeenconsideredadiagnostic
elementforMSinearlydefinitionsofthiscondition.Theprevalenceofmicroalbuminuriahasbeenshown
toincreasewiththenumberofMScomponents.MSwasalsoassociatedwithalowerglomerularfiltration
rate(GFR),asestimatedusingtheMDRDformula,inacrosssectionalsurveyofhypertensivesseenin
primarycare.Furthermore,thenumberofMScomponentswaslinearlyrelatedtotheprevalenceofGFR<
60ml/min/1.73m2.Evidenceisavailablethataorticpulsewavevelocity(PVW9)ishigherin
hypertensiveswithMS,irrespectiveofageandsystolicbloodpressurevalue.Likewise,anMETABOLIC
SYNDROMEINHYPERTENSIONJosepRedonUniversityofValencia,andCIBER06/03Fisiopatologa
delaObesidadyNutricin,InstituteofHealthCarlosIII,Madrid,Spain2011;12:No.38revisedversion
Table1.Criteriafordiagnosingmetabolicsyndromeaccordingtodifferentscientificorganisations:World
HealthOrganization(WHO),EuropeanGroupofInsulinResistance(EGIR),AdultTreatmentPanel(ATP
III),InternationalDiabetesFederation(IDF),AmericanHeartAssociation(AHA)OrganisationPrincipal
criteriaAbdominalobesityGlucose[mg/dl]HDL[mg/dl]TG[mg/dl]BP[mmHg]WHODM,GIorIR
BMI30kg/m2M35150140/90*M0.90W39(1.7mmol/L)W0.85(1.02mmol/L)EGIR
IRorFI>P75BMI30kg/m2110*<40180140/90*M102cm(6.1mmol/L)(1.03mmol/L)W
88cmATPIIIM102cm110*M40150135/85*W88cm(6.1mmol/L)(1.03mmol/L)
(1.7mmol/L)W50(1.29mmol/L)IDFCentralobesityM94cm100*M40150*135/85*W
80cm(5.6mmol/L)(1.03mmol/L)(1.7mmol/L)W50*(1.29mmol/L)AHAM94cm100*M
40150*135/85*W80cm(5.6mmol/L)(1.03mmol/L)(1.7mmol/L)W50*(1.29mmol/L)
Diagnosisofmetabolicsyndromeisbasedon:a)principalcriteriaplusatleasttwoothers;b)inthose
withoutprincipalcriteria,atleastthree.Shadedareadenotesthedefinitionsbasedoncarbohydrate
metabolismabnormalities.Theremainingarebasedonabdominalobesity;*orintreatmentfor;BMI
bodymassindex;DMdiabetesmellitus;GIglucoseintolerance;IRinsulinresistance;FI
fastinginsulin;TGtriglycerides;Mmen;Wwomen76References1.RedonJ,CifkovaR,
LaurentS,etal;ScientificCounciloftheEuropeanSocietyofHypertension.Themetabolicsyndromein
hypertension:Europeansocietyofhypertensionpositionstatement.JHypertens2008;26:18911900.2.
TheExpertCommitteeontheDiagnosisandClassificationofDiabetesMellitus.Followupreportonthe
diagnosisofdiabetesmellitus.DiabetesCare2003;26:31603167.3.RedonJ,CifkovaR,LaurentS,etal.
Mechanismsofhypertensioninthecardiometabolicsyndrome.JHypertens2009;27:441451.4.Mancia
G,BombelliM,CorraoG,etal.MetabolicsyndromeinthePressioniArterioseMonitorateELoro
Associazioni(PAMELA)study:dailylifebloodpressure,cardiacdamage,andprognosis.Hypertension
2007;49:4047.5.RahmouniK,CorreiaMLG,HaynesWG,MarkAL.Obesityassociatedhypertension.
Newinsightsintomechanisms.Hypertension2005;45:914.6.ManciaG,DellOroR,QuartiTrevanoF,
ScopellitiF,GrassiG.Angiotensinsympatheticsysteminteractionsincardiovascularandmetabolic
disease.JHypertens2006;24:S51S56.7.SonnenbergGE,KrakowerGR,KissebahAH.Anovel
pathwaytothemanifestationsofmetabolicsyndrome.ObesRes2004;12:180186.8.HallJE,Brands
MW,HenegatJR.Mechanismsofhypertensionandkidneydiseaseinobesity.AnnNYAcadSci1999;
892:91107.9.KimJA,MontagnaniM,KohKK,QuonMJ.Reciprocalrelationshipsbetweeninsulin
resistanceandendothelialdysfunction:molecularandpathophysiologicalmechanisms.Circulation2006;
113:18881904.10.MuldowneyS,LuceyAJ,PaschosG,etal.RelationshipsbetweenVitaminDStatus
andCardioMetabolicRiskFactorsinYoungEuropeanAdults.AnnNutrMetab.2011;58:8593.11.
GrassiG,PadmanabhanS,MenniC,etal.AssociationbetweenADRA1Ageneandthemetabolic
syndrome:candidategenesandfunctionalcounterpartinthePamelapopulation.JHypertens2011;29:
11211127.12.MuldowneyS,KielyM.VitaminDandcardiometabolichealth:areviewoftheevidence.
NutrResRev2010;1:120.13.ManciaG,DeBackerG,DominiczakA,etal.ManagementofArterial
HypertensionoftheEuropeanSocietyofHypertension;EuropeanSocietyofCardiology.2007Guidelines
fortheManagementofArterialHypertension:TheTaskForcefortheManagementofArterial
HypertensionoftheEuropeanSocietyofHypertension(ESH)andoftheEuropeanSocietyofCardiology
(ESC).JHypertens2007;25:11051187.14.JeppesenJ,HeinHO,SuadicaniP,GynterbergF.Low
triglycerideshighhighdensitylipoproteincholesterolandriskofischemicheartdisease.ArchInternMed
2001;16:361366.15.SchillaciG,PirroM,VaudoG,etal.Prognosticvalueofthemetabolicsyndromein
essentialhypertension.JAmCollCardiol2004;43:18171822.16.OnatA,HergencG,SariI,etal.
Dyslipidemichypertension:distinctivefeaturesandcardiovascularriskinaprospectivepopulationbased
study.AmJHypertens2005;18:409416.17.DekkerJM,GirmanC,RhodesT,etal.Metabolic
syndromeand10yearcardiovasculardiseaseriskintheHoornStudy.Circulation2005;112:666673.18.
ZanchettiA,HennigM,BaurechtH,etal.Prevalenceandincidenceofthemetabolicsyndromeinthe
EuropeanLacidipineStudyonAtherosclerosis(ELSA)anditsrelationwithcarotidintimamediathickness.
JHypertens2007;25:24632470.19.SafarME,ThomasF,BlacherJ,etal.Metabolicsyndromeandage
relatedprogressionofaorticstiffness.JAmCollCardiol2006;47:7275.20.Clinicalguidelinesonthe
identification,evaluation,andtreatmentofoverweightandobesityinadultstheevidencereport.
NationalInstituteofHealth.ObesRes1998;2(Suppl6):51S209S.21.ThompsonPD,BuchnerD,Pina
IL,etal.AmericanHeartAssociationCouncilonClinicalCardiologySubcommitteeonExercise,
Rehabilitation,andPrevention;AmericanHeartAssociationCouncilonNutrition,PhysicalActivity,and
MetabolismSubcommitteeonPhysicalActivity.Exerciseandphysicalactivityinthepreventionand
treatmentofatheroscleroticcardiovasculardisease:astatementfromtheAmericanHeartAssociation
CouncilonClinicalCardiology(SubcommitteeonNutrition,PhysicalActivityandMetabolism
(SubcommitteeonPhysicalActivity).Circulation2003;107:31093116.22.CzoskiMurrayC,WarrenE,
ChilcottJ,etal.Clinicaleffectivenessandcosteffectivenessofpioglitazoneandrosiglitazoneinthe
treatmentoftype2diabetes:asystematicreviewandeconomicevaluation.HealthTechnolAssess2004;8:
191.23.NissenSE,WolskiK.Effectofrosiglitazoneontheriskofmyocardialinfarctionanddeathfrom
cardiovascularcauses.NEnglJMed2007;356:24572471.24.LincoffAM,WolskiK,NichollsSJ,
NissenSE.Pioglitazoneandriskofcardiovasculareventsinpatientswithtype2diabetesmellitus:ameta
analysisofrandomizedtrials.JAMA2007;298:11801188.25.HealDJ,GosdenJ,SmithSL.Regulatory
challengesfornewdrugstotreatobesityandcomorbidmetabolicdisorders.BrJClinPharmacol.2009;68:
861874.26.KroneW,HanefeldM,MeyerHF,etal.Comparativeefficacyandsafetyofaliskirenand
irbesartaninpatientswithhypertensionandmetabolicsyndrome.JHumHypertens.2011;25:186195.
associationbetweenMSandcarotidintimamediathicknesshasbeenobservedinseveralstudies,although
toaweakerdegreethanthatobservedformarkersoforgandamagesuchasLVHandmicroalbuminuria.
TheprevalenceofcarotidatherosclerosisincreasesprogressivelywiththenumberofMScomponentsin
hypertensivesbutnotinnormotensives.DataontheeffectsofthecomponentsofMSonsmallarteriesare
lacking,despitethefactthatmicrovasculardysfunctionhasbeenclaimedasanexplanationforthe
associationsamonghypertension,obesity,andimpairedmediatedglucosedisposal.InthepresenceofMS,
thehighprevalenceofearlyorgandamagesupportstherecommendationofamoreindepthassessmentof
subclinicalorgandamage[13].PrognosticvalueofMSinhypertensionAlimitednumberofstudies[4,14
17]haveexaminedtheprognosticimportanceofMSanditsindividualcomponentsinhypertensioninrisk
todevelopsubclinicalorgandamageorcardiovascularevents.ThepresenceofMSincreasedtherisk
overtimetodevelophigherpulsepressure,leftventricularhypertrophy,anddiabetesinthePAMELAstudy
[4].Overall,thepresenceofMSwasanindependentpredictorofCVevents[1214]orCVandallcause
mortality[4],evenwhentheotherCVriskfactorwastakenintoaccount.Moreover,theriskincreasedwith
thenumberofMScomponents[4].Incontrast,intheELSAstudy,inalargecohortofwelltreated
patients,outcomeswerenotdifferentbetweenMSandnonMSpatients,suggestingthateffective
antihypertensivetreatmentmaylargelycounteracttheobnoxiouseffectsofMS[18].TheimpactofMSon
intermediateobjectivessuchasPWV[19]orIMT[18]hasbeenevaluated.WhileprogressionofPWVwas
significantlyhigherinsubjectswithMSthaninsubjectswithzero,one,ortwofactorsevenafter
adjustmentsforconfoundingfactors,theprogressionofIMTwasalsoslightlygreaterinMSpatients,but
thesignificancewaslostwhenadjustedforcovariates.ManagementofhypertensionwithMSInMS,the
objectiveoftreatmentisbothtoreducethehighriskofaCVorrenaleventandtopreventthemuchgreater
chancethatMSpatientshaveofdevelopingtype2diabetesorhypertension.Theaimisalsotodelayor
preventtheprogression(aswellastofavourregression)ofthetypesoforgandamagethatarefrequently
presentandhaveanadverseprognosticsignificance.TargetingmetabolicsyndromemechanismsLifestyle
measuresTheunderlyingfactorspromotingthedevelopmentofMSareoverweightandobesity,physical
inactivity,andanatherogenicdiet.MostindividualswhodevelopMSfirstacquireabdominalobesity
withoutriskfactors,but,withtime,multipleriskfactorstendtoappear,initiallyonlywithborderline
elevationsbutthenwithprogressiveworsening.Thus,areductioninbodyweightbymeansofaproper
lowcaloriedietandanincreaseinphysicalactivitycanaddresstheverymechanismofMSandis
consequentlyrecommendedasfirstlinetherapyaccordingtoallcurrentguidelines[20,21].Amodest
caloricreduction(5001000cal/day),ontheotherhand,isusuallyeffectiveandbeneficialforlongterm
weightloss.Arealisticgoalistoreducebodyweightby710%overaperiodof612months.Longterm
maintenanceofweightlossisthenbestachievedwhenregularexerciseispartofweightreduction
management[21].Currentguidelinesrecommendadailyminimumof30minutesofmoderateintensity
physicalactivity.Additionalincreasesinphysicalactivityappeartoenhancethebeneficialeffects.
Nutritionaltherapycallsforlowintakeofsaturatedfats,transfattyacids,andcholesterol.Reduced
consumptionofsimplecarbohydratesandincreasedintakeoffruits,vegetables,andwholegrainsis
recommended.Extremesinintakesofeithercarbohydratesorfatsshouldbeavoided.Smokingcessationis
mandatory.AccumulatingevidencesuggeststhatthemajorityofindividualswhodevelopMSdonot
engageinrecommendedlevelsofphysicalactivityanddonotfollowdietaryguidelines,forfat
consumptioninparticular.DrugtreatmentTherehavebeen,todate,twotypesofdrugsinterferingwiththe
mechanismsofMS:insulinsensitizersandendogenouscannabinoidreceptorblockers(CB1receptor
blockers).Whiletheformerincreaseperipheralglucosedisposalbyactingintheperoxisomeproliferator
activatedreceptorgamma(PPARg),thelatterreduceabdominalobesityleadingtofavourable
modificationsinthestatusofadiposetissuetypicalofthiscondition.Apromisingnewtypeofdrug,
11betaHSD1enzymeinhibitors,willcomeinthenearfuture.Systematicreviewsoftheliteraturehave
foundnonotablebenefitsofPPARgagonistswithregardtobloodpressure,althoughsomeevidencepoints
tosomebloodpressureloweringeffect,atleastintype2diabeticindividualsandinthosewithrefractory
hypertension[22].Theincreaseinbodyweightresultingfromtheshiftinfatstoragefromvisceralto
subcutaneousfatandfluidretentionarethemainsideeffectsofthedrugs,whichlimitstheiruse.Thefluid
retentionincreasestheriskofdevelopingcongestiveheartfailure.TheincreaseinCVriskclaimedfor
rosiglitazone[23],whichhasnotbeenfoundforpioglitazone[24],hasresultedinitswithdrawalfromthe
market.OthertherapeuticfailurealsooccuredintheendocannabinoidC1receptorblockers(CB1blocker).
Rimonabant,thefirstdrugofthegroup,ledtomodestbutsignificantSBPandDBPreductionsin
overweight/obesepatients,althoughtheeffectappearstobemediatedbyweightloss.Increasedincidence
ofdepressionandasmallbutsignificantlygreaterrisk,amongdepressedpeople,ofsuicidecausedconcern,
andthedrugwaswithdrawnfromthemarket[25].TargetinghighbloodpressureThethresholdfor
interventioninBPvaluesisbasedontherecognitionthatunderlyingriskfactorsraiseBPtorangesthat
increasetheriskofCVdisease.Consequently,130/85mmHgshouldbethethresholdforinterventionin
theabsenceofdiabetes.HypertensivepatientswithMSshouldreceivehypertensivedrugs,accordingtothe
2007ESH/ESCguidelinesonhypertensiondiagnosisandtreatment[13].Inadditiontorecommendations
toundergointenselifestylemodifications,antihypertensivedrugsshouldbegivenwheneverbloodpressure
ispersistently140mmHgsystolicor90mmHgdiastolic.Inthepresenceofdiabetes,thethresholdfor
druginterventionshouldbelower,i.e.bloodpressurevalues130mmHgsystolicor85mmHgdiastolic,
whereasthetargetbloodpressurevaluesshould,inbothinstances,be<130/80mmHg,inlinewiththe
goalthatisrecommendedwhenevertotalCVriskishigh[3].Similargoalsandanevenlowerthresholdfor
drugintervention(130/80mmHg)shouldbeconsideredwhenMSispresentinsubjectswithaveryhigh
CVrisk,suchasthosewithmanifestCVoradvancedrenaldisease.Thechoiceofthresholdbloodpressure
fordruginterventiontobeconsideredinMSindividualswhohavenodiabetesorhistoryofCVor
advancedrenaldiseaseisdifficultbecausenotrialhastestedthebenefitofantihypertensivedrug
interventionsinthisspecificpopulation.Whenmicroalbuminuriaorothertypesoforgandamageof
prognosticsignificance(LVH,carotidatherosclerosis,arterialstiffening)arepresent,inadditiontointense
lifestylechanges,administrationofantihypertensivedrugsshouldbeatleastconsidered,withthegoalof
loweringbloodpressureatleastto<140/90mmHgandbelow.Treatmentshouldaimatpreventing
progressionorcausingregressionoftheexistingorgandamageaswellasreducingthemuchgreaterchance
anindividualwithMShastodevelopnewonsetdiabetesorhypertension.Thiscallsforavoidanceofsome
antihypertensiveagentsandelectiveuseofsomeothersasoutlinedinthefollowingsection.Treatments
Ideally,treatmentofhighBPinMSshouldbebasedonlifestylechanges(dietandphysicalexercise),
whichallowsforweightreductionandimprovesmuscularbloodflow.Concerningantihypertensivedrugs,
whetherornotaparticularantihypertensiveagentissuperiortoothershasnotbeentestedintrials
includingindividualsspecificallywithMS.However,alargebodyofinformationisavailablefromlong
termantihypertensivetrialswithmajoroutcomesaswellasfromamyriadofshorterstudies.Afterchanges
inlifestyleareintroduced,thedrugstobepreferredshouldbethosewhichinducereductionofIRand
subsequentchangesinthelipidprofileandinglucoselevels.Therefore,angiotensinconvertingenzyme
inhibitors(ACEI),angiotensinIIAT1receptorblockers(ARAII),orevencalciumchannelblockersare
preferabletodiureticsandbblockersinmonotherapy,ifnocompellingindicationsarepresentfortheir
use.Ifacombinationofdrugsisrequired,lowdosediureticscanbeused.Acombinationofthiazide
diureticsandbblockersshouldbeavoided.Theserecommendationsarebasedontheimpactofparticular
antihypertensivedrugsonothercomponentsofMS.Changesinmetaboliccomponents,mainlyinthelipid
profileandIR,duringantihypertensivetreatmentwithdiureticsandbblockershavebeenclaimedasthe
culpritofpoorerreductionsthanexpectedincoronaryheartdiseasemorbidityandmortality.However,
reductionsintheratesofnewonsetdiabeteshavebeenobservedduringtreatmentwithACEI,angiotensin
IIAT1receptorblockers(ARB),orevencalciumchannelblockersascomparedwithdiureticsandb
blockers.Anovelgroupofantihypertensivedrugs,thedirectinhibitorsofrenin(DIR),canbeconsideredin
patientswithmetabolicsyndromeduetotheneutralorevenbeneficialimpactinglucosemetabolism[26].
EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement77
IntroductionStrokeisthesecondleadingcauseofdeathandthenumberonecauseofdisabilityworldwide
[1].Aswellasage(nonmodifiableriskfactor),highbloodpressure(BP)isamajorriskfactorforstroke,
andacontinuousrelationshipbetweenBPandtheoccurrenceofstrokehasbeenwellestablished[2].On
theotherhand,evidencefromhypertensiontreatmenttrialshasshownthatrelativelysmallreductionsin
BP(56mmHgindiastolicBP,1012mmHginsystolicBPover35years)reducetheriskofstrokeby
morethanonethird[3].TheprimarypreventionofstrokethroughantihypertensivetherapyandBPcontrol
iswellestablished.Likewise,higherBPlevelsafterstrokeincreasetheriskofrecurrentstroke[4],and
therearetrialsthatindicatethatBPreductionwithantihypertensivetherapyisbeneficialinreducingstroke
recurrenceandothervasculareventsinpatientswhohavehadastroke[5].Pathophysiologyofvascular
cerebraldamageinessentialhypertensionMultiplebiologicalsystemsareinvolvedinthepathogenesisof
stroke[6](Table1).ThebrainrepresentsanearlytargetfororgandamagebyelevatedBP,whichisthe
majormodifiableriskfactorinmenandwomenfordevelopingischaemicandhaemorrhagicstroke,aswell
assmallvesseldiseasepredisposingtolacunarinfarction,whitematterlesions(WML),andcerebral
microbleeds.Cerebralsmallvesseldiseaseisanimportantriskfactorfordevelopingstrokeanddementia
[7,8].Hypertensioncausesvascularbraininjurydirectly(smallvesseldisease)orbypromoting
atherosclerosisorcardiacdamage.Inflammationplaysacentralroleinthepathogenesisandprogressionof
atherosclerosisand,consequently,stroke.Inthesamewayaccumulatingevidenceimplicatesoxidative
stressasanimportantunderlyingcauseofcerebralendothelialdysfunction.Inthedevelopmentand
progressionofchronichighBP,hypertensivecerebralvasculopathyoccursintheformofreparative
changesandadaptiveprocessesatallstructuralandfunctionallevelsofthecerebralvascularsystem.
Chronicintraluminalpressurestimulatesthegrowthofsmoothmusclecellsandenhancedmediathickness
inresistancearteriesthatresultsinhypertrophicremodelling.Alternatively,inwardremodellingmayoccur,
leadingtoeutrophicremodelling.Hypertensioncausesmarkedadaptivechangesinthecerebralcirculation,
includingincreasedbrainvascularresistanceandlossofthephysiologicalmechanismofautoregulation.
Thus,hypertensioninfluencestheautoregulationofcerebralbloodflowbyshiftingboththelowerand
upperlimitsofautoregulatorycapacitytowardshigherbloodpressure,whilehypertensivepatientsmaybe
especiallyvulnerabletoepisodesofhypotension,whichmayplayaroleinthedevelopmentofsilent
cerebrovasculardamagesuchasWML[8].Increasedcerebralvascularresistancecouldbedueto
narrowingofsmallvesselsbylipohyalinosisandmicroatherosclerosis.Afamilyhistoryofcerebrovascular
diseaseandstrokeisoftenperceivedasariskfactorforstroke[9].TheFraminghamHeartStudyfounda
positiveassociationbetweenaverifiedpaternalormaternalhistoryofstrokeandanincreasedriskofstroke
inoffspring.Theinheritanceiscomplex,multigenic,andheterogeneous.Associationswithpolymorphisms
havebeeninvestigatedinavarietyofcandidategenes,includinghaemostaticgenes,genescontrolling
homocysteinemetabolismandlipidmetabolism,theangiotensinconvertingenzyme(ACE)gene,andthe
endothelialnitricoxidesynthasegene,withconflictingresults,whichmayreflectmethodological
difficultiessincemanystudiesweresmallandunderpoweredorrequiredcarefulcasecontrolmatching.
RelationshipbetweenhighbloodpressureandstrokeriskHypertensionrepresentsarelativeriskofstroke
upto6timeshigher,whilestrokeisthemostfrequentcomplicationinhypertensives[10].InWestern
countries,ischaemicstrokeaccountsforapproximately80%ofallstrokesandhaemorrhagicstrokeforthe
remaining20%.Incidencerates,commonlyquotedat2per1000population,risesteeplyfromlessthan1
per1000amongpeopleagedunder45,tomorethan15per1000amongthoseaged85ormore,butvary
widely.Inindustrializedcountries,approximately75%ofallstrokesoccurinpeopleagedover65years.
Around80%ofpeoplesurvivethefirstfourweeksfollowingstrokeand70%surviveforayearormore.
OverviewsoflargescaleobservationalstudieshavedemonstratedthatusuallevelsofBParepositivelyand
continuouslyassociatedwiththeriskofstrokeinaloglinearfashion[2].ThisrelationshipbetweenBPand
strokeholdsoverawideBPrange,fromsystoliclevelsaslowas115mmHganddiastoliclevelsaslowas
70mmHg[2].DatafromprospectiveobservationalstudiesindicatethatusuallevelsofBParedirectlyand
continuouslyrelatedtotheriskofinitialstroke,andaprolongeddifferenceinusualBPlevelsofjust9/5
mmHgisassociatedwithanapproximatelyonethirddifferenceinstrokerisk,withsimilarproportional
effectsinhypertensivesandnormotensives[2,3].Each56mmHgreductioninusualdiastolicBPis
associatedwitha38%lowerriskofstroke[3].ElevatedBPispositivelyassociatedwithbothischaemic
andhaemorrhagicstroke,buttheassociationappearstobesteeperforhaemorrhagicstroke.The
relationshipbetweenBPandstrokeriskremainsvirtuallyunchangedafteradjustmentforserumcholesterol
levels,smoking,alcohol,orahistoryofpreviouscardiovasculardisease[11].Similarassociationsappearto
existbetweenBPandtheriskofrecurrentstrokealthoughthereislessevidence.DatafromtheUnited
KingdomTransientIschaemicAttack(UKTIA)CollaborativeGroupshowedthata10mmHgreductionin
usualsystolicBPwasassociatedwitha28%reductionintheriskofrecurrentstroke[4].Althougha
continuousrelationshipbetweenbothsystolicanddiastolicBPandtheoccurrenceofstrokehasbeenwell
established,thereisepidemiologicalevidencefromtheMRFITstudythatthesystoliccomponentofBP
mayexertastrongdeleteriouseffectoncerebrovasculardisease[11].Itisknownthatincreasedarterial
stiffnessresultsinincreasedcharacteristicimpedanceoftheaortaandincreasedpulsewavevelocity,which
increasesystolicandpulsepressures.Largearterystiffnessisthemaindeterminantofpulsepressure.Data
fromtheSHEPstudyshowan11%increaseinstrokeriskanda16%increaseintheriskofallcause
mortalityforeach10mmHgincreaseinpulsepressure[12].Laurentetal.[13],inalongitudinalstudy,
foundthataorticstiffness,assessedbycarotidfemoralpulsewavevelocity,isanindependentpredictorof
fatalstrokeinpatientswithessentialhypertension.Antihypertensivetherapyandprimarypreventionof
strokeItisgenerallybelievedthatanyofthecommonlyusedantihypertensivedrugsareeffectivein
loweringtheincidenceofstroke,withlargerreductionsinBPresultinginlargerriskreductions.As
mentionedearlier,inareviewof17randomizedtrialsofantihypertensivetreatment,anetBPreductionof
1012mmHgsystolicand56mmHgdiastolicconferredareductioninstrokeincidenceof38%(SD4),
withsimilarreductionsinfatalandnonfatalstroke[14].Becausetheproportionaleffectsoftreatmentwere
similarinhigherandHYPERTENSIONANDSTROKECristinaSierra,AntonioCocaHypertensionUnit,
DepartmentofInternalMedicine,InstituteofMedicineandDermatology,HospitalClinic(IDIBAPS),
UniversityofBarcelona,Barcelona,Spain2011;12:No.39revisedversionTable1.Mechanismsthat
increasetheriskofcerebrovasculardiseaseOxidativestressandendothelialdysfunctionLowgrade
inflammationIncreasedarterialstiffness(synthesisofcollagenandfibronectin)Upregulationofrenin
angiotensinsystemImpairedendothelialprogenitorcellfunctionIncreasedvascularpermeability
Remodellingofresistancearteries(reducedlumen,reducedcerebralbloodflow,increasedvascular
resistance)Contractionofsmoothmusclevascularvessels(reducedcerebralbloodflow,increasedvascular
resistance)SmallvesseldiseaseCerebralamyloidangiopathy78References1.DiCarloA.Humanand
economicburdenofstroke.AgeAgeing2009;38:45.2.InternationalSocietyofHypertensionWriting
Group;InternationalSocietyofHypertension(ISH).Statementonbloodpressureloweringandstroke
prevention.JHypertens2003;21:651663.3.CollinsR,PetoR,MacMahonS,etal.BloodPressure,
stroke,andcoronaryheartdisease.Part2:Shorttermreductionsinbloodpressure.Overviewof
randomiseddrugtrialsintheirepidemiologicalcontext.Lancet1990;355:827838.4.RodgersA,
MacMahonS,GambleG,etal.Bloodpressureandriskofstrokeinpatientswithcerebrovasculardisease:
theUnitedKingdomTransientIschaemicAttackCollaborativeGroup.BMJ1996;313:147150.5.Furie
KL,KasnerSE,AdamsRJ,etal.Guidelinesforthepreventionofstrokeinpatientswithstrokeortransient
ischemicattack.AGuidelineforhealthcareprofessionalsfromtheAmericanHeartAssociation/American
StrokeAssociation.Stroke2011;42:227276.6.SierraC,CocaA,SchiffrinEL.Vascularmechanismsin
thepathogenesisofstroke.CurrHypertensRep2011;13:200207.7.DebetteS,BeiserA,DeCarliC,et
al.AssociationofMRImarkersofvascularbraininjurywithincidentstroke,mildcognitiveimpairment,
dementia,andmortality.TheFraminghamOffspringstudy.Stroke2010;41:600606.8.PantoniL.
Cerebralsmallvesseldisease:frompathogenesisandclinicalcharacteristicstotherapeuticchallenges.
LancetNeurol2010;9:689701.9.HassanA,MarkusHS.Geneticsandischaemicstroke.Brain2000;23:
17841812.10.KjeldsenSE,JuliusS,HednerT,HanssonL.Strokeismorecommonthanmyocardial
infarctioninhypertension:analysisbasedon11majorrandomizedinterventiontrials.BloodPress2001;
10:190192.11.StamlerJ,StamlerR,NeatonJD.Bloodpressure,systolicanddiastolic,and
cardiovascularrisks.ArchInternMed1993;153:598615.12.DomanskiMJ,DavisBR,PfefferMA,
KastantinM,MitchellGF.IsolatedSystolicHypertension.Prognosticinformationprovidedbypulse
pressure.Hypertension1999;34:375380.13.LaurentS,KatsahianS,FassotC,etal.Aorticstiffnessis
anindependentpredictoroffatalstrokeinessentialhypertension.Stroke2003;34:12031206.14.
MacMahonS.Bloodpressureandthepreventionofstroke.JHypertens1996;14:S39S46.15.Blood
PressureLoweringTreatmentTrialistsCollaboration.EffectsofACEinhibitors,calciumantagonists,and
otherbloodpressureloweringdrugs:resultsofprospectivelydesignedoverviewsofrandomisedtrials.
Lancet2000;355;19551964.16.BloodPressureLoweringTreatmentTrialistsCollaboration.Effectsof
differentregimenstolowerbloodpressureonmajorcardiovasculareventsinolderandyoungeradults:
metaanalysisofrandomisedtrials.BMJ2008;336:11211123.17.BeckettNS,PetersR,FletcherAE,et
al.Treatmentofhypertensioninpatients80yearsofageorolder.NEnglJMed2008;358:112.18.
AngeliF,GentileG,ReboldiG,VerdecchiaP.Angiotensinconvertingenzymeinhibitors,angiotensin
receptorblockersandprotectionfromstroke.ExpertRevCardiovascTher2008;6:11711174.19.Mancia
G,DeBackerG,DominiczakA,etal.2007ESHESCPracticeGuidelinesfortheManagementofArterial
Hypertension:ESHESCTaskForceontheManagementofArterialHypertension.JHypertens2007;25:
17511762.20.MorgensternLB,HemphillJC3rd,AndersonC,etal.Guidelinesforthemanagementof
spontaneousintracerebralhemorrhage:aguidelineforhealthcareprofessionalsfromtheAmericanHeart
Association/AmericanStrokeAssociation.Stroke2010;41:21082129.21.TheEuropeanStroke
Organization(ESO)ExecutiveCommitteeandtheESOWritingCommittee.Guidelinesformanagementof
ischaemicstrokeandtransientischaemicattack2008.CerebrovascDis2008;25:457507.22.RashidP,
LeonardiBeeJ,BathP.Bloodpressurereductionandsecondarypreventionofstrokeandothervascular
events:asystematicreview.Stroke2003;34:27412748.23.SchraderJ,LdersS,KulchewskiA,etal.
Morbidityandmortalityafterstroke,eprosartancomparedwithnitrendipineforsecondaryprevention.
Principalresultsofaprospectiverandomizedcontrolledstudy(MOSES).Stroke2005;36:12181224.24.
YusufS,DienerHC,SaccoRL,etal.PRoFESSStudyGroup.Telmisartantopreventrecurrentstrokeand
cardiovascularevents.NEnglJMed2008;359:1225237.25.ManciaG,LaurentS,AgabitiRoseiE,et
al.ReappraisalofEuropeanguidelinesonhypertensionmanagement:aEuropeanSocietyofHypertension
TaskForcedocument.JHypertens2009;27:21212158.26.PROGRESSCollaborativeGroup.
Randomisedtrialofaperindoprilbasedbloodpressureloweringregimenamong6105individualswith
previousstrokeortransientischaemicattack.Lancet2001;358:10331041.lowerriskpatientgroups,the
absoluteeffectsoftreatmentonstrokevariedindirectproportiontothebackgroundriskofstroke.The
greatestpotentialbenefitswereobservedamongthosewithahistoryofcerebrovasculardisease.Inthe
overviewsofrandomisedtrialsperformedbytheBloodPressureLoweringTreatmentTrialists
Collaboration(BPLTTC)[15]in2000,thedatashowedthatplacebocontrolledtrialsofcalcium
antagonistsreducedtheriskofstrokeby39%(95%CI:1556)andthatplacebocontrolledtrialsofACE
inhibitorsreducedtheriskofstrokeby30%(95%CI:1543),withoutsignificantdifferencesbetween
thesegroupsofregimens.Moreintensivetherapywasassociatedwitha20%strokeriskreduction(95%
CI:235)comparedwithnormalBPreduction.ThedifferencesinBPbetweenthetwoBPlowering
strategies(normalversusintensive)wereonly3mmHg.Inthesamelinewasthelastreviewofthe
BPLTTCin2008(190,606individualsincludedfrom31clinicaltrials)[16].Inthisreview,reductionof
BPproducedbenefitsinyounger(< 65 years) and older ( 65 years) adults, with
reductioninbloodpressure.Atthevascularlevel,increasedsodiumintakehasbeenreportedtoinduce
pronouncedstructuralalterationsofarteries,suchascerebralorrenalarteries,independentlyofBPlevels
[12,13].Throughchangesinshearstressandendothelialfunction,highsodiumintakecaninducepressure
independenteffectsonthevascularwall,affectingthevascularcontentofcollagenandelastinfibres.
Clinically,thereisalsoevidencethatsaltaffectsarterialstiffnessandhencesystolicandpulsepressure.In
aChinesestudy,theageassociatedincreaseinpulsewavevelocitywaslowerinthecommunitywitha
lowersaltintake[13].Interestingly,saltconsumptionwasdoubleintheurbanChinesepopulationthanin
theruralpopulation,andtheagerelatedchangesinsystolicBPandaorticstiffnessoccurred30yearsof
agelaterintheruralthanintheurbancommunity.Areductionindietarysaltintakereducedpulsepressure,
suggestinganimprovementinarterialdistensibility[14].Experimentally,alowsodiumdietpreventsrenal
alterationsinseveralmodelsofhypertensionandrenaldiseases.Inratmodelsofhypertensionandreduced
renalmass,saltrestrictionpreventsanincreaseinproteinuria,compensatorykidneygrowth,and
glomerulosclerosis[15].Similarly,indiabeticanimals,longtermsaltrestrictionattenuatestheprogressive
riseinalbuminuriaandthedevelopmentofrenalhypertrophy.Alowsodiumintakemayalsoinducerenal
protectionbyreducingglomerularhyperfiltration[16].Inhumans,thelongtermbenefitsofalowsodium
intakeontheprogressionofnondiabeticordiabeticnephropathiesarelesswelldocumented.However,in
aretrospectiveanalysisofchronickidneydiseaseprogression,therateofdeclineincreatinineclearance
overa43monthperiodwastwofoldgreaterinpatientsonahighsodiumintake(>200mmol/day)when
comparedtopatientsonalowsodiumintake(<100mmol/day)[17].Severalshorttermstudieshave
shownthatahighsodiumintakeincreasesglomerularfiltrationandmayhaveadetrimentaleffecton
glomerularhaemodynamics,asreflectedbyanincreaseinfiltrationfractionandhenceinintraglomerular
pressure.Themostsignificantimpactofdietarysaltintakeonrenalfunctioniscertainlyitseffecton
urinaryalbuminexcretion.InacrosssectionalstudyincludinguntreatedsubjectswithawiderangeofBP
levels,theprevalenceofmicroalbuminuriawasmarkedlyhigherinsubjectswithasodiumintakehigher
than12g/day[18].ThisfindingiscorroboratedbytheresultsoftheGroningenpopulationbasedstudy
including7850subjects,inwhichaninteractionbetweensodiumintakeandobesityontheprevalenceof
microalbuminuriawasfound[19].Loweringsaltintakeinproteinuricpatientsisassociatedwitha
significantreductioninurinaryproteinexcretion,andsaltrestrictionincreasestheantiproteinuriceffectof
blockersofthereninangiotensinsystem,aneffectthatcanbemimickedbytheadministrationofathiazide
diureticincombinationwithanRASblocker.Dietarysaltintakeandtheincidenceofcardiovascularevents
Severalprospectiveobservationalstudieshaveanalysedtheassociationofdietarysodiumintakeandall
causemortality.Tuomilehtoetal.reportedthatdietarysodiumintakeisassociatedwitha32%increasein
allcausemortalityinmen,buttheassociationwasonlyobservedinoverweightmen[20].Otherstudies
[21]foundapositiveassociationbetweendietarysodiumintakeandcardiovascularmortality,inparticular
inoverweightsubjects,whereasotherstudiesfoundnosuchassociation.IntheScottishHeartHealth
Study,apositiveassociationbetweendietarysodiumintakeandcoronarydeathwasfoundinwomenbut
notinmen[22].IntheNHANESIfollowupstudy,anegativeassociationwasfoundbetweendietarysalt
intakeandcardiovascularmortality,buttheassociationwaspositivewhensodiumexcretionwascorrected
forcalorieintake[23].Inarecentpopulationstudyinvolvingratheryoungsubjects,Staessenetal.founda
higherincidenceofcardiovascularmortalityamongsubjectswiththelowestsodiumexcretion.This
surprisingfindingdeservesfurtherconfirmationinanelderlygroupofsubjectsmorelikelytobesalt
sensitivethanyoungnormotensiveCaucasianswithalowincidenceofcardiovascularcomplications[24].
Severalprospectivestudieshaveexaminedtheassociationofdietarysodiumintakeandtheriskofstroke.
Thedatagatheredsofarareinconsistent.However,basedonthechangesinbloodpressurefromthemeta
analysisofrandomizedsaltreductiontrialsandtherelationshipbetweenBPandstrokeandischaemic
heartdisease,ithasbeenestimatedthata3g/dayreductionofdietarysaltintakewouldreducestrokeby
13%andischaemicheartdiseaseby10%[25].DIETARYSODIUMINTAKEANDHYPERTENSION
MichelBurnier1,MurielleBochud2,RolandSchmieder31ServiceofNephrologyandHypertension
Consultation,UniversityofLausanne,Switzerland2InstituteofSocialandPreventiveMedicine,
UniversityofLausanne,Switzerland3DepartmentofNephrologyandHypertension,FriedrichAlexander
UniversityErlangenNrnberg,UniversityHospital,Erlangen,Germany2011;12:No.40revisedversion
80References1.LawesCM,VanderHS,RodgersA.Globalburdenofbloodpressurerelateddisease,
2001.Lancet2008;371:15131518.2.DentonD,WeisingerR,MundyNI,etal.Theeffectofincreased
saltintakeonbloodpressureofchimpanzees.NatMed1995;1:10091016.3.ElliottP,WalkerLL,Little
MP,etal.Changeinsaltintakeaffectsbloodpressureofchimpanzees:implicationsforhumanpopulations.
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Group.BMJ1988;297:319328.5.FrostCD,LawMR,WaldNJ.Byhowmuchdoesdietarysalt
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Analysisofdatafromtrialsofsaltreduction.BMJ1991;302:819824.7.KhawKT,BinghamS,Welch
A,etal.Bloodpressureandurinarysodiuminmenandwomen:theNorfolkCohortoftheEuropean
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VerdecchiaP,PorcellatiC,ReboldiG,etal.Leftventricularhypertrophyasanindependentpredictorof
acutecerebrovasculareventsinessentialhypertension.Circulation2001;104:20392044.9.BurnierM,
PhanO,WangQ.Highsaltintake:acauseofbloodpressureindependentleftventricularhypertrophy?
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BD.Dietarysaltintake.Adeterminantofcardiacinvolvementinessentialhypertension.Circulation1988;
78:951956.11.DanielsSD,MeyerRA,LoggieJM.Determinantsofcardiacinvolvementinchildrenand
adolescentswithessentialhypertension.Circulation1990;82:12431248.12.TobianL.Saltand
hypertension:lessonsfromanimalmodelsthatrelatetohumanhypertension.Hypertension1991;17(Suppl
I):I52I58.13.AvolioAP,DengFQ,LiWQ,etal.Effectsofagingonarterialdistensibilityinpopulations
withhighandlowprevalenceofhypertension:comparisonbetweenurbanandruralcommunitiesinChina.
Circulation1985;71:202210.14.GatesPE,TanakaH,HiattWR,SealsDR.Dietarysodiumrestriction
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2004;44:3541.15.LaxDS,BensteinJA,TolbertE,etal.Effectsofsaltrestrictiononrenalgrowthand
glomerularinjuryinratswithremnantkidneys.KidneyInt1992;41:15271534.16.BankN,LahorraG,
AynedjianHS,etal.Sodiumrestrictioncorrectshyperfiltrationofdiabetes.AmJPhysiol1988;254:F668
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MimranA.Dietarysodiumandtargetorgandamageinessentialhypertension.AmJHypertens2002;15:
222229.19.VerhaveJC,HillegeHL,BurgerhofJG,etal.Sodiumintakeaffectsurinaryalbumin
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P,RastenyteD,etal.UrinarysodiumexcretionandcardiovascularmortalityinFinland:aprospective
study.Lancet2001;357:848851.21.HeJ,OgdenLG,VupputuriS,etal.Dietarysodiumintakeand
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PedoeH,WoodwardM,TavendaleR,ABrookR,McCluskeyMK.Comparisonofthepredictionby27
differentfactorsofcoronaryheartdiseaseanddeathinmenandwomenoftheScottishHeartHealthStudy:
cohortstudy.BMJ1997;315:722729.23.AldermanMH,CohenH,MadhavanS.Dietarysodiumintake
andmortality:theNationalHealthandNutritionExaminationSurvey(NHANESI).Lancet1998;351:
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10931099.25.StolarzSkrzypekK,KuznetsovaT,ThijsL,etal;EuropeanProjectonGenesin
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pressurechangesinrelationtourinarysodiumexcretion.JAMA2011;305:1777178526.HeFJ,
MacGregorGA.Effectofmodestsaltreductiononbloodpressure:ametaanalysisofrandomizedtrials.
Implicationsforpublichealth.JHumHypertens2002;16:761770.27.PimentaE,GaddamKK,OparilS,
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Group.JAMA1998;279:839846.29.Theeffectsofnonpharmacologicinterventionsonbloodpressure
ofpersonswithhighnormallevels.ResultsoftheTrialsofHypertensionPrevention,PhaseI.JAMA1992;
267:12131220.30.Effectsofweightlossandsodiumreductioninterventiononbloodpressureand
hypertensionincidenceinoverweightpeoplewithhighnormalbloodpressure.TheTrialsofHypertension
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Med1997;157:657667.31.SacksFM,SvetkeyLP,VollmerWM,etal.Effectsonbloodpressureof
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pressureinnondiabeticpeopleinChina:adietaryinterventionstudy.Lancet2009;373:829835.
InterventionstolowerdietarysaltintakereduceBPandcardiovasculareventsNumerousinterventional
studieshavebeenconductedtoinvestigatetheclinicalimpactofloweringdietarysodiumintakeonBP.
Severalofthemwerelimitedeitherbytheshortdurationoftheinterventionorbytheverysmallor
excessivechangesinsodiumintakeobtainedduringthestudy.Thelastmetaanalysisofrandomized
studies,whichtookintoaccountonlystudieswithadurationofatleastonemonthandmodestreductions
ofsodiumintakethatcanbeachievedindailylifepractice(mean4.44.6gofsalt/day),demonstratedthat
areductioninsaltintakeisassociatedwithasignificantdecreaseinBP,bothinnormotensiveand
hypertensiveindividuals[26].Arecentstudyhasalsodemonstratedthebenefitsofreducingsaltintakein
patientswithresistanthypertension[27].Severallargeclinicaltrialshaveinvestigatedtheimpactof
loweringsaltintakealoneorinassociationwithotherdietaryornonpharmacologicalinterventionson
bloodpressureandcardiovascularevents.Thetrialofnonpharmacologicinterventionsintheelderly
(TONE)[28]implementedweightlossand/orsodiumreductioninobesepatientsorsodiumreductionin
nonobesehypertensivesubjectsaged6080yearstreatedwithoneantihypertensivedrug.Thegoalwas
toobtainandmaintainaurinarysodiumexcretionoflessthan80mmol/24h(<4.7gsalt/24h)inaddition
toaweightlossofatleast4.5kg.Ausualcaregroupwascomparedtoanactiveinterventiongroup.The
combinedoutcomemeasures(incidenthypertensionand/orcardiovascularevents)werelessfrequent
amongthoseassignedcomparedwiththosenotassignedtoreducedsodiumintake(relativehazardratio
0.69).Relativetousualcare,hazardratiosamongtheobeseparticipantswere0.60forreducedsodium
intakealone,0.64forweightlossalone,and0.47forreducedsodiumintakeandweightlosscombinedafter
amedianfollowupof29months.IntheTrialofHypertensionPreventionI(TOHPI),multiplelifestyle
changeswerecomparedinparallel,includingdietarysodiumreductionandweightreduction[29].The
targetpopulationwerehealthymenandwomenagedbetween30and54years,withhighnormaldiastolic
bloodpressure,whowerenottakingantihypertensivetreatment.Asignificant55mmolreductionin
urinarysodiumexcretionwasachievedinthesodiumreductiongroup,butnotinthecontrolgroupat18
months.SystolicanddiastolicBPsweresignificantlyreducedintheactivegroupversusthecontrolgroup
forthesodiumreductionandweightlossinterventions.Inthesodiumreductiongroup,therewasanon
significant16%reductionintheincidenceofhypertension(RR:0.84,95%CI:0.621.13),whereasinthe
weightlossgroup,therewasasignificant36%reductionintheincidenceofhypertension(RR:0.66,95%
CI:0.460.94).TheaimoftheTrialofHypertensionPreventionII(TOHPII)(22factorialrandomized,
openmulticentretrial)wastodeterminewhetherweightlossalone,dietarysodiumreductionalone,ora
combinationofbothinterventionscouldlowerBPandreducetheincidenceofhypertensioninsubjects
withhighnormalBP[30].ParticipantsinthistrialhadhighnormaldiastolicBP(8389mmHg)with
systolicBP<140mmHg.Bloodpressurewassignificantlylowerintheinterventiongroupsineachtime
period.Thesizeableeffectsobservedat6monthsgreatlydiminishedduringfollowup,indicatingthatlong
terminterventionsforsodiumreductionaredifficulttomaintain.At48monthsoffollowup,theincidence
ofhypertensionwassignificantlylowerineveryinterventiongroupascomparedtotheusualcaregroup.
Theresultsofthelongtermfollowup(1015years)ofpatientsenrolledintheTHOP1andTHOPIItrials
showedanonsignificant20%lowerallcausemortalityinthegroupofsubjectsassignedtothesodium
restrictioninterventionbutasignificant30%lowerincidenceofcardiovasculardisease(definedas
myocardialinfarction,stroke,coronaryarterybypassgraft,coronaryangioplasty,ordeathofany
cardiovascularcause)ascomparedtopersonsinthecontrolgroups.TheDASHstudyisalandmarktrial
whichcomparedacontroldietwithadietrichinfruit,vegetables,andlowfatdairyproducts(i.e.DASH
diet).TheDASHdietsignificantlyreducedbloodpressureat1month.InthesubsequentDASHsodium
trial,threedifferentdietarysodiumintakeswerecompared,150,100,and50mmol/24h,whichcorrespond
toapproximately8.8,5.8,and2.9gofsaltperday,respectively,withandwithoutDASHdiet[31].Blood
pressurewassignificantlylowerwhengoingtoalowergroupofdietarysaltintakeinboththecontroldiet
andtheDASHdietgroups.TheresultsoflowsodiumDASHdiettrialfurtherstrengthentheconclusion
thatreductionofdietarysodiumintakethroughlowsaltdietlowersBPeffectivelyandaddstothebenefits
conferredbytheDASHdiet.Morerecently,alargeinterventionalstudywasconductedtoexaminethe
associationbetweenmetabolicsyndromeandsaltsensitivity,definedastheBPresponsetolow(50
mmol/day)andhigh(300mmol/day)saltintake[32].Theresultsofthisstudyperformedinnondiabetic
ChinesesubjectsrevealedthatthepresenceofmetabolicsyndromeincreasestheBPresponsetosaltintake.
Hence,sodiumrestrictioncouldbeanimportantcomponentinthestrategytolowerBPinsubjectswith
metabolicsyndrome.ConclusionsNonpharmacologicaldietaryinterventionspromotinglowsaltintake
shouldbemoresystematicallyconsideredinthepreventionandmanagementofessentialhypertensionand
preventionofhypertensivetargetorgandamage.Althoughtheseapproachesareconsidereddifficultto
implementandsustainoveranumberofyearsinmostsubjects,theyprovideuniquecosteffective
opportunitiestoavoiddrugtreatmentintheearlystagesofhypertensionandtoreducedrugtherapiesin
patientswithestablishedhypertension.Inviewofthedifficultyinachievinglongtermchangesindietary
habitsattheindividuallevel,nationwideinterventionsaimedatreducingthesodiumcontentofprocessed
foodsmayprovidesubstantialhealthbenefitstothegeneralpopulationandalsotohypertensivepatients.
EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement81
IntroductionAsearlyasthe19thcenturyretinalabnormalitiesinhypertensivesubjectsweredescribedby
Liebreich[1]andGunn[2].Thetraditionalclassificationsystemofhypertensiveretinopathygoesbackto
thepioneeringworkbyKeith,Wagner,andBarkerin1939,inwhichtheydemonstratedtheprognostic
significanceoffunduscopicabnormalitiesinhypertensivepatients[3].Theimpactoffunduscopicfindings
onriskstratificationwassoonsupportedbyseveralstudiesthatwereconductedinthe1950sand1960s[4,
5]Nowadays,funduscopystillplaysamajorroleinthemanagementandriskstratificationofhypertensive
patients:TheESH/ESC2007guidelineconsidershypertensiveretinopathygrade3and4astargetorgan
damage[6].PathophysiologyandclinicalmanifestationsRetinalcirculationundergoesaseriesof
pathophysiologicalchangesinhypertension[7].Thesechangesaremediatedeitherdirectlybyelevated
bloodpressureorindirectlyviavasoactivesubstances(angiotensinII,endothelin1,decreasedbasalnitric
oxideactivity,amongothers).Mildchangesarereflectedbyvasoconstriction(generalizedandfocal
arteriolarnarrowing),growthofsmoothmusclecells,andhyalinedegenerationofthewallofretinal
arterioles(opacificationofarteriolarwallswithwideningandaccentuationofthecentrallightreflex,also
describedassilverorcopperwiring)aswellaschangesinthearteriolarandvenularjunctions
(arteriovenousnicking).Advancedchangesincludebreakdownofthebloodretinabarrieroftheretinal
arterioles(haemorrhages,hardexudatesandcottonwoolspots),microandmacroaneurysms,branchvein
occlusions,andopticdiscswelling(papilloedema).ClassificationIntheirfamousworkin1939Keith,
Wagener,andBarkercategorizedthesignsofhypertensiveretinopathyinto4gradesofincreasingseverity
(Table1)anddemonstratedthatatthattimehypertensivepatientswithhypertensiveretinopathygrade4
hada3yearsurvivalrateof6%versushypertensivepatientswithgrade1signswhohada3yearsurvival
rateof70%[3].TheusefulnessofthefourgradeclassificationsystemofKeith,Wagener,andBarkerand
thefivestageclassificationofScheie[8]anditsimportanceincurrentclinicalpracticehasbeenquestioned
repeatedlyinrecentyears[9,10].Criticismrefersespeciallytohypertensiveretinopathygrades1and2.
Lowretinopathygrades(grade1andgrade2signs)cannoteasilybeendistinguishedevenbyexperienced
investigatorsandreveallowinterandintraobservervariability[11,12].Onlyadvancedhypertensive
retinopathygradescanbereliablyassessed.However,nowadaysmosthypertensivepatientsreveallow
retinopathygrades(e.g.generalizedretinalarteriolarnarrowing)whereasveryfewpatientshaveadvanced
hypertensiveretinopathy.Moreover,retinopathysignsdonotnecessarilycorrelatewiththeseverityof
hypertension,andthepositiveandnegativepredictivevaluesfortheassociationbetweenhypertensive
retinopathyandbloodpressurearelow[6,12].PrognosticsignificanceRecentstudiesevaluatingfundus
findingsandtheirrelationtosystemicdisease,suchastheBlueMountainsEyeStudy,theAtherosclerosis
RiskinCommunities(ARIC)Study,theMultiEthnicStudyofAtherosclerosis,andtheBeaverDamEye
Study,havedemonstratedthevalueoffundusfindingsandtheirassociationwiththeriskofhypertension
andassociatedcomorbidities[9,13].Thereissolidevidencethatadvancedhypertensiveretinopathysigns,
suchasisolatedmicroaneurysms,haemorrhages,hardexudates,andcottonwoolspots,arestrongly
associatedwithsubclinicalcerebrovasculardiseaseandpredictincidentclinicalstroke,coronaryartery
disease,congestiveheartfailure,andcardiovascularmortality,independentlyofbloodpressureandother
traditionalriskfactors[9,10].Incontrast,theimpactofmildhypertensiveretinopathysigns,suchas
generalizedandfocalarteriolarnarrowingandarteriovenousnicking,onsystemicvasculardiseaseand
cardiovascularmortalityislessstringent[9,10].Asaconsequence,anewclassificationofhypertensive
retinopathyhasbeenposited(Table2)[9].RecentapproachesinimagingtechnologiesInparalleltothe
repeatedcriticismconcerningthetraditionalclassificationsystemstocurrentmanagementofhypertensive
patients,newmethodologicalapproacheshavebeendevelopedfocusingonmorepreciselyandreliably
assessingearlyretinalarteriolarabnormalitiesinhypertensivepatients,aimingtoimprovethediagnostic
andprognosticpowerofmildhypertensiveretinopathy[10,13].Arterioletovenuleratioofretinalvessels
Theabilitytodigitizeretinalphotographsallowedtheassessmentofouterarteriolarandoutervenule
diameterofretinalvesselsandsubsequentcalculationofthearterioletovenuleratio[14].The
measurementofthearterioletovenuleratioofretinalvesselsisbasedontheconceptthatalowerarteriole
tovenuleratioofretinalvesselsreflectsgeneralarteriolarnarrowing,whichrepresentsanearlystepof
hypertensionrelatingtoretinalvascularalterations.Some,butnotall,largepopulationbasedstudies
identifiedthearterioletovenuleratiotobepredictiveofcardiovascularevents[9,15].However,nostudy
thusfarhasrevealedthatthearterioletovenuleratioofretinalvesselshasaclearlyindependentvalueof
predictingcardiovascularortotalmortality[9,15].Recentdataindicatethattheoutervenulediameteralso
changesinseveralmetabolicconditionsthatarefrequentlyassociatedwithhypertension[16],whichmay
dilatetheprognosticpowerofthearteriolevenuleratio.Thus,thelackofaprognosticroleofthe
arterioletovenuleratioofretinalvesselsisprobablyduetoconcomitantchangesinvenulediametersinthe
majorityofhypertensivepatientsandhasalsobeenfoundtobepredictthedevelopmentofhypertension.
WalltolumenratioofretinalarteriolesThedevelopmentofscanninglaserDopplerflowmetry(SLDF)
withautomaticfullfieldperfusionimaginganalysis(AFFPIA)nowallowsHYPERTENSIVE
RETINOPATHYRolandE.Schmieder,MDDepartmentofNephrologyandHypertension,Universityof
ErlangenNrnberg,Germany2011;12:No.41revisedversionTable1.KeithWagenerBarker
classification[3]ofhypertensiveretinopathyGrade1Grade2Grade3Grade4Arteriolarnarrowing+++
+++++++Arteriovenousnicking++++++Retinalhaemorrhages+++Microaneurysms+++Hard
exudates+++Cottonwoolspots+++Opticdiscswelling+Macularoedema+Table2.Classificationof
hypertensiveretinopathy[9]Grade1MildGeneralisedandfocalarteriolarnarrowing,retinopathyarteriolar
wallopacification,andarteriovenousnippingGrade2ModerateFlameshapedorblotshaped
haemorrhages,retinopathycottonwoolspots,hardexudates,microaneurysms,oracombinationofallof
thesefactorsGrade3SevereSomeoralloftheseretinopathysigns,retinopathyaswellasswellingofthe
opticdisc82References1.LiebreichR.OphthalmoskopischerBefundbeiMorbusBrightii.Albrechtvon
GraefesArchOphthalmol1859;5:265268.2.GunnRM.Ophthalmoscopicevidenceof(1)arterial
changeswithchronicrenaldiseasesand(2)ofincreasedarterialtension.TransOphthalmolSocUK1892;
12:124125.3.KeithNM,WagenerHP,BarkerNW.Somedifferenttypesofessentialhypertension:their
courseandprognosis.AmJMedSci1939;197:332343.4.BreslinDJ,GiffordRW,Jr.,FairbairnJF,2nd,
KearnsTP.Prognosticimportanceofophthalmoscopicfindingsinessentialhypertension.JAMA1966;
195:335338.5.FrantR,GroenJ.Prognosisofvascularhypertension;a9yearfollowupstudyof418
cases.ArchInternMed(Chic)1950;85:727750.6.ManciaG,DeBackerG,DominiczakA,etal.2007
GuidelinesfortheManagementofArterialHypertension:TheTaskForcefortheManagementofArterial
HypertensionoftheEuropeanSocietyofHypertension(ESH)andoftheEuropeanSocietyofCardiology
(ESC).JHypertens2007;25:11051187.7.TsoMO,JampolLM.Pathophysiologyofhypertensive
retinopathy.Ophthalmology1982;89:11321145.8.ScheieHG.Evaluationofophthalmoscopicchanges
ofhypertensionandarteriolarsclerosis.AMAArchOphthalmol1953;49:117138.9.WongTY,Mitchell
P.Hypertensiveretinopathy.NEnglJMed2004;351:23102317.10.SchmiederRE.Hypertensive
retinopathy:Awindowtovascularremodelinginarterialhypertension.Hypertension2008;51:4344.11.
DimmittSB,WestJN,EamesSM,etal.Usefulnessofophthalmoscopyinmildtomoderatehypertension.
Lancet1989;1:11031106.12.vandenBornBJ,HulsmanCA,HoekstraJB,SchlingemannRO,van
MontfransGA.Valueofroutinefunduscopyinpatientswithhypertension:systematicreview.BMJ2005;
331:73.13.DellaCroceJT,VitaleAT.Hypertensionandtheeye.CurrOpinOphthalmol2008;19:493
498.14.HubbardLD,BrothersRJ,KingWN,etal.Methodsforevaluationofretinalmicrovascular
abnormalitiesassociatedwithhypertension/sclerosisintheAtherosclerosisRiskinCommunitiesStudy.
Ophthalmology1999;106:22692280.15.PortaM,GrossoA,VeglioF.Hypertensiveretinopathy:theres
morethanmeetstheeye.JHypertens2005;23:683696.16.NguyenTT,WongTY.Retinalvascular
manifestationsofmetabolicdisorders.TrendsEndocrinolMetab2006;17:262268.17.MichelsonG,
WelzenbachJ,PalI,HaraznyJ.Automaticfullfieldanalysisofperfusionimagesgainedbyscanninglaser
Dopplerflowmetry.BrJOphthalmol1998;82:12941300.18.HaraznyJM,RittM,BaleanuD,etal.
Increasedwall:lumenratioofretinalarteriolesinmalepatientswithahistoryofacerebrovascularevent.
Hypertension2007;50:623629.19.RittM,HaraznyJM,OttC,etal.Analysisofretinalarteriolar
structureinnevertreatedpatientswithessentialhypertension.JHypertens2008;26:14271434.20.Park
JB,SchiffrinEL.Smallarteryremodelingisthemostprevalent(earliest?)formoftargetorgandamagein
mildessentialhypertension.JHypertens2001;19:921930.21.HeagertyAM,AalkjaerC,BundSJ,
KorsgaardN,MulvanyMJ.Smallarterystructureinhypertension.Dualprocessesofremodelingand
growth.Hypertension1993;21:391397.22.IntenganHD,SchiffrinEL.Vascularremodelingin
hypertension:rolesofapoptosis,inflammation,andfibrosis.Hypertension2001;38:581587.23.Rizzoni
D,PorteriE,BoariGE,etal.Prognosticsignificanceofsmallarterystructureinhypertension.Circulation
2003;108:22302235.24.MathiassenON,BuusNH,SihmI,etal.Smallarterystructureisan
independentpredictorofcardiovasculareventsinessentialhypertension.JHypertens2007;25:10211026.
25.BaleanuD,RittM,HaraznyJ,etal.Walltolumenratioofretinalarteriolesandarterioletovenule
ratioofretinalvesselsinpatientswithcerebrovasculardamage.InvestOphthalmolVisSci2009;50:4351
4359.26.HaraznyJM,RaffU,WelzenbachJ,etal.Newsoftwareanalysesincreasethereliabilityof
measurementsofretinalarteriolesmorphologybyscanninglaserDopplerflowmetryinhumans.J
Hypertens2011;29:777782.preciseassessmentofretinalarteriolarstructureandremodellingby
analysingtheouterandinnerdiametersofretinalarteriolesandsubsequentassessmentofthewalltolumen
ratio,wallthickness,andwallcrosssectionalarea(volumeofvascularwallperunitlength)oftheretinal
arteriole,aspreviouslydescribedindetail[1719].Inbrief,theouterdiameteroftheretinalarterioleis
assessedinreflectionimages,andtheinnerdiameterisassessedinperfusionimages,andthewallto
lumenratioisthancalculatedaccordingtotheformula(outerdiameterinnerdiameter/innerdiameter)[17,
18](Figure1).TheassessmentofthewalltolumenratioofretinalarterioleswithSLDFwithAFFPIAwas
foundtobereliable[18,19].Studiesanalyzingarteriolarstructureofvesselsobtainedthroughbiopsiesof
subcutaneoustissuefromabdominalandglutealregionobservedthatremodellingofresistancearterioles
andsmallarteriespredictcardiovascularcomplications.Increasedwalltolumenratioofarterialvessels
indicatesanearly(probablytheearliest)formofhypertensionrelatedatheroscleroticvascularchanges
andisofprognosticsignificanceinhypertensivepatients,withadverseprognosisinthosewiththegreatest
walltolumenratio[20].Anincreaseinthewalltolumenratioofretinalvesselscanbetheresultofeither
vasoconstriction,growthofvascularsmoothmusclecells,orboth[21,22].Recentdatasuggestthatretinal
arteriolesandsubcutaneoussmallarteriolesundergothesametypeofremodellinginhypertension,andthe
patternandquantityofvascularchangesarecomparable[19].Thus,itisreasonabletohypothesizethat
assessmentofretinalarteriolarstructureandremodellingbyassessmentoftheretinalarteriolarwallto
lumenratiomayserveasapotentialfutureparameteroftargetorgandamageinhypertension.The
prognosticvalueofremodellingofthesmallarteriestakenfrombiopsieshasalreadybeenproven[23,24].
Untilnow,onlyafewstudieshaveexaminedretinalarteriolarstructureinhypertension.Inuntreated
patientswithstage1and2essentialhypertensionacloserelationbetweensystolicanddiastolicblood
pressureandwalltolumenratioofretinalarterioleswasfoundindependentlyfrompotentialconfounding
factors,includingclassicalcardiovascularriskfactors,urinaryalbuminexcretion,sodiumintake,andbasal
nitricoxideactivity[19].Moreover,thewalltolumenratioofretinalarterioleswasfoundtobegreaterin
patientswithessentialhypertensioncomparedtonormotensivecontrols[19].Hypertensivepatientswitha
historyofacerebrovasculareventrevealedagreaterwalltolumenratioofretinalarteriolesthan
hypertensiveandnormotensivecontrols[18].Treatedhypertensivesubjectswithpoorbloodpressure
controlwerefoundtohaveagreaterwalltolumenratioofretinalarteriolesthanthosewithgoodblood
pressurecontrol[18].Moreover,thewalltolumenratioofretinalarterioleswasfoundtobeassociated
withotherparametersoftargetorgandamageincludingintimamediathicknessofcarotidarteries[25]and
urinaryalbuminexcretion.Nostudythusfarhasbeenconductedtoevaluatetheprognosticvalueofthe
walltolumenratioofretinalarterioles,butitsreproducibilityhasbeenrecentlydemonstrated[26].
ConclusionsandprospectsThereissolidevidencethatmoderateorseverehypertensiveretinopathyisof
prognosticsignificanceforfuturecardiovascularevents.Noneoftheprospectivetrialshadadequately
correctedforconcurrentmeasuresofhypertensivetargetorgandamage.Newmethodologiesthatdetermine
hypertensiveretinalvascularchangesearlierandmorepreciselyareonthehorizonandmayserveastools
fordetectinghypertensiveretinopathy.Figure1.Assessmentofthewalltolumenratioofretinalarterioles
[19].Aspecificlengthofthearteriolereflectingoneheartbeat(onesystoleplusonediastole)isconsidered
foranalyses,anddiametersatevery10mofthisspecificlengtharemeasured.Outerdiameters(AD)are
measuredinreflectionimageandinnerdiameters(LD)aremeasuredinperfusionimage.Themeanofthe
measureddiametersisfinallycalculatedandtheaveragefrom3singularmeasurementsiscompletedfor
furtheranalysesEuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management83Whydiscussatrialfibrillationinhypertension?Atrialfibrillation(AF)isthemostcommon
clinicallysignificantsustainedcardiacarrhythmiaanditisassociatedwithincreasedriskofcardiovascular
morbidityandmortality.Itisadiseaseofaging,andtheprevalencedoubleswitheachdecadeafter50years
andapproaches10%inthosemorethan80yearsofage[1].Inmenandwomen,respectively,hypertensive
patientshavea1.4and1.5foldriskofdevelopingAF[1].Hypertensionisassociatedwithleftventricular
hypertrophy,impairedventricularfilling,slowingofatrialconductionvelocity,structuralchanges,and
enlargementoftheleftatria[2].Allthesechangesincardiacstructureandphysiologyfavourdevelopment
ofAF,andincreasetheriskofcomplications.Inthefollowing,wewillreviewpossiblemechanismsfor
increasedriskofAFinhypertensivesandlookintotheeffectofdifferentantihypertensivetreatment
regimens.Hypertensionisaprevalent,independent,andpotentiallymodifiableriskfactorforAF
development[1].Therelativerisk(RR)ofdevelopingAFinpatientswithhypertensionhasbeencalculated
tobe1.42.1,whichismodestcomparedto,forexample,heartfailureandvalvulardisease,whichhave
relativerisksofAFdevelopmentof6.117.5and2.28.3,respectively[2].However,duetothehigh
prevalenceofhypertensioninthepopulation,hypertensionaccountsformorecasesofAFthananyother
riskfactor[1].Increasedpulsepressurehasrecentlybeenrecognizedasapossible,evenmoreimportant,
riskfactor[3].IntheFraminghamdatabase,increasedsystolicpressurewasassociatedwithAF,butthe
associationwasevenstrongerwhenlowdiastolicpressurewithahigherpulsepressureeffectwasadded
intothestatisticalmodel[3].OtherknownriskfactorsforAFareleftventricularhypertrophy,leftatrial
size,heartfailure,valvular(inparticularmitralvalve)andischaemicheartdisease,heartrate,gender,
diabetesmellitus,hyperthyroidism,severeinfection,pulmonarypathology,stroke,obesity,alcoholabuse,
andsmoking[4].Recently,newriskfactorsforAF,suchassleepapnoea,excessivesportspractice,
inflammation,andgeneticinfluence,havealsobeenrecognized[5].LoneAFisdefinedasAFin
individualsyoungerthan60yearswithoutclinicalorechocardiographicevidenceofcardiopulmonary
disease,includinghypertension[6].Thesepatientshaveafavourableprognosiswithrespectto
thromboembolismandmortality[6].However,underlyinghypertensionoftenmaynotberecognizedin
thesepatientsdiagnosedwithloneAFduetoinadequatediagnosticinvestigations(e.g.no24hour
ambulatorybloodpressuremeasurement)ortreatmentwithbetablockersorcalciumchannelblockersfor
AF,whichalsohaveantihypertensiveeffects[5].Atrialfibrillationitselfproduceselectricalandstructural
remodellingoftheheart,andmaybeimportantfortherecurrenceorthemaintenanceoftheAF.
AngiotensinIIhasbeensuggestedasoneimportantmechanismfortheatrialremodelling,andblockersof
thereninangiotensinsystem(RAS),suchasangiotensinconvertingenzymeinhibitors(ACEIs)and
angiotensinIIreceptorblockers(ARBs),haveshownpromisingresultsinreducingtheincidenceofAFin
heartfailureandhypertensiontrials[7].NewonsetAFinhypertensiontrialsusingRASblockerAsyet,no
prospectivehypertensiontrialhasinvestigatedtheeffectofRASblockadeonthedevelopmentofAFasa
primaryendpoint,butthereareseveralsecondaryanalysesoflargerandomizedtrials.However,thereare
limitationsintheevaluationofnewonsetAFinthesetrials,whichwerenotdesignedtoinvestigatethisas
theprimaryendpoint,especiallyasthedefinitionsandevaluationsofAFdifferbetweenthetrials.Annual
ECGrecordingsmayunderestimatetheprevalenceofAF(althoughequalbetweenthetreatmentgroups);
therefore,inrecentlypublishedandongoingtrials,newonsetAFisaprespecifiedendpoint,andtrans
telephonicECGmonitoringisalsoincludedtorecognizeasymptomaticAF.Therehavebeensome
hypertensiontrialswithACEIsreportingtheeffectonAF,andnosignificanteffectsofRASblockadehave
beenfound[8,9].However,thesetrialswerenotdesignedtoinvestigateAFandmustbelookeduponmore
aschancefindings.IntheLIFEstudy,morethan9000hypertensivepatientswithsignsofleftventricular
hypertrophyintheirelectrocardiogram(ECG)wererandomizedtoatenolol(betablocker)orlosartan
(ARB)basedantihypertensivetreatmentwithsimilarbloodpressurereductionbetweenthetwotreatment
groups[10].IncludedintheanalysesofAFwere8851patientswithnoprevioushistoryofAFandinsinus
rhythmatbaseline.NewonsetAFwasidentifiedin371ofthesepatientsfromannualinstudyECGs
analysedatasinglecentre,duringthemean4.8yearsoffollowup:221oftheatenololtreatedand150in
thelosartantreatedpatients[11].ThisindicatesthatrandomizationtoARBtreatmentwasassociatedwitha
relativeriskreductionof33%ofnewonsetAF,independentofotherriskfactors(p<0.001)[11].Patients
withnewonsetAFhadanapproximatelytwofoldincreaseinriskofcardiovascularevents,athreefold
increaseinriskofstroke,andfivefoldincreaseinrateofhospitalizationforheartfailure,evenafter
adjustmentforcovariates[11].IntheVALUEtrial,morethan15,000highriskhypertensivepatientswere
treatedwithamlodipine(calciumchannelblocker[CCB])orvalsartan(ARB),andnewonsetAFwasa
secondaryprespecifiedendpoint,andECGswereobtainedeveryyearandcentrallyanalysed[12].
Duringtheaverage4.2yearsoffollowupofthetrialtheincidenceofatleastoneECGdocumented
episodeofnewonsetAFwas3.67%inthevalsartantreatedand4.34%intheamlodipinetreatedpatients,
resultinginahazardratioof0.84(0.7130.997,p=0.0455)[12].TheincidenceofpersistentAFwas
1.35%withvalsartantreatmentand1.97%withamlodipinetreatment,resultinginanunadjustedhazard
ratioof0.68(0.5250.889,p=0.0046).Whentakingpotentialconfoundingcovariatesintoaccount(age,
historyofcoronaryarterydisease,leftventricularhypertrophy)theincidenceofAFreductionwithARB
treatmentremainedsignificant[12].InastudycomparingvariousantihypertensiveagentsonAF
recurrence,369mildhypertensivepatientsinsinusrhythm(butwithatleasttwoepisodesofAFduringthe
lastsixmonths)wererandomizeddoubleblindlyintotreatmentwithARB(valsartan),ACEI(ramipril),or
CCB(amlodipine)foroneyear[13].AFrecurrencewasreducedsignificantlyaftertreatmentwithRAS
blockade(ARBandACEI)comparedwithtreatmentwithCCB,despiteasimilarbloodpressurelowering
effect[13].Consistently,intheONTARGETtrial,about69%ofthepatientswerehypertensiveandno
significantdifferencewasseenbetweentheACEIramipril,theARBtelmisartan,orthecombinationof
bothACEIandARBincasesofnewonsetAF[14].Severalsmallerstudieshaveanalysedtheeffectof
RASblockadeincombinationwithantiarrhythmicamiodaroneafterelectricalcardioversioninpatients
withAF.Inastudyof154patientsrandomizedtoopenlabeltreatmentwiththeARBirbesartan,thetime
untilrecurrenceandtheprobabilityofremainingfreeofAFweregreateraftertreatmentwithirbesartanand
amiodaronethanaftertreatmentwithamiodaronealone(80%vs.56%,p=0.007)[15].Inthehypertensive
subgroup(<50%)therewasatrendforirbesartanplusamiodaronetobesuperiortoamiodaronealonein
reducingAFrecurrence,witharelativeriskreduction(RR)of0.49(0.112.06)[15].UseofARBwasthe
onlysignificantvariablerelatedtothemaintenanceofsinusrhythmaftercardioversioninamultivariate
analysis[15].AndinanotherstudytheadditionofACEIenalapriltoamiodaronefacilitatedsubsequent
longtermmaintenanceofsinusrhythmaftercardioversion[16].Inastudyof213patientswithmild
hypertensionandparoxysmalAFtreatedwithamiodarone,additionaltreatmentwiththeARBlosartanfor
oneyearyieldedasignificantlylowerrecurrencerateofAFcomparedwithpatientstreatedwiththeCCB
amlodipine:13patientsversus39patients,respectively(p<0.01)[17].TreatmentwithARBalone,
withoutadjunctantiarrhythmictherapybeforeelectricalcardioversionforAF,wastestedintheCAPRAF
study[18].Inthisstudyonly2535%ofthepatientswerehypertensiveandnostatisticallysignificant
differenceinAFrecurrencewasfoundbetweenthetwotreatmentregimens[18].IntheGISSIAFtrial,
secondarypreventionwithARBwasalsonotsuccessfulinpreventingrecurrentAF[19].Therefore,the
effectofRASblockadeonAFrecurrencewithouthypertensionandantiarrhythmictreatmentisnot
knownforsure.Inarecentmetaanalysis,theeffectsofRASblockadeforthepreventionofAFwere
investigated,aimingtodefinewhentheinhibitionismosteffective[20].Atotalof23randomisedstudies
withatotalof87,048patientswereincluded(6hypertensiontrials,2postmyocardialinfarctiontrials,3
heartfailuretrials(primaryprevention),8studiesaftercardioversion,and4onmedicalpreventionof
paroxysmalAFHYPERTENSIONANDATRIALFIBRILLATION,WITHANEMPHASISON
PREVENTIONSverreE.Kjeldsen1,TonjeA.Aksnes1,RolandE.Schmieder21Departmentof
Cardiology,OsloUniversityHospital,Ullevaal,Norway2DepartmentofNephrology,UniversityHospital,
Erlangen,Germany2011;12:No.42revisedversion84References1KannelWB,WolfPA,BenjaminEJ,
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treatmentofhypertensionandheartfailure.JHypertens2007;25:1523.8.HanssonL,LindholmLH,
EkbomT,etal.Randomisedtrialofoldandnewantihypertensivedrugsinelderlypatients:cardiovascular
mortalityandmorbiditytheSwedishTrialinOldPatientswithHypertension2study.Lancet1999;354:
17511756.9.HanssonL,LindholmLH,NiskanenL,etal.Effectofangiotensinconvertingenzyme
inhibitioncomparedwithconventionaltherapyoncardiovascularmorbidityandmortalityinhypertension:
theCaptoprilPreventionProject(CAPPP)randomisedtrial.Lancet1999;353:611616.10.DahlfB,
DevereuxRB,KjeldsenSE,etal.CardiovascularmorbidityandmortalityintheLosartanInterventionfor
Endpointreductioninhypertensionstudy(LIFE):arandomisedtrialagainstatenolol.Lancet2002;359:
9951003.11.WachtellK,LehtoM,GerdtsE,etal.AngiotensinIIreceptorblockadereducesnewonset
atrialfibrillationandsubsequentstrokecomparedtoatenolol:theLosartanInterventionForEndPoint
ReductioninHypertension(LIFE)study.JAmCollCardiol2005;45:712719.12.SchmiederRE,
KjeldsenSE,JuliusS,etal.ReducedincidenceofnewonsetatrialfibrillationwithangiotensinIIreceptor
blockade:theVALUEtrial.JHypertens2008;26:403411.13.FogariR,DerosaG,FerrariI,etal.Effect
ofvalsartanandramiprilonatrialfibrillationrecurrenceandPwavedispersioninhypertensivepatients
withrecurrentsymptomaticloneatrialfibrillation.AmJHypertens2008;21:10341039.14.YusufS,Teo
KK,PogueJ,etal.Telmisartan,ramipril,orboth,inpatientsathighriskforvascularevents.NEnglJMed
2008;358:15471559.15.MadridAH,BuenoMG,RebolloJM,etal.Useofirbesartantomaintainsinus
rhythminpatientswithlonglastingpersistentatrialfibrillation:aprospectiveandrandomizedstudy.
Circulation2002;106:331336.16.UengKC,TsaiTP,YuWC,etal.Useofenalapriltofacilitatesinus
rhythmmaintenanceafterexternalcardioversionoflongstandingpersistentatrialfibrillation.Resultsofa
prospectiveandcontrolledstudy.EurHeartJ2003;24:20902098.17.FogariR,MugelliniA,DestroM,
etal.Losartanandpreventionofatrialfibrillationrecurrenceinhypertensivepatients.JCardiovasc
Pharmacol2006;47:4650.18.TveitA,GrundvoldI,OlufsenM,etal.Candesartaninthepreventionof
relapsingatrialfibrillation.IntJCardiol2007;120:8591.19.GISSIAFInvestigators,DisertoriM,Latini
R,BarleraS,etal.Valsartanforpreventionofrecurrentatrialfibrillation.NEnglJMed2009;360:1606
1617.20.SchneiderMP,HuaTA,WachtellK,KjeldsenSE,SchmiederRE.Preventionofatrialfibrillation
byreninangiotensinsysteminhibition:Ametaanalysis.JACC2010;55:22992307.21.AksnesTA,
StrandAH,FlaaA,KjeldsenSE.Preventionofnewonsetatrialfibrillationwithblockadeoftherenin
angiotensinsystem.SeminarsinCardiology2006;12:125135.22.ManciaG,DeBackerG,Dominiczak
A,etal.2007GuidelinesfortheManagementofArterialHypertension:TheTaskForceforthe
ManagementofArterialHypertensionoftheEuropeanSocietyofHypertension(ESH)andoftheEuropean
SocietyofCardiology(ESC).JHypertens2007;25:11051187.23.AksnesTA,SchmiederRE,Kjeldsen
SE,etal.ImpactofNewOnsetDiabetesMellitusonDevelopmentofAtrialFibrillationandHeartFailure
inHighRiskHypertension(fromtheVALUETrial).AmJCardiol2008;101:634638.24.NasrIA,
BouzamondoA,HulotJS,etal.Preventionofatrialfibrillationonsetbybetablockertreatmentinheart
failure:ametaanalysis.EurHeartJ2007;28:457462.25.BradleyD,CreswellLL,HogueCWJr.,etal.
Pharmacologicprophylaxis:AmericanCollegeofChestPhysiciansguidelinesforthepreventionand
managementofpostoperativeatrialfibrillationaftercardiacsurgery.Chest2005;128(2Suppl):39S47S.
26.VanNoordT,VanGelderI,TielemanRG,etal.VERDICT:theVerapamilversusDigoxin
CardioversionTrial:Arandomizedstudyontheroleofcalciumloweringformaintenanceofsinusrhythm
aftercardioversionofpersistentatrialfibrillation.JCardiovascElectrophysiol2001;12:766769.27.
GottdienerJS,RedaDJ,MassieBM,etal.Effectofsingledrugtherapyonreductionofleftventricular
massinmildtomoderatehypertension:comparisonofsixantihypertensiveagents.TheDepartmentof
VeteransAffairsCooperativeStudyGrouponAntihypertensiveAgents.Circulation1997;95:20072014.
28.GottdienerJS,RedaDJ,WilliamsDW,etal.Effectofsingledrugtherapyonreductionofleftatrial
sizeinmildtomoderatehypertension:comparisonofsixantihypertensiveagents.Circulation1998;98:
140148.(secondaryprevention)[20].TreatmentwithRASblockadereducedtheoddsratioforatrial
fibrillationby32%(0.220.43,p<0.00001),withsimilareffectsofACEIsandARBs[20].Inprimary
preventionRASblockadewasmosteffectiveinpatientswithleftventricularhypertrophyand//orheart
failure[20].Insecondaryprevention,RASblockadereducedtheoddsforAFrecurrenceaftercardio
versionby45%(0.340.89,p=0.01)andonmedicaltherapyby63%(0.270.49,p<0.00001)[20].
However,noeffectwasfoundinthosewiththemostrefractoryAF[20].PossiblemechanismsfortheAF
reducingeffectsofRASblockersaresummarizedinFigure1.Thesemechanismscangivenon
haemodynamicorhaemodynamiceffects,forexample,byreducingbloodpressureperse[21].Reduction
ofleftventricularhypertrophybyblockersofRASmayimproveleftventricularhaemodynamicsandthe
riskofdevelopingAF.Otherantiarrhythmiceffectsbeyondbloodpressureloweringhavealsobeen
suggested,e.g.ionchannelfunction,reductionofPwavedispersion,cardiacfibrosis,atrialstretchand
leftatrialdilatation,andmodulationofsympatheticactivity[7].BlockadeofRASmayalsohave
potassiumsparingeffectsthatmayreducetheriskoftachyarrhythmia,andadirectantiarrhythmiceffectof
thedrugshasalsobeensuggested.ARBsareeffectiveinbothnonACEandACEdependentproductionof
angiotensinIIbygivingadirectblockadeatthereceptorsite,whileanACEIisonlyacompetitiveinhibitor
ofACEthatcanalsobeovercomebyariseinreninduringantihypertensivetreatment.Theabove
observationsprovidenodefinitiveindicationfortheuseofRASblockadetopreventAF,buttheirusein
patientswithrecurrentAFhasbeensuggested,particularlyifthereareotherindicationssuchas
hypertension,heartfailure,ordiabetesmellitus[22].Ithasalsobeenshownthathypertensivepatients
includedintheVALUEtrialwithnewonsetdiabetesmellitushadasignificantlyhighereventrateofnew
onsetAFwithahazardratioof1.49(1.141.94,p=0.0031)comparedwithpatientswithoutdiabetes
mellitus,andthismayexplainsomeofthesepatientsconcomitanthighriskofhospitalizationforheart
failure[23].PreventingtheprogressionfromhighbloodpressuretoAFandtoheartfailuremaybeofgreat
importancenotonlyforthepatients,butalsoforthehealthcaresystem.NewonsetAFintrialsusingother
antihypertensivetreatmentregimensLately,theuseofbetablockersasfirstlinetherapyforhypertension
hasbeenquestioned[22].However,betablockershaveknowneffectsinAFratecontrolandapossible
effectinmaintainingsinusrhythm,especiallyinheartfailureandincardiacpostoperativesettings[24,25].
Inametaanalysisincludingalmost12,000patientswithsystolicheartfailure(about90%receivedRAS
blockade),betablockerssignificantlyreducedtheincidenceofonsetofAFwitharelativeriskreductionof
27%(RR0.610.86,p< 0.001) [24]. The non-selective beta-blocker sotalol is
reduction in left atrial size than the other agents [27, 28]. Left
ventricular mass and left atrial size are both known AF risk factors, but
the effect on new-onset AF is not known. Conclusions AF and
hypertension are two prevalent and often coexistent conditions, and
both are responsible for considerable morbidity and mortality.
Aggressive treatment of hypertension, especially with RAS-blockers,
may postpone or prevent development and recurrence of AF and
reduce thromboembolic complications. Primary prevention is a new
strategy in the treatment of AF as it has previously been more common
to focus on prevention of adverse outcome and rate- and rhythmcontrol of the final condition. However, as our population is aging and
an increase in the number of patients with AF is expected, focus on
primary prevention with optimal antihypertensive treatment may be
important to reduce morbidity, mortality, and health care expenditure
in the future. Figure 1. Possible mechanisms of how RAS-blockade may
reduce new- -onset AF and AF recurrence (reproduced with permission
from Seminars in Cardiology [21]) European Society of Hypertension
Scientific Newsletter: Update on Hypertension Management 85 The
term paraganglioma identifies a category of tumour arising from
neuroendocrine cells that migrate from the neural crest at the time of
embryonic development and cluster in the proximity of
parasympathetic and sympathetic ganglia, where they form the socalled paraganglia. The term pheochromocytoma should be reserved
for those paragangliomas originating from catecholamine-producing
chromaffin cells located in the adrenal medulla. On the other hand,
paragangliomas of parasympathetic origin are usually located in the
head and neck region, rarely synthesize catecholamines, and are
chromaffin negative since these non-functioning paragangliomas are
not associated with signs of sympathetic overactivity, they are not
seen in the context of arterial hypertension and will be excluded from
further consideration in this newsletter. A rare disease? A reliable
estimate of the incidence of pheochromocytoma has been obtained at
the Mayo Clinic in the population of Rochester, resulting in
approximately one case per 100,000 subject/years [1]. Lower values
(approx. 0.2 cases per 100,000 subject/years) have been found in
Japan, Sweden
enmark, and Spain. On the other hand, different groups report the
occurrence of pheochromocytoma in 15/1000 hypertensive patients.
This apparent inconsistency could be explained by a presumable
selection bias in hypertensive patients observed at specialized centres.
From another perspective, adrenal incidentalomas were found in 0.4%
of individuals from a series of more than 60,000 abdominal CT scans,
and another report suggests that approximately 4% of adrenal
incidentalomas are pheochromocytomas [2]. Presentation of
pheochromocytoma Signs and symptoms of pheochromocytoma and
functional paraganglioma are particularly variable [3]. In some
conditions(seeTable1)[3,6].TheARRshouldthereforeberegardedasadetectiontestonlyandshould
berepeatediftheinitialresultsareinconclusiveordifficulttointerpretbecauseofsuboptimalsampling
conditions.ItshouldalsobeappreciatedthattheARRconveysquantitativeinformation:inotherwordsa
markedlyelevatedvalueshouldbetakenasastrongindicationforthepresenceofPA,whichcanwarrant
adrenalveinsamplingwithoutanyfurtherconfirmation,whileborderlineelevatedvaluesshouldbe
repeatedandperhapsfollowedbyanexclusiontest.Inrecentyearsithasbecomemorecommontousethe
directactivereninassayinsteadoftheplasmareninactivity(PRA)toevaluatethereninangiotensin
system.Amajorproblemisthatthereareimportantandconfoundingdifferencesacrosslaboratories
regardingthemethodsandunitsusedtoreportvaluesofreninandaldosterone;this,togetherwiththelack
ofuniformityindiagnosticprotocols,hasbeenassociatedwithsubstantialvariabilityincutoffvaluesused
bydifferentgroups,rangingfrom20to100asng/dlAldooverng//dl/hr(or68to338aspMol/Lover
mU/L)[7].Mostgroups,however,usecutoffsof2040(forAldoinng/dloverPRAinng/ml/h)(68135)
whentestingisperformedinthemorningonaseatedambulatorypatient.Inthelargestavailablestudyin
whichtheARRwasusedtoidentifytheonlyPAsubtypethatcouldbeconclusivelydiagnosedbasedonthe
fourcornerscriteria,theoptimalcutofffortheARR(PACinng/dl,PRAinng/ml/h)was25.86[3].
CaseconfirmationOnceahighARRhasbeendeterminedconfirmatorytestsshouldbeperformedto
definitivelyconfirmorexcludePA[5].Atpresent,fourconfirmatoryteststodefinitivelyconfirmor
excludethediagnosisareused:oralsodiumloading,salineinfusion,fludrocortisonesuppression,and
captoprilchallenge.Thesefourtestsareincommonuseeventhoughtheirusefulnessissupportedatbestby
alevelofevidenceCbytheAHAcriteria,andthereforethelevelofrecommendationfortheiruseisonly
Iib.Moreover,thereiscurrentlyinsufficientdirectevidencetorecommendanyoneoftheseabovethe
others.Thesetestsmaydifferintermsofsensitivity,specificity,andreliability,butthechoiceofa
confirmatorytestisusuallydeterminedbyconsiderationsofcost,patientPRIMARYALDOSTERONISM
FrancoMantero1,GianPaoloRossi2,EnricoAgabitiRosei31EndocrineUnit,DepartmentofMedical
andSurgicalSciences,UniversityofPadua,Italy2InternalMedicine4,DepartmentofClinicaland
ExperimentalMedicine,UniversityofPadua,Italy3ClinicaMedica,DepartmentofMedicalandSurgical
Sciences,UniversityofBrescia,Italy2010;11:No.44Figure1.Flowchartoutliningthesuggestedwork
upofpatientswithhypertensionandincreasedriskofhyperaldosteronism[5]Table1.Factorsthatmay
affectthealdosteronereninratioandthusleadtofalsepositiveorfalsenegativeresults[5]FACTOR
EffectonEffectonEffectaldosteronelevelsreninlevelsonARRMedicationsBetaadrenergicblockers
(FP)Centrala2agonists(FP)NSAIDs(FP)K+wastingdiuretics(FN)K+
sparingdiuretics(FN)ACEinhibitors(FN)ARBs(FN)Ca2+blockers(DHPs)
(FN)Renininhibitors*(FN)*(FP)*PotassiumstatusHypokalaemia(FN)Potassium
loading(FP)DietarysodiumSodiumrestricted(FN)Sodiumloaded(FP)Advancing
age(FP)OtherconditionsRenalimpairment(FP)PHA2(FP)Pregnancy(FN)
RenovascularHT(FN)MalignantHT(FN)*RenininhibitorslowerPRAbutraiseDRC.
ThiswouldbeexpectedtoresultinfalsepositiveARRlevelsforreninmeasuredasPRAandfalse
negativesforreninmeasuredasDRC;PHA2pseudohypoaldosteronismtype2(familialhypertension
andhyperkalemiawithnormalglomerularfiltrationrate)88References1.KaplanNM.Clinical
hypertension.6thed.Williams&Wilkins,Baltimore1994:389408.2.MulateroP,StowasserM,Loh
KC,etal.Increaseddiagnosisofprimaryaldosteronism,includingsurgicallycorrectableforms,incenters
fromfivecontinents.JClinEndocrinolMetab2004;89:10451050.3.RossiGP,BerniniG,CaliumiC,et
al.Aprospectivestudyoftheprevalenceofprimaryaldosteronismin1,125hypertensivepatients.JAm
CollCardiol2006;48:22932300.4.MilliezP,GirerdX,PlouinPF,etal.Evidenceforanincreasedrate
ofcardiovasculareventsinpatientswithprimaryaldosteronism.JAmCollCardiol2005;45:12431248.
5.FunderJW,CareyRM,FardellaC,etal.Casedetection,diagnosis,andtreatmentofpatientswith
primaryaldosteronism:anEndocrineSocietyClinicalPracticeGuideline.JClinEndocrinolMetab2008;
93:32663281.6.StowasserM,GordonRD.Thealdosteronereninratioforscreeningforprimary
aldosteronism.Endocrinologist2004;14:267276.7.YoungWF.Primaryaldosteronism:renaissanceofa
syndrome.ClinEndocrinol2007;66:607618.8.RossiGP,BelfioreA,BerniniG,etal.;andforthe
PrimaryAldosteronismPrevalenceinItalyStudyInvestigators.Comparisonofthecaptoprilandthesaline
infusiontestforexcludingAldosteroneProducingAdenoma.Hypertension2007;50:424431.9.Young
WF,StansonAW,ThompsonGB,etal.Roleforadrenalvenoussamplinginprimaryaldosteronism.
Surgery2004;136:12271235.10.NwariakuFE,MillerBS,AuchusR,etal.Primaryhyperaldosteronism:
effectofadrenalveinsamplingonsurgicaloutcome.ArchSurg2006;141:497502.11.SecciaTM,
MiottoD,DeToniR,etal.Adrenocorticotropichormonestimulationduringadrenalveinsamplingfor
identifyingsurgicallycurablesubtypesofprimaryaldosteronism:comparisonof3differentprotocols.
Hypertension2009;53:761766.12.StewartPM,AllolioB.AdrenalveinsamplingforPrimary
Aldosteronism:timeforarealitycheck.ClinEndocrinol(Oxf)2010;72:146148.13.EspinerEA,Ross
DG,YandleTG,RichardsAM,HuntPJ.Predictingsurgicallyremedialprimaryaldosteronism:roleof
adrenalscanning,posturetesting,andadrenalveinsampling.JClinEndocrinolMetab2003;88:3637
3644.14.MansoorGA,MalchoffCD,AriciMH,KarimeddiniMK,WhalenGF.Unilateraladrenal
hyperplasiacausingprimaryaldosteronism:limitationsofI131norcholesterolscanning.AmJHypertens
2002;15:459464.15.LiftonRP,DluhyRG,PowersM,etal.Achimaeric11beta
hydroxylase/aldosteronesynthasegenecausesglucocorticoidremediablealdosteronismandhuman
hypertension.Nature1992;355:262265.16.SoA,DuffyDL,GordonRD,etal.Familial
hyperaldosteronismtypeIIislinkedtothechromosome7p22regionbutalsoshowspredicted
heterogeneity.JHypertens2005;23:14771484.17.SawkaAM,YoungWF,ThompsonGB,etal.
Primaryaldosteronism:factorsassociatedwithnormalizationofbloodpressureaftersurgery.AnnIntern
Med2001;135:258261.18.RossiGP,BolognesiM,RizzoniD,etal.Vascularremodelingandduration
ofhypertensionpredictoutcomeofadrenalectomyinprimaryaldosteronismpatients.Hypertension2008;
51:13661371.19.JacobsenNE,CampbellJB,HobartMG.Laparoscopicversusopenadrenalectomyfor
surgicaladrenaldisease.CanJUrol2003;10:19951999.20.BurgessED,LacourciereY,RuilopeUrioste
LM,etal.Longtermsafetyandefficacyoftheselectivealdosteroneblockereplerenoneinpatientswith
essentialhypertension.ClinTher2003;25:23882404.21.LimPO,YoungWF,MacDonaldTM.A
reviewofthemedicaltreatmentofprimaryaldosteronism.JHypertens2001;19:353361.compliance,
laboratoryfacilities,andlocalexpertise.Themostcommonlyusedtestisthesalineinfusiontest(2Lover4
hrs)withatemptativecutoffforpostinfusionplasmaaldosteroneabove7ng/dl[8].Itshouldbenotedthat
confirmatorytestsrequiringoralorIVsodiumloadingshouldbeadministeredwithcautioninpatientswith
uncontrolledhypertensionorcongestiveheartfailure.Asallthesetestsrelyonthepresumedautonomyof
thealdosteroneproductionfromangiotensinII,whichapparentlyisnotthecaseinallaldosterone
producingadenoma,thesetestsarefraughtwithalargenumberoffalsenegativeandfalsepositiveresults,
andthereforesomeexpertssupporttheviewthattheyshouldnotbeusedastheycanleadtocurative
adrenalectomynotbeinggiventomanypatients.SubtypeclassificationAllpatientswithprimary
aldosteronismshouldundergoadrenalcomputedtomography(CT)astheinitialsubtypestudy,toexclude
largemassesthatmayrepresentadrenocorticalcarcinomaandtoascertaintherightadrenalveinanatomy,
whichisusefulforplanningandadrenalveinsampling.Oftheseindications,adrenalCThasnoplacefor
differentiationofPAsubtypes.Infact,smallAPAsmaybeoverlooked,and/ornonfunctioningadenoma
(incidentaloma)ononesidecanbeconsideredtheculpritforPAwhileinsteadthelatterisduetoa
smallCTundetectableAPAorunilateralhyperplasiaonthecontralateralside.Moreover,apparentadrenal
microadenomasmayactuallyrepresentareasofhyperplasia,andunilateraladrenalectomywouldbe
inappropriate.Inaddition,nonfunctioningunilateraladrenalmacroadenomasarenotuncommon,
especiallyinolderpatients(>40yearsold)andareindistinguishablefromAPAsonCT.UnilateralUAH
(unilateraladrenalhyperplasia)maybevisible,butalsoinvisibleonCT.Magneticresonanceimaginghas
noadvantageoverCTinsubtypeevaluationofPA,beingmoreexpensiveandmorepronetomotion
artefactsthanCT.Lateralizationofthesourceofexcessivealdosteronesecretioniscriticaltoguidethe
managementofPA.Imagingcannotreliablyvisualizemicroadenomasordistinguishincidentalomasfrom
APAswithconfidence[9],makingAdrenalVeinSampling(AVS)themostaccuratewayofdifferentiating
unilateralfrombilateralformsofPA.ItmustbeunderstoodthatAVSshouldbeofferedtothepatientsonly
ifsurgicaltreatmentispossibleanddesiredbythepatient.ThesensitivityandspecificityofAVS(95and
100%,respectively)fordetectingunilateralaldosteroneexcessaresuperiortothoseofadrenalCT(78and
75%,respectively)[10].AlthoughAVScanbeadifficultprocedure,especiallyontherightadrenalvein
(whichissmallerthantheleftandusuallyemptiesdirectlyintotheIVCratherthantherenalvein),the
successrateusuallyimprovesquicklyastheangiographerbecomesmoreexperienced[9].Currently,three
protocolsforAVSareused:1)unstimulatedsequentialorsimultaneousbilateralAVS,2)unstimulated
sequentialorsimultaneousbilateralAVSfollowedbyboluscosyntropinstimulatedsequentialor
simultaneousbilateralAVS,and3)continuouscosyntropininfusionwithsequentialbilateralAVS.There
areactuallynoclearguidelineswhichrecommendanyparticularprotocolanddataarelackingonthe
impactofAVSonclinicaloutcomes[11].Someformofpatientstratificationisrequired,possiblyfirstly
identifyingwhichpatientsshouldproceedtosurgerysetagainstthosewhocanbemanagedoneffective
medicaltherapywithMineralocorticoidReceptorantagonists.TheuseofAVSmustbejustifiedonacase
bycasebasis,askinghowitwillimprovepatientcareandoutcome,andbeundertakenincentresof
excellencetoachieveoptimalsensitivity[12].OtherscreeningtestsPosturestimulationtest.Inpatients
withunsuccessfulAVSandwithaCTscanshowingaunilateraladrenalmass,someexpertsusetheposture
stimulationtest.Thistest,developedinthe1970s,wasbasedonthefindingthatthePACinpatientswith
APAshoweddiurnalvariationandwasrelativelyunaffectedbychangesinangiotensinIIlevels,whereas
IHAwascharacterizedbyenhancedsensitivitytosmallchangesinangiotensinIIthatoccurwithstanding.
Recentreviewsshowedanaccuracyof85%ofthistest.Thelackofaccuracyisexplainedbythefactthat
someAPAsaresensitivetoangiotensinIIandsomepatientswithIHAhavediurnalvariationinaldosterone
secretion.Thus,theposturestimulationtestmayhaveanancillaryrole,forexample,inthosepatientsfor
whomAVSwasunsuccessfulandCTshowsaunilateraladrenalmass[13].Iodocholesterolscintigraphy.
[131I]19Iodocholesterolscintigraphywasfirstusedintheearly1970s,andanimprovedagent,[6b
131I]iodomethyl19norcholesterol(NP59),wasintroducedin1977.TheNP59scan,performedwith
dexamethasonesuppression,hadtheputativeadvantageofcorrelatingfunctionwithanatomical
abnormalities.However,thesensitivityofthistestdependsheavilyonthesizeoftheadenoma;
consequently,thismethodisuselessininterpretingmicronodularfindingsobtainedwithhighresolution
CTandhasnomajorroleinsubtypeevaluation[14]inmostcentres.Moreover,theshortageofthe
radiotracercurrentlymakesthistestunfeasibleformostcentres.18Hydroxycorticosteronelevels.18
Hydroxycorticosteroneisformedby18hydroxylationofcorticosterone.PatientswithAPAgenerallyhave
recumbentplasma18hydroxycorticosteronelevelsgreaterthan100ng/dlat0800h,whereaspatients
withIHAhavelevelsthatareusuallylessthan100ng/dl.However,thistestlackstheaccuracyneededto
guidetheclinicianinthesubtypeevaluationofPA[5].TestingforfamiliarformsofPA[FHI(GRA)].
FH1syndromeisresponsibleforlessthan1%ofcasesofPAanditisinheritedinanautosomaldominant
fashion.ItmaybediagnosedinpatientswithonsetofPAearlierthanat20yearsofageandinthosewho
haveafamilyhistoryofPAorofstrokesatyoungage.GenetictestingbyeitherSouthernblot[15]orlong
PCRtechniquesissensitiveandspecificforGRA.FHIIsyndromeusclinicallyindistinguishablefrom
nonfamiliarPA.Itisanautosomaldominantdisorder.GRAmutationtestingisnegative.Itsprevalence
hasnotbeenestablished.Anassociationwithchromosomalregion7p22hasbeenshown[16].Afurther
approachthatisbeingtestedtoidentifylateralizedaldosteroneexcessentailsC11methomidatepositrone
emissiontomography.However,itremainstobedemonstratedifitcouldidentifythemajorityofAPAsthat,
asmentionedabove,aresmall.TreatmentTreatmentofchoiceindocumentedunilateralPA(APAorUHA)
isunilaterallaparoscopicadrenalectomy,whereasmedicaltreatmentwithmineralocorticoidreceptor
antagonistsisindicatedinpatientswithbilateraladrenaldisease(idiopathicadrenalhyperplasia,bilateral
APA,GRA).SurgicaltreatmentinpatientswithunilateralPAshowsimprovementofserumpotassium
concentrationsinnearly100%ofpatientspostoperatively[5]whenthediagnosisandtheindicationof
adrenalectomyaremadebasedonAVS.Hypertensioniscured(definedasbloodpressure<140/90mmHg
withouttheaidofantihypertensivedrugs)inabout50%(range3560%)ofpatientswithAPAafter
unilateraladrenalectomy,withacurerateashighas5677%whenthecurethresholdisbloodpressureless
than160/95mmHg[5].Factorsassociatedwithresolutionofhypertensioninthepostoperativeperiod
includehavingnomorethanonefirstdegreerelativewithhypertension,preoperativeuseofoneortwo
antihypertensivedrugs[17],knowndurationofhypertension,andthepresenceofvascularremodelling
[18].Ascomparedwithopenadrenalectomy,laparoscopicadrenalectomyisassociatedwithshorter
hospitalstaysandfewercomplications[19].Inpatientswhodonotundergosurgeryandinthosepresenting
bilateraladrenaldisease,medicaltreatmentisindicatedasfollows:MRantagonistsappeartobeeffective
inthecontrolofbloodpressureandprovidingtargetorganprotection.Spironolactonehasbeentheagent
ofchoiceinthemedicaltreatmentofPAformorethanfourdecades.Severalobservationalstudiesin
patientswithIHAhavereportedameanreductioninsystolicbloodpressureof25%anddiastolicblood
pressureof22%inresponsetospironolactone50400mg/dfor196months[5].Theincidenceof
gynaecomastiawithspironolactonetherapyisdoserelated,whereastheexactincidenceofmenstrual
disturbancesinpremenopausalwomenwithspironolactonetherapyisunknown.Whereavailable,
canrenone(anactivemetaboliteofspironolactone)orpotassiumcanrenoate,mightbeconsideredbecause
theypossiblyhavefewersexsteroidrelatedsideeffects.Inaddition,asmalldoseofathiazidediuretic,
triamterene,oramiloridecanbeaddedtoavoidahigherdoseofspironolactonewhichmaycauseside
effects.Thestartingdoseforspironolactoneshouldbe12.525mgdailyinasingledose.Thelowest
effectivedoseshouldbefoundbyverygraduallytitratingupwardtoamaximumdoseof100mg/d.
Eplerenoneisanewer,selectiveMRantagonistwithoutantiandrogenandprogesteroneagonisteffects,thus
reducingtherateofadverseendocrinesideeffects.Eplerenonehas60%oftheMRantagonistpotencyof
spironolactone;itsbettertolerabilityprofileneedstobebalancedagainstitshighercost,shorterdurationof
actionrequiringmultipledailydosing,andthelackofcurrentclinicaltrialevidenceforitsuseinPA[20].
Thestartingdoseforeplerenoneis25mgonceortwicedaily.OtheragentsUpregulationofdistaltubular
sodiumepithelialchannelactivityisamajormechanismwherebyaldosteroneexertsitsactionsonsodium
andpotassiumhandling.Oftheavailableepithelialsodiumchannelantagonists,amiloridehasbeenthe
moststudiedasamodeoftreatmentforPA.Althoughlessefficaciousthanspironolactone,amiloridemay
beuseful.Beingapotassiumsparingdiuretic,amiloridecanamelioratebothhypertensionand
hypokalaemiainpatientswithPAandisgenerallywelltolerated,lackingthesexsteroidrelatedsideeffects
ofspironolactone,butwithoutthebeneficialeffectsonendothelialfunction[21].Calciumchannel
blockers,angiotensinconvertingenzymeinhibitors,andangiotensinreceptorblockershavebeenevaluated
inveryfewpatientswithPA,andingeneraltheyareantihypertensivedrugswithoutamajoreffecton
aldosteroneexcess.Supportivestudiesaresmallandmethodologicallyweakandhavenotmeasured
patientimportantoutcomes.Aldosteronesynthaseinhibitorsmayplayaroleinthefuture.European
SocietyofHypertensionScientificNewsletter:UpdateonHypertensionManagement89Hypertension,
beyonditswellknowneffectontheoccurrenceofclinicalstroke,isalsoassociatedwiththeriskof
subclinicalbraindamagenoticedoncerebralMRI,inparticularinelderlyindividuals[1,2].Themost
commontypesofbrainlesionsareWhiteMatterHyperintensities(WMH)whichcanbeseeninalmost
allelderlyindividualswithhypertension[1,2]althoughwithavariableseverity(Figure1)andsilent
infarcts,thefrequencyofwhichvariesbetween10%to30%accordingtostudies(Figure2)[3].Both
lesionsarecharacterizedbyhighsignalonT2weightedimages.Silentinfarctsmaybesingledoutbytheir
lowsignalonT1weightedimages(Figure2).Anothertypeoflesion,morerecentlyidentified,are
microbleeds,whichareseeninabout5%ofindividualsandaresmall,homogeneous,roundfocioflow
signalintensityonMRIGradientecho(GRE)T2*images.LikeWMHandsilentinfarcts,microbleedsare
morefrequentinindividualswithhypertension.Hypertensionisthemainmodifiableriskfactorfor
subclinicalbraindamage.Severalstudieshavesuggestedthatsustainedoruncontrolledhypertensionis
associatedwithagreaterWMHload[2,4].Thelevelofbloodpressurealsoseemstoplayarolehigher
bloodpressurevaluesbeingassociatedwithhighergradesofWMH[4,5].Thesedosedependenteffectsof
thedurationandlevelofBPprovidestrongsupportforacausalrelationshipbetweenhighBPandWMH,
similartothatalreadyreportedforstroke.Predictivevalueofsubclinicalbraindamageforcognitive
impairmentandstrokeAtfirst,theseMRIcerebrallesionswereconsideredbenignandmerelyassociated
withaging.TheywereevencalledUBOsUnidentifiedBrightObjects!Inthepast15years,severallarge
communitybasedstudiesthathaveincludedlargenumbersofindividualswithMRIexamshaveshown
thattheselesionswerenotsosilentandwereassociatedcrosssectionallywithsubtlecognitiveofmotor
impairment.Itwasalsorecentlydiscoveredthattheywereassociatedwithincidentcognitivedeterioration
ordementia[6],depression[7],andgaitdisturbances[8].Theseassociationsareprobablylargelyduetothe
directconsequencesoftheselesionsonthebraincircuitsandparticularlytothedisconnectionof
subcorticalcorticalloops.Indeed,small,clinicallysilentbraininfarctionsappeartobeatleastasstronga
riskforsubsequentdementia[6]aslarger,clinicallyevidentstrokes.Inmostcasesdementiaisnotcaused
bythesimpleburdenofvascularlesionsbutalsobypreexistingneurodegenerativelesionswhicharevery
commonintheelderly.Theoccurrenceofvascularlesionscouldsimplyrevealtheongoingdevelopmentof
Alzheimersdiseaseinthepatient.Theinteractionbetweenneurodegenerativefactorsandstrokeintherisk
ofdementiawashighlightedintheNunstudy[9].Inthisstudy,basedonautopsyfindings,thepresenceof
asmalllacunarinfarctwasfoundtomultiplytheriskofclinicaldementiabyafactorof20inpeople
meetingtheneuropathologicalcriteriaforAlzheimersdisease.SeveralstudieshavedescribedWMHorthe
presenceofsilentinfarctasapredictorofincidentstrokeinthegeneralpopulation[10,11]andofstroke
recurrenceamongpatientswithtransientischaemicattackorstrokehistory.Insuchinstances,WMHcould
beconsideredastheharbingeroffurtherclinicalevents.Inthe3Cstudy,alargepopulationbasedcohort
studyintheelderlyinwhichweperformedcerebralMRIin1924participants65yearsoldandover,we
foundthatthoseinthehighestquartileofWMHhadamorethanfivefoldincreasedriskofstrokeduring
followupcomparedtothosewithaWMHloadbelowthemedian[12].Interestingly,therewasno
increasedriskofothervascularevents,suggestingthatWMHwasaspecificpredictoroftheriskofstroke.
SystemicarterialdamageandsubclinicalbraindamageTheprecisemechanismsunderlyingthe
developmentofWMH,silentinfarcts,andmicrobleedsremainunclear.Inrecentyearsalargenumberof
studieshavereportedstrongrelationshipsbetweenperipheralarterydamageandeithersubclinicalbrain
damageorcognitiveimpairment.Alterationsofcarotidwallthickening,aorticstiffening,andsmallartery
remodellinginpatientswithcognitivedeclinehaveallowedalinktobemadebetweenvascularagingand
vascularcognitiveimpairment(VCI),underliningtheaggravatingroleofhypertension.Therelationship
betweencarotidintimamediathickness(IMT)andcognitivefunctionhasbeenanalyzedcrosssectionally
[13]andlongitudinally[1416]infewstudies.Studiesdifferedasfarasthestudypopulation,thedefinition
ofcarotidIMT,andtheneuropsychologicaltestadoptedtoevaluatecognitionwereconcerned.Despitethis
heterogeneity,asignificantinverserelationshipbetweencarotidIMTandcognitivefunctionwasobserved
inallstudies.Inotherwords,thethickerthearterythelowerthecognitiveperformance.Thisrelationship
wassignificantaftercontrollingforageandeducation;somestudiesfurtheradjustedforthepresenceof
depressivesymptoms[15,16]and/orlevelofCVriskfactors[15].SUBCLINICALBRAINDAMAGE
ANDHYPERTENSIONChristopheTzourio,MD,PhD1,PeterM.Nilsson,MD,PhD2,AngeloScuteri,
MD,PhD3,StphaneLaurent,MD,PhD41INSERMU708andParis6University,Paris,France2
DepartmentofClinicalSciences,LundUniversity,UniversityHospital,Malm,Sweden3UOGeriatria,
INRCA/IRCCS,ViaCassia1167,00189Roma,Italy4DepartmentofPharmacology,PompidouHospital,
InsermU970andUniversityParisDescartes,France2010;11:No.45Figure1.T2weightedMRIexams
oftwo65yearoldindividuals.Thesubjectonthelefthasnoapparentsubclinicalbrainlesionsonthisslice
whereasthesubjectontherighthasaseveregradeofwhitematterhyperintensities(arrows)Figure2.T2
weighted(ontheleft)andT1weighted(ontheright)MRIexamsofthesamesubjectat75yearsold.This
subjecthasaseveregradeofWMH(arrow),mainlyintheperiventriculararea,easilyseenontheT2exam
(left).Healsohasasilentinfarct(arrow)inthewhitematterwhichappearsinhyposignalontheT1
weightedexam(right)90References1.LongstrethWT,ManolioTA,ArnoldA,etal.Clinicalcorrelatesof
whitematterfindingsoncranialmagneticresonanceimagingof3301elderlypeople:thecardiovascular
healthstudy.Stroke1996;27:12741282.2.deLeeuwFE,deGrootJC,OudkerkM,etal.Hypertension
andcerebralwhitematterlesionsinaprospectivecohortstudy.Brain2002;125:765772.3.VermeerSE,
LongstrethWTJ,KoudstaalPJ.Silentbraininfarcts:asystematicreview.LancetNeurol2007;6:611619.
4.vanDijkEJ,BretelerM,SchmidtR,etal;fortheCASCADEConsortium.TheAssociationBetween
BloodPressure,Hypertension,andCerebralWhiteMatterLesions.TheCardiovascularDeterminantsof
DementiaStudy.Hypertension2004;44:625630.5.LiaoDP,CooperL,CaiJW,etal.Presenceand
severityofcerebralwhitematterlesionsandhypertension,itstreatment,anditscontrol:tTheARICstudy.
Stroke1996;27:22622270.6.VermeerSE,PrinsND,denHeijerT,HofmanA,KoudstaalPJ,Breteler
M.Silentbraininfarctsandtheriskofdementiaandcognitivedecline.NEnglJMed2003;348:1215
1222.7.GodinO,DufouilC,MaillardP,etal.Whitematterlesionsasapredictorofdepressioninthe
elderly:the3CDijonstudy.BiolPsychiatry2008;63:663669.8.SoumareA,ElbazA,ZhuY,etal.
Whitematterlesionsvolumeandmotorperformancesintheelderly.AnnNeurol2009;65:706715.9.
SnowdonDA,GreinerLH,MortimerJA,etal.BraininfarctionandtheclinicalexpressionofAlzheimer
disease:thenunstudy.JAMA1997;277:813817.10.WongTY,KleinR,SharrettAR,etal.Cerebral
whitematterlesions,retinopathy,andincidentclinicalstroke.JAMA2002;288:6774.11.KullerLH,
LongstrethWTJr.,ArnoldAM,etal;fortheCardiovascularHealthStudyCollaborativeResearchGroup.
WhiteMatterHyperintensityonCranialMagneticResonanceImaging:aPredictorofStroke.Stroke2004;
35:18211825.12.BuyckJF,DufouilC,DucimetiereP,etal.Cerebralwhitematterlesionsareassociated
withtheriskofstrokebutnotwithothervascularevents.The3CDijonStudy.Stroke2009;40:2327
2331.13.MullerM,GrobbeeDE,AlemanA,BotsM,vanderSchouwYT.Cardiovasculardiseaseand
cognitiveperformanceinmiddleagedandelderlymen.Atherosclerosis2007;190:14314914.Wendell
CR,ZondermanAB,MetterEJ,NajjarSS,WaldsteinSR.Carotidintimalmedialthicknesspredicts
cognitivedeclineamongadultswithoutclinicalvasculardisease.Stroke2009;40:31803185.15.
KomulainenP,KivipeltoM,LakkaTA,etal.Carotidintimamediathicknessandcognitivefunctionin
elderlywomen:apopulationbasedstudy.Neuroepidemiology2007;28:207213.16.SilvestriniM,
GobbiB,PasqualettiP,et.al.CarotidatherosclerosisandcognitivedeclineinpatientswithAlzheimers
disease.NeurobiolAging2009;30:11771183.17.LaurentS,CockcroftJ,VanBortelL,et.al.Expert
consensusdocumentonarterialstiffness:methodologicalissuesandclinicalapplications.EurHeartJ2006;
27:25882605.18.HanonO,HaulonS,LenoirH,et.al.Relationshipbetweenarterialstiffnessand
cognitivefunctioninelderlysubjectswithcomplaintsofmemoryloss.Stroke2005;36:21932197.19.
ScuteriA,BrancatiAM,GianniW,AssisiA,VolpeM.Arterialstiffnessisanindependentriskfactorfor
cognitiveimpairmentintheelderly:apilotstudy.JHypertens2005;23:12111216.20.ScuteriA,Tesauro
M,AppolloniS,etal.Arterialstiffnessasanindependentpredictoroflongitudinalchangesincognitive
functionintheolderindividual.JHypertens2007;25:10351040.21.WaldsteinSR,RiceSC,ThayerJF,
etal.PulsepressureandpulsewavevelocityarerelatedtocognitivedeclineintheBaltimoreLongitudinal
StudyofAging.Hypertension2008;51:99104.22.DufouilC,GodinO,ChalmersJ,et.al;forthe
PROGRESSMRISubstudyInvestigatorsSeverecerebralwhitematterhyperintensitiespredictsevere
cognitivedeclineinpatientswithcerebrovasculardiseasehistory.Stroke2009;40:22192221.23.
HenskensLH,KroonAA,vanOostenbruggeRJ,et.al.Increasedaorticpulsewavevelocityisassociated
withsilentcerebralsmallvesseldiseaseinhypertensivepatients.Hypertension2008;52:11201126.24.
KearneySchwartzA,RossignolP,BracardS,et.al.Vascularstructureandfunctioniscorrelatedto
cognitiveperformanceandwhitematterhyperintensitiesinolderhypertensivepatientswithsubjective
memorycomplaints.Stroke2009;40:12291236.25.CheungN,SharrettRA,KleinR,et.al.Aortic
DistensibilityandRetinalArteriolarNarrowing.TheMultiEthnicStudyofAtherosclerosis.Hypertension
2007;50:617622.26.HaraznyJM,RittM,BaleanuD,et.al.IncreasedWall:LumenRatioofRetinal
ArteriolesinMalePatientsWithaHistoryofaCerebrovascularEvent.Hypertension2007;50:623629.
27.EliasMF,EliasPK,RobbinsMA,WolfPA,DAgostinoRB.Cardiovascularriskfactorsandcognitive
functioning:anepidemiologicalperspective.In:WaldsteinSR,EliasMF(eds).Neuropsychologyof
CardiovascularDisease.Erlbaum,Mahwah2001:83104.28ZiemanSJ,MelenovskyV,KassDA.
Mechanisms,pathophysiology,andtherapyofarterialstiffness.ArteriosclerThrombVascBiol2005;25:
932943.29.LaurentS,BrietM,BoutouyrieP.Large/smallarterycrosstalkandrecentmorbidity
mortalitytrialsinhypertension.Hypertension2009;54:388392.30.ORourkeMF,SafarME.
Relationshipbetweenaorticstiffeningandmicrovasculardiseaseinbrainandkidney.CauseandLogicof
therapy.Hypertension2005;46:200204.Carotidfemoralpulsewavevelocity(PWV),thegold
standardforevaluatingarterialstiffness[17],washigherinanygroupofcognitivelyimpairedsubjects
withorwithoutdementia[18].AninverserelationshipbetweenPWVandcognitiveperformancewas
reportedcrosssectionally[13,19].CarotidfemoralPWVwasalsoassociatedprospectivelywithcognitive
declinebeforedementia,instudiesusingacognitivescreeningtest[20,21]andmorespecificallytestsof
verballearninganddelayedrecall,nonverbalmemory[21].Theserelationshipsremainedsignificantafter
controllingforage,gender,education,andbloodpressurelevels.Otherstudiesreportedasignificant
positiverelationshipbetweenarterialstiffnessandvolumeorlocalizationofWMHaknownfactor
predisposingtovasculardementia[22]onneuroimaging[23,24].Toourknowledge,nostudyhas
investigatedtherelationshipbetweencognitivedeclineorWMH,andtheremodellingofsmallarteries
harvestedfromhumansubcutaneousandomentalfattissue.Retinalarterialnarrowing,assessednon
invasivelyfromfundoscopicmethodologyorscanninglaserflowmetry[25,26],correlateswithincreased
arterialstiffness[25]andcerebralsmallvesseldisease[26].Mechanismsrelatingsystemicarterialdamage
tosubclinicalbraindamageinhypertensionHypertensionisassociatedwithabnormalitiesoflargearteries:
mainlyincreasedwallthicknessandstiffness,andsmallarteries:mainlyinternalremodelling.The
pathophysiologicalassociationbetweensystemicarterialdamageandVCIcanbeanalysedforeachtypeof
arterialdamage,althoughthecausallinkisdifficulttodetermine.Carotidwallthickening,whichreflects
bothatherosclerosisandahigherstrainduetohypertension,hasbeenassociatedwithseveralCVrisk
factors,includingmetabolic,inflammatory,anddietaryfactors,whichhavealsobeenassociatedwith
cognitivedecline[14,27].Anincreasedaorticstiffness,inresponsetohighbloodpressurelevelsloading
thestiffcomponentsofthearterialwall,mayberelatedtomicrovascularbraindamagethroughseveral
mechanisms:(a)endothelialdysfunctionandoxidativestress[28],(b)amutuallyreinforcingremodelling
oflargeandsmallvessels(i.e.large/smallarterycrosstalk)[29],and(c)exposureofsmallvesselstothe
highpressurefluctuationsofthecerebralcirculation[30],whichispassivelyperfusedathighvolumeflow
throughoutsystoleanddiastole,withverylowvascularresistance.Internalremodellingofsmallarteries,
whichisacceleratedbyhypertension,ultimatelyleadstoocclusionofendarterioles.Finally,WMHand
silentinfarctsareconsideredtobemarkersofchroniccerebralischaemiaresultingfromdamagetosmall
cerebralvessels.PreventionofsubclinicalbraindamagebyantihypertensivedrugsWMHandother
subclinicalbrainlesionsareinvolvedintheoccurrenceofmajorneurologicaldisordersandappeartocause
acceleratedagingofthebrain.Tryingtocontroltheiraggravationisthereforeanimportantgoal.As
hypertensionistheirmajormodifiableriskfactoritseemslogicaltotestfirstthehypothesisthatablood
pressureloweringtreatmentmaymodifytheirevolution.Thisquestionwasaddressedinaclinicaltrial,the
PROGRESSMRIstudy[22],asubstudyofthePROGRESStrial.Inthissubstudy,192patientswere
enrolled(meanageof60years),89ofwhomwereintheactivetreatmentarmofthestudy,theother103
patientsbeingassignedtotheplaceboarm.EachparticipantunderwentaninitialbrainMRIatthestartof
thestudyandasecondMRIexaminationafterameanfollowupperiodof36months.Thevariability
betweenthetwoexaminationsduetotechnicalaspects(positionoftheheadinthescanner,sectionsof
differentsizestakenindifferentpositions)waslimitedbyusingimageanalysistechniquestorealignthe
imagesandforautomaticsegmentationaftertherecordingofscansinanobjectorienteddatabase.These
techniquesrenderedtheimagesascomparableaspossible,andanindependentobserverblindtotheclinical
dataandorderofexaminationswasthenabletocomparethescansindetail,detectingandmeasuringeach
newlesion.Aneurologistanalyzedtheinitialscanresultsandidentified13%ofthepatientsashaving
moderateWMHand19%ashavingsevereWMH.AtthetimeofthesecondMRIscan,SBPhaddecreased
byameanof11.2mmHgandDBPby4.3mmHg.TheoverallriskofanewWMHlesionwas43%lower
inthetreatmentarmthanintheplaceboarmofthestudy,althoughthisdifferencewasnotstatistically
significant(p=0.10)[22].ThevolumeofnewWMHlesionsinthetreatmentarmwasonlyonefifthofthat
intheplaceboarmofthestudy(0.4cm3versus2cm3;p==0.047).Thegreatestdifferencewasobserved
inthegroupofpatientswithsevereWMHonthefirstMRIscan.Inthisgroup,nonewlesionswere
observedinthetreatmentarmofthestudy,whereasthevolumeofWMHincreasedby7.6cm3inthe
placeboarmofthestudy(p=0.001)[22].ThisgroupalsodisplayedthemostmarkedprogressionofWMH
overthefouryearfollowupperiod,thusconfirmingtheresultsofseveralobservationstudies.Finally,it
wasrecentlyshowninthePROGRESStrialthatpatientswithahighloadofWMHlesionshada7.7times
higherriskofseverecognitivedeteriorationordementia(95%CI=2.128.6).Thesepreliminaryresults
areencouragingbecausetheyshow,forthefirsttime,thatitispossibletodecreasethedevelopmentof
WMHbyloweringarterialbloodpressure.However,giventherelativelysmallnumberofpatientsstudied,
theseresultscannotbeconsideredasconclusive.Theyrequireconfirmation(ornegation)inlargergroups
ofpatients.Furthermore,allthepatientsinthePROGRESSstudyhadahistoryofstroke,limitingthe
extenttowhichtheseresultscanbegeneralized.Ideally,thenextstepwouldbeatrialinpatientswith
moderatetosevereWMHgrades.Thereisnowstrongevidencethatthisgroupisexposedtoarapid
increaseinWMHvolumebutalsotoanimmediateriskofseverecognitivedeteriorationanddementia.As
WMHhasbeenshowntoplayaroleintheoccurrenceoraggravationofcognitivedeclineanddementia,
limitingtheirprogressionmaybethecornerstoneinawiderstrategytopreventdementiabycontrolling
vascularfactors.EuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management91IntroductionCardiovascularcontrolismarkedlyaffectedbynormalsleepwitha
differentialautonomicregulationofthecardiovascularsystemwiththedifferentsleepstages[1].Blood
pressure(BP)andheartrate(HR)decreasethroughoutnonrapideyemovement(NREM)sleep,
particularlyduringslowwavesleep(dippingpattern),whereasinREMsleepBPishighlyvariableand
approximateswakefulnesslevels.Duringthenight,normalindividualsdidnotexhibitsignificantchangein
cardiacoutput,andthenocturnalfallinarterialpressureisactuallytheresultofadecreaseintotal
peripheralvascularresistance.Anydisturbanceinsleepquantityorquality,explainedeitherbysleephabits
orsleepdisorders,mayparticipateinhypertensiondevelopmentorseverity.Inthisarticle,wewill
successivelyreviewthedifferentsleepdisordersorsleephabitsassociatedwithhypertensionand
summarizethecommonpathophysiologicalintermediarymechanismsexplainingtherelationship.
ObstructivesleepapneasyndromeandhypertensionObstructivesleepapnea(OSA)isassociatedwith
changesinintrathoracicpressuresduringsleepreflectingvariationsinrespiratoryeffort,frequenttransient
arousals,modificationsinsleepstructure,andintermittenthypoxia.Allthesefactorshaveanimpacton
sympatheticactivityandmayresultinlongtermsympatheticactivationcontributingtocardiovascular
morbidity.Duringabnormalrespiratoryeventsthereisaprogressiveincreaseinsympatheticactivityand
anacuteriseinbloodpressure,whichcorrelateswiththeseverityofoxygendesaturation.Acuterespiratory
eventsduringsleeparesuperimposedonchronicadaptationsofthecardiovascularsysteminresponseto
longtermsleepapneaexposure,leadingtodaytimesustainedelevationofsympatheticactivity[2].
Obstructivesleepapneasyndrome(OSA)andhypertensionarelinkedinadoseresponsefashion.Thisis
trueevenwhentakingintoaccountusualconfoundingfactorssuchasage,alcohol,tobaccoconsumption,
andbodymassindex(BMI)[3].Respiratoryeventrelatedintermittenthypoxiaisthemainstimulusleading
toadrenergicandreninangiotensinsystem(RAS)overactivityandthustothedevelopmentofthe
sustainedincreaseinbloodpressure(BP)seeninOSApatients.Theendothelialdysfunctionevidencedin
OSASalsopartlyexplainshypertension,owingtodecreasedvasodilationandenhancedvasoconstriction,
resultingfromNOavailabilityreduction.Similarly,thehyperinsulinismoftenpresentinapneicsubjects,
especiallywhenoverweight,contributestoOSAinducedHTbyfavouringperipheralvasodilation
impairment,endothelialdysfunction,sympathetichyperactivity,andanincreaseinrenalsodium
reabsorption[4].HypertensionassociatedwithOSAShasseveralcharacteristics:diastolicandnocturnal
predominanceandcommonlyencounteredmaskedhypertensionwithfrequentnondipperstatus.
Furthermore,asOSASisfoundinthevastmajorityofsubjectswithrefractoryhypertension,itshouldbe
systematicallyinvestigatedinthissituation.Threemetaanalysesderivedfrom19randomizedcontrolled
trialshavedemonstratedthatcontinuouspositiveairwaypressure(CPAP),thefirstlinetherapyfor
moderatetosevereOSAS,reducesthe24hmeanBPbyapproximately2mmHg(pooledestimated
effect).Haentjensetal.[5]lookedat12studiesassessingCPAPversusplacebo(shamCPAPorpills),
includingatotalof512patients.Someoftheanalyzedstudiesexcludedhypertensivepatientswhilstothers
onlyincludedhypertensivepatients.Furthermore,thepresenceofanantihypertensivetreatmentwasnot
constant.ThismetaanalysismainlyshowedthatthereductioninmeanBPover24hourswithCPAPwas
low(1.69mmHg)butsignificant(p< 0.001). This BP reduction is more marked if
patients have severe OSAS and if they comply with CPAP treatment.
Bazzano LA et al. [6] have taken into account 16 placebo-controlled
studies comparing the effect of CPAP on BP over at least two weeks.
Out of the 818 OSAS suffering patients included, the mean BP
reduction with active treatment vs. placebo was 2.46 mm Hg (95% CI:
4.31 to 0.62) for SBP and 1.83 mm Hg (95% CI: 3.05 to 0.61) for
DBP. The SBP and DBP falls were identical for day and night. The
studies differed regarding to the BP parameters used (SBP, DBP, or
mean BP), the type of control treatment used (8 used sham CPAP, 4
provided a pill, and 4 provided usual care alone), and the outcome
measure (ABPM or clinical BP). Again, a significant BP reduction was
associated with higher baseline BP levels, and higher BMI and severity
of OSA. Mandibular advancement devices (MADs) are the only
alternative treatment to CPAP. Even if available data are limited, using
MADs has been reported to be associated with a significant reduction
in 24-h diastolic blood pressure compared to an inactive oral appliance.
The range of blood pressure decrease was similar to that achieved with
CPAP [7]. Sleep duration and hypertension Sleep duration has
decreased in the general population over the last 30 years [8]. In the
US, the National Sleep Foundation reported an increase from 12% to
16% of subjects sleeping less than 6 hours on workdays between 1998
and 2005, reflecting voluntary sleep restriction. On the other hand, the
prevalence of insomnia complaints was 23% in The Atherosclerosis
Thiscouldmainlybeactivationofthehypothalamicpituitaryadrenalaxisandelevatedsympathetic
nervoussystemactivity[19,20].SleepdeprivationhasalsobeenreHYPERTENSIONANDSLEEPJean
LouisPpin,MD,PhD14,AnneLaureBorel,MD,PhD2,5,JeanPhillipeBaguet,MD,PhD2,6,Renaud
Tamisier,MD,PhD14,PatrickLvy,MD,PhD14,JeanMichelMallion,MD2,61INSERMERI17,
HP2Laboratory(Hypoxia:Pathophysiology),Grenoble,F38042,France2JosephFourierUniversity,
Grenoble,F38043,France3GrenobleUniversityHospital,PoledeRducation&Physiologie,Grenoble,
F38043,France4GrenobleUniversityHospital,SleepLaboratory,EFCR,Grenoble,F38042,France5
GrenobleUniversityHospital,DepartmentofEndocrinology,PleDigidune,Grenoble,F38043,France6
GrenobleUniversityHospital,DepartmentofCardiology,Grenoble,F38043,France2010;11:No.4692
References1.LegramanteJM,GalanteA.Sleepandhypertension:achallengefortheautonomicregulation
ofthecardiovascularsystem.Circulation2005;112:786788.2.BaguetJP,BaroneRochetteG,PepinJL.
Hypertensionandobstructivesleepapnoeasyndrome:currentperspectives.JHumHypertens2009;3:
431443.3.PeppardPE,YoungT,PaltaM,SkatrudJ.Prospectivestudyoftheassociationbetweensleep
disorderedbreathingandhypertension.NEnglJMed2000;342:13781384.4.DuranCantollaJ,Aizpuru
F,MartinezNullC,BarbeIllaF.Obstructivesleepapnea/hypopneaandsystemichypertension.SleepMed
Rev2009;13:323331.5.HaentjensP,VanMeerhaegheA,MoscarielloA,etal.Theimpactof
continuouspositiveairwaypressureonbloodpressureinpatientswithobstructivesleepapneasyndrome:
evidencefromametaanalysisofplacebocontrolledrandomizedtrials.Arc h Intern Med 2007;
linkedwithhypertension.Insummary,theresultsofepidemiologicstudiessuggestapossiblerelationship
betweenselfreportedRLSsymptomsanddaytimehypertensionandaremoreconsistentwhenconsidering
severecasesofRLSwithdailysymptoms[23].Thecommonintermediarymechanismsforthelink
betweensleep,sleepdisorders,andhypertension(Figure1)Amongthepathophysiologicalmechanisms
associatedwithsleeprestrictionandpresentindifferentsleepdisturbancessuchasOSAS,insomnia,and
RLS//PLMS,nocturnalsympatheticactivationisprobablythekeymechanism(Figure1).Thisnocturnal
sympatheticoveractivitylimitsthenocturnalBPfallandinturnleadstoadiurnalpermanentincreasein
sympathetictone.HypertensivesubjectsinwhomthenocturnalBPfallisblunted(nondippingpattern)are
knowntodevelopahigherdegreeoftargetorgandamageandcardiovascularmorbimortality.Systemic
inflammation,oxidativestress,andendothelialdysfunctionarealsolinkedwithsleepquantityandsleep
disordersandmayalsoinfluencethedevelopmentandprogressionofhypertension.Hypertensionisa
frequentcomorbidityofdiabetesandrenalfailure,whicharealsofrequentlyassociatedwithOSASand
RLS/PLMS.Inthesesituationsboththeprimarydiseaseandtheassociatedsleepdisorderact
synergisticallytoelevateBP.Thus,werecentlydemonstratedthatintype1diabeticsubjectsshortersleep
durationwasassociatedwithnondippingpatternofBP[26].Thesamedetrimentalsituationoccursin
drugresistanthypertension.OSAishighlyprevalentandpresentinmorethan80%ofthedrugresistant
hypertensionpatients.OSAsufferingpatientswithadditiveshortersleepdurationexhibitedhigherBP
values[27].Insummary,bothalterationsinsleepqualityandsleepdisordersareassociatedwith
intermediarymechanismsthatfavourthedevelopmentofhypertension.Anycombinationofapreexisting
hypertension,whateverthecause,andsleepdisturbancesmayincreasehypertensionseverityandlimit
treatmentefficacy.ConclusionandperspectivesInhypertension,sleepmustbetakenintoaccountasa
relevantlifeperiod[1].Sleeprestrictionandsleepdisordersarebothandsynergisticallyassociatedwith
increasedprevalenceandincidenceofhypertension.Interventionstudiesarenowneededtoassesswhether
actingtopromotevoluntarylongersleepdurationand/orefficientlytotreatsleepdisorderscouldpreventor
reversehypertension.Figure1.Thecommonintermediarymechanismsforthelinkbetweensleep,sleep
disorders,andhypertension.Alterationsinsleepqualityandsleepdisordersareassociatedwith
intermediarymechanismsthatfavourthedevelopmentofhypertension.Anycombinationofapreexisting
hypertension,whateverthecause,andsleepdisturbancesmayincreasehypertensionseverityandlimit
treatmentefficacyEuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management93Hypertension(HTN)affectsonebillionindividualsworldwide,particularlytheelderly,
andrepresentsamajorriskfactorforcoronaryarterydisease,heartfailure,andrenalandcerebrovascular
disease.Elevatedbloodpressureisthemostfrequentpreoperativehealthprobleminnoncardiacsurgery
patients,withanoverallprevalenceof2025%.Numerousstudieshaveshownthatstage1orstage2HTN
(<180/110mmHg)isnotanindependentriskfactorforperioperativecardiovascularcomplications[1].
Unfortunately,despitethehighprevalenceofHTNandtheavailabilityofnumerouseffective
antihypertensiveagents,manypatientshaveuncontrolledhighbloodpressure.Accordingly,the
perioperativeevaluationisauniqueopportunitytoidentifypatientswithHTNandinitiateappropriate
therapy.AlthoughpreexistingHTNisthemostcommonmedicalreasonforpostponinganeededsurgery,
itisunclearwhetherpostponingsurgeryinordertoachieveoptimalbloodpressurecontrolwillleadto
reducedcardiacrisk[2].Ineverydayclinicalpractice,veryoftenwehavetogiveanswerstothefollowing
questions:ShouldIgoaheadwithapatientwithuncontrolledHTN,orshouldIpostponethesurgery?Are
patientswithuncontrolledHTNatanincreasedperioperativeriskforcardiovascularcomplications?What
istheriskofcardiaccomplicationsduringandaftersurgery?Howcanthatriskbereducedoreliminated?
ArethereanydataonwhichIcanbasemydecision?Inthisfield,wedonothavestrongdataaccordingto
evidencebasedmedicine,andmuchoftheevidencefortheperioperativerisksassociatedwithHTN
comesfromuncontrolledstudiesperformedbeforecurrent(moreeffective)managementwasavailable.
PathophysiologyBloodpressureelevationissustainedbyanincreaseofsystemicvascularresistance,
increasedpreload,activationofthesympatheticnervoussystem(SNS)andreninangiotensinsystem
(RAS),baroreceptordenervation,rapidintravascularvolumeshifts,serotonergicoverproduction,and
alteredcardiacreflexes.Decreasedsympathetictoneduringanaesthesiaresultsinarelativedecreasein
cardiacpreloadandafterload.Duringtheinductionofanaesthesia,sympatheticactivationcancausean
increaseinbloodpressureof2030mmHgandheartrateincreaseof1520bpminnormotensive
individuals[3].ThisresponsemaybemorepronouncedinuntreatedHTN.Astheperiodofanaesthesia
progresses,patientswithpreexistingHTNaremorelikelytoexperienceintraoperativebloodpressure
lability,whichmayleadtomyocardialischaemia.Duringtheimmediatepostoperativeperiod,asthe
patientrecoversfromtheeffectofanaesthesia,bloodpressureandheartrateslowlyincrease[4].
PerioperativeevaluationInthisprocesswehavetobalancebetweentwopoints:thesafetyofthepatient
duringandaftertheoperationandunjustifieddefermentsandcancellationsofsurgery.Itisimportantto
knowwhetherthepatientcarriedthediagnosisofHTNbeforesurgeryandwasreceivingantihypertensive
treatment,becausemanypatientsareanxiousduringthepreoperativeevaluationandmayhaveatransient
increaseinbloodpressure.ItisimportantforphysicianstofollowtheESH/ESCrecommendationsfor
bloodpressuremeasurementanddiagnosticapproach[5].Thenextandmostimportantstepisrisk
stratificationbecausehighriskpatientsmayneedfurtherevaluationwhereasintermediateandlowrisk
patientscanundergosurgerywithoutfurtherdelay.Cardiovascularcomplicationsfollowingnoncardiac
surgeryconstituteanenormousburdenofperioperativemorbidityandmortality[6].Preoperative
noninvasivecardiacstresstestingisassociatedwithimprovedoneyearsurvivalandreduced
hospitalizationinhighriskpatients;however,thebenefitswereminorinpatientswithintermediaterisk,
anddelayforcardiacworkupwasassociatedwithincreasedmortalityinlowriskpatients[7].Previousor
currentcardiacdisease,diabetesmellitus,functionalstatus,bodymassindex,nutritionalstatus,andrenal
insufficiencyallconferhigherriskforperioperativecardiaccomplications.Activecardiacconditionsfor
whichthepatientshouldundergodetailedevaluationandtreatmentbeforesurgeryincludeacutecoronary
syndrome,decompensatedheartfailure,significantarrhythmia,andseverevalvulardisease.Therevised
cardiacriskindexdiscriminatedmoderatelywellbetweenpatientsatlowversushighriskforcardiacevents
afternoncardiacsurgery[8].Inaddition,wehavetopayattentiontotheidentificationofsymptomsand
signsindicativeforsecondaryHTNfromthehistoryandphysicalexamination.Inametaanalysisof30
observationalstudiesthelikelihoodofexperiencinganadverseperioperativecardiaceventwasfoundtobe,
onaverage,1.31foldhigherinhypertensivesthannormotensives[9].Anabnormallylowankletoarm
indexisanindependentriskfactorforpostoperativecardiaccomplications[10].Althoughthereseemsto
beatendencyforincreasedincidenceofperioperativehaemodynamicinstabilityinpatientswith
myocardialischaemiaandcardiacarrhythmiasinseverehypertension,existingdatadonotunequivocally
supportthenotionthatpostponingsurgerytooptimizebloodpressurecontrolwillimproveperioperative
cardiacoutcomes.ThisisinaccordancewithACC/AHAguidelines,inwhichuncontrolledsystemicHTN
perseisconsideredonlyaminorriskfactorthatdoesnotaffectoverallperioperativemanagement[11].
However,welacklargescaletrialsthatincludeasufficientnumberofpatientswithsevereHTNtoallow
validstatisticalanalysisandhencetodrawconclusionsfromthesepatientpopulations.Electrocardiogram
shouldbepartofallroutineassessmentsofsubjectswithhighbloodpressureinordertodetectleft
ventricularhypertrophy,patternsofstrain,ischaemia,andarrhythmias.ThepresenceofQwavesor
significantSTsegmentelevationordepressionhavebeenassociatedwithincreasedincidenceof
perioperativecardiaccomplications.Therefore,itmaybehelpfulinsomecasestocontactthereferring
physicianinordertoobtainmoreaccuratearterialpressurevaluesthantheonesmeasuredathospital
admission(whitecoatHTN).Intheselines,thedoctorcanfollowaclinicalalgorithmbasedon5questions:
1)Istheoperationurgent?2)Doesthepatienthaveanyactivecardiaccondition?3)Whichisthespecific
riskassociatedwiththeparticularsurgery?4)Whatisthefunctionalcapacityofthepatient?5)Doesthe
patienthaveanyotherclinicalriskfactors?Figure1showsanalgorithmwiththediagnosticevaluationand
approachofapatientundergoingnoncardiacsurgery.PerioperativemanagementAsmentionedpreviously,
carefulevaluationpriortosurgerytoidentifytheunderlyingcausesofHTNisimportantinselectingthe
besttreatmentoption.However,notonlyHTNbutalsohypotensionisariskduringtheperioperative
period.Whilehypertensivepeaksneedtobeavoided,profoundhypotension,especiallywhenassociated
withbaroreflexmediatedtachycardia,canbeequallydetrimental.Severedecreaseinintraoperativearterial
pressure(decreaseto<50%ofpreoperativelevelsorby>33%for10min)wasanindependentpredictor
ofperioperativeadverseevents[12].Maintainingarterialpressureperioperativelyat70100%ofbaseline
andavoidingtachycardiaarekeyfactorsintheoptimalmanagementofhypertensivesurgicalpatients.
Particularcareshouldbetakentoavoidwithdrawalofbblockersandclonidinebecauseofpotentialheart
rateorbloodpressurerebound.Inpatientsunabletotakeoralmedications,parenteralbblockersand
transdermalclonidinemaybeused.Forstage3HTNthepotentialbenefitsofdelayingsurgerytooptimize
theeffectsofantihypertensivemedicationsshouldbeweighedagainsttheriskofdelayingthesurgical
procedure.Forthosepatientsunabletotakeoralmedicationbutrequiringtreatment,parenteralalternatives
mustbeused.Intravenousbblockers,includingpropranolol,atenolol,andmetoprolol,areattractive
becauseoftheirantiisPERIOPERATIVESCREENINGANDMANAGEMENTOFHYPERTENSIVE
PATIENTSAthanasiosJ.Manolis1,SerapErdine2,ClaudioBorghi3,KostasTsioufis41Departmentof
Cardiology,AsklepeionHospital,Athens,Greece2CardiologyDepartment,CerrahpasaSchoolof
Medicine,IstanbulUniversity3DipartamentodiMedicinaInterna,dellInvecchiamentoeMalattie
Nephrologiche,UniversitadeglistudidiBologna4CardiologyDepartment,HippokratioHospital,
UniversityofAthens,Greece2011;12:No.47Figure1.Cardiacalgorithmfornoncardiacsurgery94
References1.LetteJ,etal.Preoperativeandlongtermcardiacriskassessment.Predictivevalueof23
clinicaldescriptors,7multivariatescoringsystems,andquantitativedipyridamoleimagingin360patients.
AnnSurg1992;216:192.2.CasadeiB,etal.Isthereastrongrationalfordeferringelectivesurgeryin
patientswithpoorlycontrolledhypertension?JHypertens2005;23:19.3.KiharaS,etal.Hemodynamic
responseamongthreetrachealintubationdeviceinnormotensiveandhypertensivepatients.AnesthAnalg
2003;96:890.4.GoldmanL,etal.Riskofgeneralanesthesiaandelectiveoperationinthehypertensive
patient.Anesthesiology1979;50:285.5.ManciaG,etal.2007Guidelinesforthemanagementof
hypertension:thetaskforceforthemanagementofarterialhypertensionoftheESHandESC.JHypertens
2007;25:1105.6.ManganoDT,etal.Associationofperioperativemyocardialischemiawithcardiac
morbidityandmortalityinmenundergoingnoncardiacsurgery.NEnglJMed1990;323:1781.7.
WijeysunderaDN,etal.Noninvasivecardiacstresstestingbeforeelectivemajornoncardiacsurgery:
populationbasedcohortstudy.BrMedJ2010;340:5526.8.FordMK,etal.Systematicreview:prediction
ofperioperativecardiaccomplicationsandmortalitybytherevisedcardiacriskindex.AnnInternMed
2010;152:26.9.HowellSJ,etal.Hypertension,hypertensiveheartdiseaseandperioperativeheartdisease.
BrJAnesth2004;92:570.10.FisherBW,etal.Theankletoarmindexpredictsriskofcardiac
complicationsafternoncardiacsurgery.AnesthAnalg2008;107:149.11.EagleKA,etal.ACC/AHA
guidelinesupdateforperioperativecardiovascularevaluationfornoncardiacsurgery.Circulation2002;
105:1257.12.GoldmanL,etal.Riskofgeneralanesthesiaandelectiveoperationinthehypertensive
patient.Anesthesiology1979;50:285.13.BisognanoJ,etal.Perioperativemanagementofhypertension.
In:HypertensionPrimer.4thedition.2008:553.14.FleischmannKE,etal.2009ACC/AHAfocused
updateonperioperativebetablockade.JAmCollCardiol2009;54:13.15.ChopraV,etal.Perioperative
betablockersformajornoncardiacsurgery:primumnonnocere.AmJMed2009;122:222.16.Schirmer
U,etal.Preoperativeadministrationofangiotensinconvertingenzymeinhibitors.Anaesthest2007;56:
557.17.BrabantSM,etal.Thehemodynamiceffectsofanestheticinductioninvascularsurgicalpatients
chronicallytreatedwithangiotensinIIreceptorantagonists.AnesthAnalg1999;89:1388.18.
WijeysunderaDN.Calciumchannelblockersforreducingcardiacmorbidityafternoncardiacsurgery:a
metaanalysis.AnesthAnalg2003;97:634.19.PoldermansD,etal.Guidelinesforpreoperativecardiac
riskassessmentandperioperativecardiacmanagementinnoncardiacsurgery.EurHeartJ2009;30:2769.
20.WhinneyC,etal.Perioperativemedicationmanagement:generalprinciplesandpracticalapplications.
ClevClinJMed2009;76:S126S132.chaemicbenefitsintheperioperativeperiod.Otheralternativesare
intravenousenalaprilverapamil,ordiltiazemandatransdermalclonidinepatch.Formoreserious
hypertension,labetalol,nitroglycerin,andsodiumnitroprussideareappropriate.Parenteralhydralazine
shouldbeavoidedinpatientswithischaemicheartdisease(unlessthepatientisalreadyunderbblockade)
becausethereflextachycardiaproducedmayleadtoischaemia.Useofsublingualnifedipineisabsolutely
contraindicatedbecauseithasbeenassociatedwithstrokes,MI,anddeath.Duringtheintraoperative
period,controlofbloodpressuremaybeachievedbydeepsedation,theuseofvasodilatorssuchas
nitroglycerinornitroprusside,oracombinationofthetwo(Tables1,2).Asthepatientemergesfrom
surgery,anticholinesteraseoranticholinergicagentsarefrequentlygiventoreversetheneuromuscular
blockadeusedduringanaesthesia.Postanaesthesiabloodpressureelevationisfrequentlycausedby
sympatheticactivationduetopatientanxietyandpainuponawakening,alongwithwithdrawalfrom
continuousinfusionofnarcotics.Intravenousagentsofanyclasscanbeusedduringtheimmediate
postoperativeperiod;however,agentswithslightlylongerdurationofactionmaybepreferable.Becauseof
thelargevolumeshiftsthatoccurduringsurgery,administrationofblood,saline,orloopdiureticsmaybe
necessarydependingontheindividualneedsofthepatient[13].Postoperativebloodpressuretreatment
alsoincludesthecontrolofpain,anxiety,hypoxia,andhypothermia.Diuretics.Specialattentionmustbe
paidtothepotassiumlevelsofpatientsondiuretics.Diureticsshouldnotbeadministeredonthedayof
surgerybecauseofthepotentialadverseinteractionofdiureticinducedvolumedepletionand
hypokalaemiaandtheuseofanaestheticagents.Hypokalaemiamaycausearrhythmiasandpotentiatethe
effectsofdepolarizingandnondepolarizingmusclerelaxants.Betablockers.Recentstudieshavecalled
intoquestionthebenefitofnewlyadministeredperioperativebblockade,especiallyinpatientsatlowto
moderateriskofcardiacevents.Thespecificissueofwhethertoinitiateuseofbblockersperioperatively
insuchpatientshasbeenextremelycontroversialinthepastfewyears,mostlyduetoconflictingdatafrom
twolargeclinicaltrials,POISEandDECREASEIV.Accordingtorecentlypublished2009ACC/AHA
guidelines[1415],inpatientsundergoingsurgerywhoarealreadyreceivingbblockersfortreatment,b
blockersshouldbecontinuedperioperatively(classI,recommendationC).Forpatientsundergoing
vascularsurgerywhoareathighcardiacrisk,bblockerstitratedtoheartrateandbloodpressureare
probablyrecommended(IIa,B).Forpatientsundergoingeitherintermediateriskprocedureorvascular
surgery,theusefulnessofinitiatingbblockadeisuncertain.Theusefulnessofbblockersisalsouncertain
inpatientsundergoinglowerrisksurgery.FindingsfromthePOISEtrialsuggestthatstartinghigherdoses
ofbblockersacutelyonthedayofsurgeryisassociatedwithrisk.Whenbblockadeisstarted
preoperatively,itshouldbestartedwellinadvanceofsurgeryatalowdosewhichcanbetitratedupas
bloodpressureandheartrateallow.Theguidelinesrecommendcarefulpatientselection,doseadjustment,
andmonitoringthroughouttheperioperativeperiod.Table1.Perioperativeuseofantihypertensivedrugs
DrugPerioperativeuseCommentsDiureticsNotondayofsurgeryPotentialhypokalaemia,volume
depletionBetablockersAvoidstartingpreviousWithcautioninintermediatedayinhighriskpatientsand
lowriskACEI/ARB'sLastdosedaybeforeRestartACEI/ARB'swithcautionoperationifthepatientis
euvolemicCalciumDiltiazemeffectiveinCHDchannelandverapamilinsuprablockersventricular
tachycardiaClonidineContinuedoseWithdrawalmaycausebloodpressurereboundEsmololMaycause
bradycardiaandpulmonaryoedemaLabetalolMaycausebradycardia,heartblock,anddelayed
hypotensionTable2.InitialdosingofantihypertensiveagentsAgentCommentEnalaprilatIntravenous
intermittent:0.6251.25mg(lowerdoseifhyponatremia,possiblevolumedepletion,concomitantdiuretic
therapy,orrenalfailure)over5min,thendoubleat4to6hintervalsuntildesiredresponse,asingle
maximaldoseof1.255mg,toxicity,oracumulativedoseof20mgwithina24hperiodEsmolol
Intravenousinfusion:250500mg/kg/minfor1min,followedbya50100mg/kg/mininfusionfor4min,
thentitrateusingthesamesequenceuntildesiredresponse,amaximaldoseof300mg/kg/min,ortoxicity
HydralazineIntravenousintermittent:320mgslowIVpushevery2060minLabetalolIntravenous
intermittent:20mgover2min,thendoubleat10minintervalsuntildesiredresponse,asinglemaximal
doseof80mg,toxicity,oracumulativedoseof300mg/dNitroglycerinIntravenousinfusion:5mg/min
initially,thentitratein5mg/minincrementsevery35minuntildesiredresponseortoxicityNitroprusside
Intravenousinfusion:0.250.5mg/kg/mininitially,thentitratedoseevery12minuntildesiredresponse,a
maximaldoseof10mg/kg/min,ortoxicityAngiotensinconvertingenzymeinhibitors(ACEI)and
angiotensinreceptorblockers(ARBs).ThereismuchdebateintheliteratureovertheuseofACEIsor
ARBsintheperioperativeperiodduetotheirpotentialcentralvagotoniceffects.Theseagentsaloneorin
combinationhavebeenassociatedwithmoderatehypotensionandbradycardia,particularlywhen
discontinuedlessthan10hoursbeforesurgery.Insomepatientsthismayberelatedtoadecreasein
intravascularvolume.ThecontinuationofACEItherapyinthemorningisnotassociatedwithabetter
controlofbloodpressureandheartratebutcausesamorepronouncedhypotensionwhichrequires
therapeuticintervention.PatientschronicallytreatedwithACEIsandARBsshouldreceivethemlaston
thedaypriortotheoperationandwithoutpremedicationinthemorning[1617].Thereismixedevidence
thatprophylaxiswithglycopyrrolatecanattenuatethiseffect.Considerationshouldbegiventorestarting
ACEIinthepostoperativeperiodonlyafterthepatientiseuvolemic,inordertodecreasetheriskof
perioperativerenaldysfunction.Calciumchannelblockers.Inametaanalysisof11studiesinvolving1007
patients,calciumchannelblockerssignificantlyreducedischaemiaandsupraventriculartachycardia[18].
Themajorityofthesebenefitswereattributabletodiltiazem.Dihydropyridinesandverapamildidnot
decreasetheincidenceofmyocardialischaemiaalthoughverapamildiddecreasetheincidenceof
supraventriculartachycardia.Clonidine.Clonidinehasafavourablesympatheticmediatedeffectwitha
biphasicresponse(atlowerdosescentralsympatheticsuppressionwithavasodilatoryeffect,athigher
dosesperipheralactivationwithavasoconstrictoreffect).Itsignificantlyreducestherateofperioperative
cardiovascularcomplicationsinpatientswithcoronaryarterydisease.Itisonlypartiallyeffectiveforrapid
bloodpressurecontrolintheperioperativeperiodandcontributestoanalgesiaandsedation.Esmolol.
Esmololisab1selectiveadrenergicblockerthatcausesareductioninheartrateandcardiacoutputbut
mayincreasesystemicvascularresistance.Ithasarapidonsetandshortdurationofaction,andmaycause
bradycardia,bronchospasm,seizures,andpulmonaryoedema.Labetalol.Labetalolisanonselective
combinedaandbadrenergicblockerwithlittleeffectonheartrateandcardiacoutput.Ithasamoderate
hypotensiveactionoflongdurationandiscommonlyusedinemergencysituations.Itmaycause
bronchospasm,bradycardia,heartblock,anddelayedhypotension.Nitroglycerin.Nitroglycerinisthemost
widelyuseddrug.Atlowerdosesitdecreasesthepreloadwhileinhigherdosesitdecreasestheafterload,
andmayincreasetheheartrate.Itisthedrugofchoiceinpatientswithcoronaryarterydisease,aswellas
inpulmonaryoedemaandheartfailure.Thekeypointsoftheperioperativemanagementinclude:a)
accuratedocumentationofpreoperativemedication,b)decisiononstoppingmedicationspriortosurgery,
c)monitoringofappropriatechemistrystudyresultstodeterminedosagesandtheoccurrenceofadverse
effects,d)appropriatemanagementofpain,e)administrationofadjunctivemedications,andf)useof
appropriateformulations[1920].EuropeanSocietyofHypertensionScientificNewsletter:Updateon
HypertensionManagement95Theincidenceofcardiovasculardisease(CVD)isstillincreasingglobally,
butpreventionandtreatmenthaveimprovedconsiderablyduringthelast20years.Astreatmentisnot
curative,preventionispreferablealthoughitcallsforinterventioninmanymoresubjects.Inordernotto
treatmanysubjectsunnecessarily,itisimportanttoidentifythoseathighestriskofdevelopingCVDinthe
future.Forthispurpose,severaltoolsforcardiovascularriskestimationhavebeendeveloped.InEurope,
themostwidelyusedscoringsystemsareSCORE[1]insubjectswithoutknownCVDordiabetes,andthe
cardiovascularriskstratificationchartoftheEuropeanSocietyofHypertension(ESH)[2]insubjectswith
hypertension.However,manyoftheseriskscoreswill,ingeneral,overestimatethecardiovascularrisk[3]
becauseimprovedprimaryandsecondarycardiovascularpreventionhasreducedboththeincidenceof
myocardialinfarctionsandcasefatalities[4]inmanyWesterncountries.TheSCOREsystemasabasisfor
strategiesofpreventionLiketheESH,theEuropeanSocietyofCardiology(ESC)hasfocusedonCVD
prevention,asreflectedintheirguidelinesforclinicalpractice[5].InsubjectswithoutknownCVD,type2
diabetes,type1diabeteswithmicroalbuminuria,orveryhighlevelsofindividualriskfactors,theriskof
developingfatalatheroscleroticeventsiscalculatedusingtheSCOREsystem,availableinchartform
(Figure1)orasaninteractivetool(HeartScore)ontheESCwebsite(onlineversionorPCbased
program)(http://www.escardio.org/Policy/prevention/tools/healthtoolkit//Pages/HeartScore.aspx).
HeartScoreisbasedondatafromEuropeanpopulationsurveys,andnationalversionsareavailablein
severalcountries.Absoluteriskofcardiovasculardeathwithin10years<1%isdefinedaslowrisk;14%
riskisdefinedasmoderate;59%asincreased,and10%ashigh.Generally,therearetwoSCOREchart
versions:forpopulationswithlow(Belgium,France,Italy,Luxemburg,Portugal,Spain,andSwitzerland)
orhighCVDrisk.Inaddition,eachoftheSCOREchartsisbasedeitherontotalcholesterolorthetotal
cholesterol/HDLcholesterolratio.Thetreatmentgoalsforbloodpressureaswellasothercardiovascular
riskfactorsdependonthisriskstratification,buttherearenouniversalthresholdsforinitiationofdrug
treatment.Forsubjectswitha10yearriskofcardiovasculardeath<5%,inadditiontonotsmoking,BMI<
25kg/m2,and30minutesofmoderateexercisedaily,thefollowinggoalsarerecommended:Blood
pressure<140/90mmHg;totalcholesterol<5mmol/l;lowdensitylipoprotein(LDL)cholesterol<3
mmol/l;andbloodglucose<6mmol/l.Thesethresholdsarearbitraryforbloodpressureaswellasfor
cholesterolastheassociationbetweenbloodpressure[6]aswellascholesterol[7]andtheriskof
developingCVDarealsopresentatlowervalues.Ingeneral,drugtreatmentisnotrecommendedinthis
lowmoderateriskgroupiftreatmentgoalsarenotmet.Subjectsathighrisk(10%)havethesame
treatmentgoalsaspatientswithknownCVDordiabetes:Bloodpressure<130/80mmHg;totalcholesterol
<4.5(4.0)mmol/l;andLDLcholesterol<2.5(2.0)mmol/l.Inthishighriskgroup,drugtreatmentis
recommendediftreatmentgoalsarenotmet.Insubjectswithincreasedrisk(59%),alessaggressive
approachisallowed.TheimpactofageonriskcalculationAgeisthemostimportantriskfactorinthe
SCOREandmaythereforeleadtoundertreatmentinyoungersubjectsandovertreatmentinoldersubjects.
Toavoidundertreatmentinyoungersubjects,itisrecommendedtousearelativeriskchartortocalculate
theabsoluteriskasifthesubjectwere60yearsold.Toavoidovertreatmentintheelderly,cautionis
recommendedwithdrugtreatmentifageisthemajor/solereasonfortheincreasedcardiovascularrisk.The
actualcardiovascularriskmaybehigherthanindicatedintheSCOREchart(Figure1)ifsome
cardiovascularriskfactorsnotincludedintheSCOREmodelarepresent(familyhistoryofpremature
CVD,physicalinactivity,abdominalobesity,andothers).LifestylemodificationInallsubjects,
interventionshouldincluderecommendationsoflifestylechanges.Althoughlifestyleinterventionshave
beendemonstratedtoreducebloodpressure,theyhavenotyetbeendemonstratedtopreventcardiovascular
complicationsinpatientswithhypertensionandshouldthereforenotdelayinitiationofdrugtreatmentin
subjectsathighriskfordevelopingCVD.AstheriskofdevelopingCVDismultifactorial,themanagement
ofpatientswithhypertensionshouldnotberestrictedtofactorsaffectingbloodpressure,butshouldalso
includearecommendationofsmokingcessation.However,severallifestylechangeshavebeenshownto
reducebloodpressure:Weightloss[8],increasedphysicalactivity[9],saltrestriction,dailyfishoil[10],
dietaryapproachesintroducedbyDASHdiet[11],andreducedalcoholintake.Theselifestylechangeswill
besufficientinmanysubjectstoreducethecardiovascularriskandmayprovetohaveanenormousimpact
onCVDpreventiononapopulationscale.TheriskchartoftheEuropeanSocietyofHypertensionThe
ESHriskchart(Figure2)[2]usesthetermslow,moderate,high,andveryhightoindicatean
approximateriskofcardiovascularmorbidityandmortalityinthefollowing10years,whichissomewhat
analogoustotheincreasingleveloftotalcardiovascularriskestimatedbytheFraminghamorSCORE
models.However,theadditionaluseofcardiovascularmorbidityisespeciallyrelevantforpatientswith
hypertensionwhohaveincreasedriskofdetrimentalnonfatalstroke.SimilartotheESCrecommendations,
thekeymessagesintheESHriskchart[12]are:1)Alldefinitionsofhypertensionarearbitrarybecausethe
riskofCVDdecreasescontinuouslywithdecreasingbloodpressuredowntoanoptimalbloodpressure
below120/70mmHg(Figure2);2)AshypertensionisonlyoneofCARDIOVASCULARRISKPROFILE
ANDANTIHYPERTENSIVETREATMENTMichaelHechtOlsen1,EvaPrescott2,PeterM.Nilsson3,
RenataCfkov41CardiovascularResearchUnit,DepartmentofInternalMedicine,GlostrupUniversity
Hospital,Denmark2DepartmentofCardiology,BispebjergUniversityHospital,Denmark3Departmentof
ClinicalSciencesMedicine,UniversityHospital,Malm,Sweden4DepartmentofPreventiveCardiology,
InstituteforClinicalandExperimentalMedicine,Prague,CzechRepublic2011;12:No.48Figure1.The
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HypertensioncomparedwithSCOREinthegeneralpopulation.JHypertens2009;27:23512357.19.
SehestedtT,JeppesenJ,HansenTW,etal.Riskstratificationisimprovedbyaddingmarkersofsubclinical
organdamagetoSCORE.EurHeartJ2010;31:883891.severalinteractingcardiovascularriskfactors,
theabsolutecardiovascularriskisdependentonalltheriskfactors;and3)Treatmentindicationsandgoals
aredeterminedbytheabsolutecardiovascularriskandaretherebydependentoncardiovascularriskfactors,
subclinicalcardiovasculardamage,andCVD.AsillustratedbytheSCORE(Figure1),alargeproportionof
patientswithhypertensionwillnotbeathighabsoluteriskofcardiovasculardeath.However,someofthese
patientsmaybeathighriskofnonfatalcardiovascularevents,nonfatalstrokeinparticular.TheESC
guidelinesforantihypertensivetreatmentfollow,toalargeextent,theESHguidelines,buttheyare
somewhatmorerestrictiveregardinginitiationofantihypertensivedrugtreatment.Specialconsiderations
Thefollowingthreegroupsofpatientsareoftendebated:Hypertensivepatientsatlowaddedrisk,subjects
withhighnormalbloodpressureandseveraladditionalcardiovascularriskfactorsorsubclinical
cardiovasculardamage,andnormotensivepatientswithCVD.Hypertensivepatientsatlowaddedrisk
(20%ofthemiddleaged,healthypopulation[12])Inpatientswithgrade1hypertensionwithoutother
cardiovascularriskfactors,theESHprimarilyrecommendslifestylechanges,but,ifhypertensionpersists
aftersixmonths,antihypertensivedrugtreatmentisrecommendednotbasedonclearscientificevidence
butbasedonthefactthatthepatientswilleventuallydevelopadditionalriskfactors,andontheassumption
thatearlypreventionisbetterthanlate[13].However,theESCguidelinesdonotrecommend
antihypertensivedrugtreatmentinpatientswithgrade1hypertensionandSCORE<1%,duetotheirlow
cardiovascularrisk.AstheSCOREoftenunderestimatestheriskfornonfatalstrokeinwomen,therisk
associatedwithnottreatingmiddleagedwomenwithhypertensionandSCORE<1%shouldbecarefully
considered.Beforemakingthisdecision,itiscrucialtoassessallcardiovascularriskfactorsandtofollow
thesepatientsbecause,overtime,the10yearabsoluteriskofcardiovasculardeathwillincreaseabove1%
thusrequiringdrugtreatment.Thisriskofundertreatmentinmiddleagedwomenmayexplainthe
relativelyhighnumberofcardiovasculardeathsin40yearoldwomenintheVsterbottenIntervention
ProgramofnorthernSweden[3].Subjectswithhighnormalbloodpressure(15%ofthemiddleaged,
healthypopulation[12])Healthysubjectswithhighnormalbloodpressurehaveonlyslightlyelevated
cardiovascularriskcomparedtohealthysubjectswithoptimalbloodpressure(<120/80mmHg)[14].
However,alargeproportionofcardiovasculareventsoccurinthisratherlargegroup,and,sincerisk
assessmentisoftenperceivedascomplicated,theydeservespecialattention.Insubjectswithhighnormal
bloodpressureandSCORE<5%,nodiabetesandnosignofsubclinicalcardiovasculardamage,lifestyle
adviceisrecommendedbytheESC[5]andESH[2].Insubjectswithhighnormalbloodpressureand
diabetes,thesesocietiesrecommendlifestylechangesaswellasantihypertensivedrugtreatment.Inthe
intermediategroupofsubjectswithhighnormalbloodpressureandSCORE5%orwithhighnormal
bloodpressureandhighaddedcardiovascularriskduetothepresenceofanythreeothercardiovascularrisk
factors,metabolicsyndromeorsubclinicalcardiovasculardamage,theyrecommendlifestylechangesand
theconsiderationofantihypertensivedrugtreatment.However,antihypertensivetreatmentinsubjectswith
highnormalbloodpressureanddiabetesorinsubjectsathighaddedriskhasneverbeendemonstratedto
reducemajorcardiovascularevents[13],butislikelytoreducesubclinicalcardiovasculardamage[2]and
istherebyassumedtoreducecardiovascularrisk[13].Bymeasuringsubclinicalcardiovasculardamage,it
isalsopossibletotargetandmonitortreatmentonamoreindividualbasis[15].Asblockageoftherenin
angiotensinaldosteronesystemisassociatedwithregressionofsubclinicalcardiovasculardamagewithout
metabolicsideeffects,typicaltreatmentwillincludeanangiotensinconvertingenzyme(ACE)inhibitoror
anangiotensinIIreceptorblocker(ARB)[16].NormotensivepatientswithCVDDespitelittleevidence,
theESHrecommendedintheir2007guidelines[2]antihypertensivedrugtreatment,especiallyACE
inhibitorsorARBs,inpatientswithCVDorrenalinsufficiencyindependentlyofbloodpressure.However,
theclearscientificevidenceformoreaggressivetreatmentinpatientswithCVDislacking[13],andpost
hocanalysesfromtheOnTargetstudy[17]havedemonstratedaworseprognosisinpatientsreachinga
verylowbloodpressure,indicatingathresholdforhowfarbloodpressuremaybereducedinpatientswith
CVD.Therefore,theESHhavemodifiedtheirratheraggressiverecommendationforatreatmentgoaljust
below130/80mmHg[13]whichisalsousedbytheESC[5].Thefirstlineofantihypertensivedrug
treatmentisdependentonthetypeofCVD.Indiabeteswithmicroalbuminuriaorrenalinsufficiency,ACE
inhibitorsorARBsshouldbeincludedinthetreatment.PracticaluseofriskstratificationIngeneral,the
SCOREshouldbeusedinhealthy,normotensivesubjects,andtheESHriskchartinhypertensivepatients.
However,physiciansarestillreluctanttouseriskstratificationtools,andthedifferencesbetweentheESH
riskchartandtheSCORE,ifusedasrecommendedbytheESC,areonlysmall[18].Therefore,itismore
importantthatdoctorsusetheriskstratificationtoolwithwhichtheyarefamiliarandlessimportantwhich
tooltheyuse.Generalassessmentofsubclinicalcardiovasculardamageinnormotensivesubjectswith
SCORE<5%isanoverwhelmingtaskwithoutasubstantialclinicalimpact[19].However,assessmentof
subclinicalcardiovasculardamageinnormotensivesubjectswith1%<SCORE<5%mayhavesome
clinicalimpact.Insubjectswithhighnormalbloodpressure,assessmentofsubclinicalcardiovascular
damagemayincreasethesensitivityforidentifyingsubjectsexperiencinglatercardiovascularevents[12].
However,asapproximately80%ofhealthysubjectswithhighnormalbloodpressureandSCORE5%
havesubclinicalcardiovasculardamage[19],calculationoftheSCOREcouldbeconsideredinsteadof
measuringsubclinicalcardiovasculardamageinthisgroup.SummaryEstimationofabsolute
cardiovascularriskisimportantforthechoiceofprimaryaswellassecondarycardiovascularprevention.
Ingeneral,physiciansareadvisedtousetheSCOREinapparentlyhealthysubjectswithoptimalornormal
bloodpressure,theESHriskstratificationchartinpatientswithhypertension,andeitheroneor,betterstill,
acombinationofthetwoinstrumentsinapparentlyhealthysubjectswithhighnormalbloodpressure.
Figure2.Theaddedabsolute10yearriskoffatalornonfatalcardiovascular(CV)eventsaspredictedby
bloodpressure,traditionalCVriskfactors,themetabolicsyndrome(MS),subclinicalCVorgandamage
(OD),diabetesandCVorrenaldisease;HThypertension;SBPsystolicbloodpressure;DBP
diastolicbloodpressureEuropeanSocietyofHypertensionScientificNewsletter:UpdateonHypertension
Management97IntroductionFollowingthediscoverybyMahomedandGarrodintheearly1800sthat
hyperuricaemiawasthecauseofgout,itwasproposedthatitalsohadacausalroleinavarietyof
cardiovascularandrenalconditions,includinghypertension,arteriolosclerosis(thehistologicallesionof
hypertension),kidneydisease,andheartdisease[1].Bythe1990s,however,prospectivestudiescouldnot
establishuricacidasacausalfactorintheseconditions[2].Intheearly2000s,asubstantialbodyof
clinical,epidemiological,andanimalstudiesconvincinglydefinedapositiveassociationofserumuricacid
withcardiovascularevents(CVD)inthegeneralpopulationand,particularly,amonghypertensivepatients.
DefinitionofserumuratelevelsSerumuricacidlevelsaresimilarinboysandgirlsduringchildhood.
However,agenderdifferenceappearsatadolescence.Innormalhealthyadultmales,serumuratevalues
exceedthoseinfemalesofreproductiveageduetoenhancedrenalurateclearancebyoestrogenic
compounds[3].Aftermenopause,serumuratevaluesinhealthyfemalesincreaseandapproximatethosein
healthymalesofcorrespondingage.Inpostmenopausalwomen,treatmentwithhormonereplacement
therapycausesalesserriseinserumuratevalues[4].Serumuratevaluesmayvarysignificantlyasaresult
offactorsthatmodifyitsgenerationorurinaryexcretion.Highpurineorproteindiets,alcohol
consumption,highcellturnover,orenzymaticdefectsofpurinemetabolismenhancegeneration,while
reductioninglomerularfiltrationrate(GFR)oradministrationofdiuretics(suchasthiazides)decrease
urinaryexcretionofuricacid.Asaresult,serumuricacidlevelsareincreased.Ontheotherhand,drugs
thatinterferewithpurinemetabolismorenhanceincreasedurinaryexcretionareassociatedwitha
reductioninserumuricacidlevels.Hyperuricaemiaisusuallydefinedasserumlevels>6.57mg/dland>
6mg/dlinmenandwomen,respectively[3].HomeostasisofuricacidUricacid(7,9dihydro1Hpurine
2,6,8(3H)trione)isamajormetaboliteofpurinenucleotides.Inmostmammals,purinenucleotidesare
degradedtoxanthineorhypoxanthinethroughtheactionofanenzymecomplex.Inturn,xanthineand
hypoxanthinearemetabolizedtouricacidbyxanthinedehydrogenaseoruratesynthetaseand,through
urateoxidase,ahepaticderivedenzyme,toallantoin,whichishighlysolubleinurine[5].Duringthe
MiocenePeriod(about20to5millionyearsago),twoparallelbutdistinctmutationsoccurredduringthe
primateevolutionrenderingtheuricasegenenonfunctional,preventingthefurtheroxidationofuricacidto
allantoininhumans[5].Thisresultedinserumuricacidlevelsbeinghigherinhumansandgreatapesthan
inothermammals.Uricacidisaweak,odourlessorganicacid.ItssolubilityispooratacidpHbutis
greatlyenhancedathighpHdissociatingintourateandahydrogenion:uricacidurate+H+Atthe
normalpHof7.4,thisreactionisshiftedtotheright.Asaresult,mosturicacidcirculatesasurateanions.
Normalhumanshaveserumurateconcentrationsapproachingthetheoreticallimitofsolubilityofuratein
plasma(about6.8mg/dl)andexcreteurinethatissupersaturatedwithrespecttouricacid.Uricacidisnot
typicallyingested.Itisproducedintheliverfromthedegradationofdietaryandendogenouslysynthesized
purinecompounds.Dietaryintakeappearstoprovideasignificantsourceofurateprecursors[6].The
normaladultmalehasatotalbodyurateofabout1200mg,twicethatofthefemale.Serumuratelevels
reflectthenetbalancebetweenitsconstantproductionandexcretion.Urateisnotmetabolizedbyhuman
tissues.Tomaintainhomeostasis,urateiseliminatedbythekidneyandthegastrointestinaltract[5].Renal
urateexcretionaccountsforabout2/3oftheuricacidturnover.Fourdistinctprocessesareinvolvedinthe
renalhandlingofurate:1)glomerularfiltration;2)presecretorytubularreabsorption;3)tubularsecretion;
and4)postsecretoryreabsorption.Tubularreabsorptionandsecretionmechanismsaremediatedbya
urate/anionexchangerandavoltagesensitiveuratechannel[5].Undernormalconditions,urateisfreely
filteredattheglomerulusasonly5%isboundtoplasmaproteins.Glomerularfiltrationaccountsforonly
712%oftheexcretedfilteredurateload.Afterglomerularfiltration,uricacidundergoesbothpreand
postsecretoryreabsorptionandsecretionintheproximalconvolutedtubule.Incompletepostsecretory
reabsorptionisamajorcontributorofurinaryexcretionofuricacid[5].Theremaining1/3ofurateloadis
excretedthroughthegastrointestinaltract.Urateentersthegutbypassivediffusionwhereitiscompletely
degradedbycolonicbacteriawithlittlebeingexcretedinthestools[5].Persistenthyperuricaemiacan
resulteitherfromdiminishedrenalexcretionorexcessiveoverproductionofuricacid.In8590%of
individualsreduceduricacidexcretionbythekidneysaccountsfortheelevatedserumuricacidlevels[7].
BiologicaleffectsofuricacidSeveralpathophysiologicalmechanismslinkingserumuricacidto
cardiovasculardamageatthecellularandtissuelevelshavebeenproposed.Solubleuricacid(urate)isnot
aninertmolecule,butpossessesseveralbiologicalactionsthatcouldbeeitherbeneficialordetrimental[5].
AntioxidantpropertiesOneofthebeneficialpropertiesofurateisitsabilitytoactasanaqueous
antioxidant.Alongwithascorbate,uratemaybeoneofthemostimportantantioxidantsintheplasma,
reactingwithavarietyofoxidants.Inparticular,byscavengingsuperoxideanions,itblocksthereactionof
superoxidewithnitricoxideandpreventstheformationofperoxynitrite,whichisaverytoxicproductto
thecells[8,9].Uricacidmayalsopreventthedegradationofextracellularsuperoxidedismutase(SOD3),
anextracellularenzymewhichiscriticalinblockingthereactionandinactivationofnitricoxideby
superoxideanions[5].Ithasbeenpostulatedthattheabilityofuratetoreactwithoxidantsmaybean
attemptofthehosttomaintainintegrityandfunctionofvascularcellsinconditionsassociatedwith
oxidativestress[5].HypertensionHyperuricaemiaisverycommoninhypertension.Ithasbeenreportedin
2540%ofuntreatedhypertensiveindividuals,in50%ofthosetreatedwithdiuretics,andinover80%of
thosewithmalignanthypertension[3].Thehighserumuricacidlevelsinhypertensionhavebeenattributed
toseveralmechanisms:1)thereducedrenalbloodflowthatoftenaccompaniesthehypertensivestate
stimulatesuratereabsorptionintheproximaltubule[3];2)thehypertensivemicrovasculardiseaseleadsto
localtissueischaemia,thereleaseoflactatethatblocksuratesecretionintheproximaltubuleandincreases
uricacidsynthesis[13].TissueischaemialeadstoATPdegradationtoadenosineandxanthineoxidase.
Bothincreasedxanthineandxanthineoxidaseresultinincreasedgenerationofuricacidandoxidant(O2
)formation;and3)additionalfactorscancontributetohyperuricaemiainhypertensionsuchasalcohol
abuse,leadintoxication,anddiureticuse.Duringthepastfewyears,severalclinicalandexperimental
studieshaveindicatedthaturicacidmightbeanimportantfactorinthedevelopmentofprimary
hypertension.Pathophysiologicalmechanismsbywhichhighlevelsofuricacidcanleadtohypertension
havebeenelucidatedinexperimentalanimalstudies.Ratsrenderedhyperuricaemicwithoxonicacid,a
uricaseinhibitor,develophypertensionwithinseveralweeks[14].Bloodpressure(BP)elevationwas
showntobeduetouricacidmediatedsystemicandrenalvasoconstrictionasaresultofactivationofthe
reninangiotensinsystemandareductioninendothelialnitricoxidelevels[14].Renalarteriolesare
functionallyconstrictedresultinginadeclineinrenalplasmaflow,butarestructurallynormal[14].Atthis
initialstage,controllinghyperuricaemiawithallopurinol,axanthineoxidaseinhibitor,orwithauricosuric
agentpreventsorreversesBPelevationandisassociatedwithreversalofabnormalhormonalchanges[14].
Withpersistentandchronichyperuricaemia,hypertensionisassociatedwiththedevelopmentof
preglomerulararteriopathyandtubulointerstitialdisease,reminiscentoftheclassiclesionsofessential
hypertension[15].Controllinghypertensionwithdiureticsdoesnotpreventthedevelopmentof
microvasculardisease.Coupledwithreporteddirectactionsofuricacidonendothelialandvascularsmooth
musclecells,theseobservationssuggestthaturicacidmayinducemicrovasculardiseaseindependentlyof
hypertension[15].Atthisstage,hypertensionbecomessaltsensitiveandcanbecontrolledwithsalt
restriction.Incontrast,withholdinguricaseinhibitortherapydoesnotreversetheBPelevation[15].In
humans,thelinkbetweenhyperuricaemiaandhypertensionhasbeenreportedinseveralstudies.Among
childrennewlydiagnosedwithhypertension,serumuricacidwashighlycorrelatedwithbothsystolicand
diastolicBP[16].TheFraminghamHeartStudyindicatedthathyperuricaemiaprecededtheonsetof
hypertensionwithanoddsratioof1.17foreachincreaseinserumuricacidby1.3mg/dl[17].Similar
findingswerereportedintheMultipleRiskFactorIntervention(MRFIT).Innormotensivemenwithout
metabolicsyndrome,hyperuricaemia(definedasaserumuricacid>7mg/dl)wasassociatedwithan80%
increasedriskofdevelopinghypertension,independentofbaselineBPmeasurements,lipidprofile,
proteinuria,orrenalfunction[18].Serumuricacidappearstobearisk,notonlyforhypertension,butalso
formilderdegreesofelevatedBPlevels.Inacommunitybasedstudyof14,451Chinesesubjects,alinear
interactionwasobservedbetweenserumuricacidandriskofprehypertension,especiallyatserumuric
levelsbetween200mol/l(3.4mg/dl)and380mol/l(6.4mg/dl)[19].Incontrast,inthisstudyaswellas
inothers,thiscorrelationwaslostinsubjectsolderthan60yearsofage[19,20].Hyperuricaemiaisalso
morecommoninprimarythaninsecondaryhypertension,atleastinadolescents[21].Inonestudy,
elevateduricacidlevels(> 5.5 mg/dl) were observed in nearly 90% of
is not limited to frankly elevated serum uric acid levels, but has been
reported with uric acid levels within the high normal range [3]. 98
References 1. Mahomed FA. On chronic Brights disease, and its
essential symptoms. Lancet 1879; 113: 399401. 2. Culleton BF,
Larson MG, Kannel WB, Levy D. Serum uric acid and risk for
cardiovascular disease and death: the Framingham Heart study. Ann
Intern Med 1999; 131: 713. 3. Feig DI, Rang DH, Johnson RJ. Uric acid
and cardiovascular risk. N Engl J Med 2008; 359: 18111821. 4. Sumino
H, Ichikawa S, Kanda T, et al. Reduction of serum uric acid by hormone
replacement therapy in postmenopausal women with hyperuricaemia.
Lancet 1999; 354: 650. 5. Rafey MA, Lipkowitz MS, Leal-Pinto E,
Abramson RG. Uric acid transport. Curr Opin Nephrol Hypertens 2008;
12: 511516. 6. Griebsch A, Zollner N. Effects of ribomononucleotides
given orally on uric acid production in man. Adv Exp Med Biol 1974;
41B: 443449. 7. Wyngaarden JB, Kelly WN. Gout and hyperuricemia.
Grune and Straaton, New York 1976. 8. Simic MG, Jovanovic SV.
Antioxidation mechanisms of uric acid. J Am Chem Soc 1989; 111:
57785782. 9. Squadrito GL, Cueto R, Splenser AE, et al. Reaction of
uric acid with peroxynitrite and implications for the mechanism of
neuroprotection by uric acid. Arch Biochem Biophys 2000; 376: 333
337. 10. Warning WS, Webb DJ, Maxwell SRJ. Effect of local
hyperuricemia on endothelial fuction, in the human forarm vascular
bed. Br J Clin Pharmacol 2000; 49: 511. 11. Rao GN, Corsen MA, Berk
BC. Uric acid stimulates vascular smooth muscle proliferation by
increasing platelet derived growth factor A-charm expression. J Biol
Chem 1991; 266: 86048608. 12. Kang DH, Seoh Y, Yoon K-I. A possible
link between hyperuricemia and systemic inflammatory reaction as a
mec
ism of endothelial dysfunction in chronic renal failure presented at
American Society of Nephrology 35th Annual meeting and scientific
exposition, October 30November 4, 2002: Philadelphia. In: Program
and abstracts 2002; 13: 466A (abstract). 13. Faller J, Fox IH. Ethanolinduced hyperuricemia: evidence for increased urate production by
activation of adenine nucleotide turnover. N Engl J Med 1982; 307:
15981602. 14. Mazzali M, Kanellis J, Han L, et al. Hyperuricemia
induces a primary arteriolopathy in rats by a blood pressureindependent mechanism. Am J Physiol Renal Physiol 2002; 282: 991
997. 15. Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid
increases blood pressure in the rat by a novel cryptal independent
mechanism. Hypertens 2001; 38: 11011106. 16. Alper AB Jr, Chen W,
Yau L, et al. Childhood uric acid predicts adult blood pressure. The
Bogalusa Heart Study. Hypertension 2005; 45: 3438. 17. Sundstrom J,
Sullivan L, DAstino RB, et al. Relations of serum uric acid to
longitudinal blood pressure tracking and hypertension incidence.
Hypertension 2005; 45: 2833. 18. Krishnan E, Kwoh CK, Schumacher
HR, Kuller L. Hyperuricemia and incidence of hypertension among men
beencitedasapossibleriskfactorforhyperuricaemiainducedCKD.Clinicalandpopulationbasedstudies
haveindicatedthatdiureticusageoftenacceleratesprogressiontoCKDinhypertensivesubjects.Theuse
ofdiureticsintheSystEuro,SHEP,INSIGHT,andALLHATstudieswasassociatedwithagreaterdecline
inrenalfunctioncomparedwithothertreatmentgroups[3].Inarandomizedclinicaltrialin54
hyperuricaemicpatientswithstage3or4CKD,allopurinoltherapy,comparedtoplacebo,duringa1year
followupwasassociatedwithasignificantreductioninserumuricacidlevelsanddelayinprogressionof
CKD(definedasanincreaseinserumcreatininelevel>40%ofbaselineortheneedforreplacement
therapy)[28].Theseinterestingobservationsgivesupporttothehypothesisthathyperuricaemiamaybe
nephrotoxicinCKD,acceleratingprogressiontoESRD.Incontrast,twootherstudiesfailedtosubstantiate
arelationshipbetweenserumuricacidlevelsandCKD.Inaseparateanalysisof5800participantsfromthe
CardiovascularHealthStudy(CHS)therewasnoassociationbetweenserumuricacidlevelsandincident
CKDdefinedaseGFR<60ml/min/1.73m2.Likewise,inacohortofpatientswithpredominantly
nondiabeticstages3to4CKD,hyperuricaemiawasnotanindependentpredictorofprogressiontoend
stagerenalfailure[29].Ingout,whetherornotgoutynephropathyorchronicuricacidnephropathyexistas
aspecificentityresultingfromthedirectrenalinjuryfromuricaciddepositioninrenalSimilarly,
epidemiologicalstudieshavelinkedfructoseintakewithincreasedprevalenceofhyperuricaemia,obesity,
hypertension,andCKD;featurescommontometabolicsyndrome.Thereisstrongevidenceassociating
fructoseintakewithhyperuricaemiaandincreasedincidenceofgout[31].However,itisunclearwhether
fructoseintakeiscausallyrelatedtoincidenthypertensionandCKD.Althoughhigherserumuricacid
levelsareassociatedwithanincreasedriskofhypertensioninyoungerindividuals,severallinesof
evidencesuggestthaturicacidmayonlybeamarkerofhypertensionriskinhumans[32].Large
prospectivestudiesinmalesandfemalesfoundnoassociationbetweenfructoseintakeandriskofincident
hypertension[32].Anassociationbetweenfructoseintake,hyperuricaemia,albuminuria,andchronic
kidneydiseasehasbeenwelldocumentedinseveralstudies.However,acausalrelationshipbetween
fructoseintakeandincidentCKDremainscontroversial.RecentanalysisofthedataoftheAtherosclerosis
RiskinCommunitiesStudy(ARIC)hasprovidedpossibleanswerstothesequeries.Thesedatasuggestthat
increasedfructoseconsumptionisassociatedwithanincreasedprevalenceofCKDmainlyinparticipants
withserumuricacid>9mg/dl.However,therewasnoevidenceofincreasedincidenceofCKD.These
datacastsomedoubtovertheassociationoffructoseintakewiththedevelopmentofhypertensionand
chronickidneydisease[33].ConclusionsSerumuricacid,themajormetaboliteofpurinenucleotides,isa
recentlyrecognizedriskfactorforhypertension,CVD,andCKDandmayactasalinkbetweenmetabolic
syndromeandtheincreasingincidenceofthenewlyrecognizedassociatednephropathy.Reductionof
elevatedserumuricacidlevelsmayreversehypertensioninadolescentswithnewonsethypertensionand
maydelaytheprogressionofrenaldysfunctioninpatientswithestablishedCKD.Figure2.Relationship
betweenoxonicacid/fructoseinducedhyperuricaemia,hypertension,andCKD;RASreninangiotensin
system;NOnitricoxideparenchymaremainscontroversialbutappearstobeunlikely.Priortothe
adventofhypouricosurictherapy,patientswithgoutexhibitedevidenceofCKD(albuminuria,renal
functionalimpairment),hypertension,andhistologicalrenallesionswhichincludedarteriolosclerosis,
glomerulosclerosis,andtubulointerstitialdiseasewithorwithoutpatchydepositionofuricacidcrystalsin
theoutermedulla,andwereattributedtocoexistenthypertensionandagingindependentofcrystal
deposition[3].Fructoseconsumption,metabolicsyndrome,andriskofcardiovasculardiseaseThepastfew
decadeshavewitnessedamajorincreaseintheprevalenceofobesity,hypertension,diabetesmellitus,and
metabolicsyndrome.Thereisevidencethatserumuricacidlevelsarerisingaswell.Theseobservations
havebeenassociatedwithalargeincreaseinfructoseintake.Fructoseisanisomerofdextrosesynthesized
fromcornsyrupandiscurrentlyusedasasweetenerinpreferencetonaturallyoccurringsucrose[30].
FructoseisuniqueamongsugarsinthatitrapidlycausesdepletionofATPandincreasesboththe
generationandthereleaseofuricacid.Experimentalobservationssupportalinkbetweenfructoseintake,
hyperuricaemia,andhypertension.Ratsfedwithfructosedevelophyperuricaemia,hypertension,metabolic
likesyndrome,andrenalhaemodynamicandhistologicalchangesverysimilartothoseobservedwith
hyperuricaemia[3].Controllinghyperuricaemiawithxanthineoxidaseinhibitorsintheseratspartially
preventedthesechanges(Figure2).EuropeanSocietyofHypertensionScientificNewsletter:Updateon
HypertensionManagement99IntroductionHypertensionhaslongbeenrecognizedasamajor
cardiovascular(CV)riskfactor.Itpromotestheformationofatheromatouslesionsinthelargearteries,
includingtheaorta.Increasedstiffnessoftheaorticwallwhichcanbenoninvasivelyinvestigatedby
measuringthecarotidtofemoralpulsewavevelocity(PWV)canleadtosystolichypertension,
especiallyintheelderly.Hypertensionmayalsobesecondarytoaorticcoarctation,inwhichcaseitaffects
theupperlimbseventhoughthereishypoperfusiondownstreamoftheaorticlesion,whichisusually
isthmic.Thisnewsletterwillnotaddresstheabovementionedabnormalitiesbutwillfocusonthe
relationshipsbetweenhypertensionandaorticaneurysm,dissection,andhematoma,allproblemswhich
requiremultidisciplinarycarebyclinicians,radiologists,andsurgeonsinconcert.Aorticaneurysm
AbdominalaorticaneurysmAnaneurysmisalocalisedfusiformorsacciformdilatationofanartery.
Aneurysmoftheabdominalaorta(AAA)isdiagnosedwhenthegreatestaorticdiameterreaches30mm.Its
physiopathology usually involves an atheromatous deposit associated
recommendedinpatientswithasymptomaticTAAinwhomtheascendingaortaoraorticsinusdiameteris
55mmorgreater(classI)[15].InpatientswithMarfanssyndromeorothergeneticallymediateddisorders
(includingabicuspidaorticvalve),oriftheaorticgrowthrateisover5mmperyear(classI),elective
surgeryisindicatedatsmallerdiameters(4050mmdependingonthecondition).Thoracicaortic
dissection/haematomaAorticdissection(AD)ischaracterizedbytherapidappearanceofanintimalflap
separatingthetrueaorticlumenfromafalsechannel.Thisproblemisrarewithanestimatedprevalenceof
between0.53/100,000inhabitantsperyear[19].ADsareclassifiedintwodifferenttypes:typeAinvolves
theascendingaorta(Figure2)whereasintypeBtheascendingaortaisuntouched.Themainpredisposing
factorsarestructuralabnormalityoftheaorticwalleitherconstitutional(Marfan,typeIVEhlers
DanlosorLoeysDietzsyndrome)oracquired(atherosclerosisandaortitis)andhypertension.The
prevalenceofhypertensionisthereforeveryhighinpatientswithAD:6070%ofpatientswithahistoryof
ADhadhighBPpriortotheaccident[20].InpatientswiththoracicAD,theprevalenceofOSAishighand
respiratoryeventsaremoresevere[21].ThishasledtoaproposalthatOSAshouldbesystematically
investigatedfollowingAD.ADhasaverypoorprognosiswithhighmorbimortality,notonlyintheacute
phasebutthroughoutfollowup[22].TreatmentfortypeAADissurgicalwithreplacementofthe
ascendingaorta.MosttypeBADsaretreatedwithdrugs,sometimeswithacomplementaryendovascular
orsurgicalprocedure.AlthoughprognosisismorefavourableintypeBAD,therisksofaorticrupture,
visceralischaemia,anddeatharestillhigh.Theseeventsareallthemorecommonifthefalsechannel
remainspatent,iftheinitialaorticdiameterislarge,ifitsexpansionisrapid,orifBPremainsuncontrolled
[23,24].Anintramuralhematomaofthethoracicaorta(AH)isahaemorrhagethatdissectstheaorticwall.
Anintimallesionatear,ulcer,orrupturedplaqueisoftendetected.AHtendstostrikepatientsolder
thanthosewhohavehadADanddevelopsatatheromatouslesions,usuallyagainstabackgroundoflong
standing,uncontrolledhypertension[25].TypeAAHoftendeterioratestoADwithahighriskof
mortality:surgicalrepairisindicated.TypeBAHcanbetreatedwithdrugs,possiblywitha
complementaryendovascularorsurgicalprocedure.ADandAHconstitutelifethreateningemergencies
whichrequireimmediate,multidisciplinarycare[26],alwaysincludingintravenousantihypertensive
medicationoftenacombinationofabetablocker(labetalol)andavasodilator(nitroprussideor
nitroglycerin)tobringsystolicBPtolessthan100mmHg[27].PatientswhohaveexperiencedADor
AHwhetherornottheyhavebeenoperatedonshouldbemonitoredforalongtimetocutdownthe
riskofcomplicationsorrecurrence[28].Thisshouldincludebothclinicalmonitoringandradiology.
DespiteaclinicalconsensusontheimportanceofBPcontrolafterAD,onlytwostudieshaveevaluatedthe
effectivenessofcontrolfollowingAD.Thefirst,conductedinpatientswithahistoryofchronictypeAAD,
showedthatcloseBPmonitoring(selfmeasurement)wasassociatedwithbetterlongtermprognosis[29].
Thesecondfoundaprevalenceofuncontrolledhypertensionin60%of40patientswithchronicAD[30].
Todate,therearenospecificguidelinesforBPmonitoringintheseveryhighriskpatients.Athresholdof
135/80mmHghasbeenproposedforpatientswhohavehadsurgeryforAD[27].Toachievethis,itis
importantnottohesitatetoprescribeseveraldifferentclassesofantihypertensivedrugs,especiallybeta
blockers.ThesameistrueforAH,inwhichithasbeenshownthatfailuretoprescribeabetablockeris
predictiveofpooroutcome[31].StaticphysicalexerciseshouldbelimitedinthemonthsfollowingADor
AH.ConclusionAbnormalitiesoftheaorticwallcanpromotethedevelopmentofaneurysmswhichare
verylikelytorupture.Whensuchanabnormalityisdetected,everythingmustbedonetominimizethis
risk,includingdrugtreatmentfollowedbyimaging,surgery,orprophylacticendovasculartreatment.In
additiontorupture,ADorAHcansuddenlydevelop,necessitatingemergencycare.Allthesepathologies
especiallyADandAHarepromotedbyhypertension.Inthesesituations,drugtreatmentisbasedon
betablockersand/orreninangiotensinsystemFigure2.CTscanwithcontrastinjection:typeAaortic
dissectionantagonists.