5:Hypertension

Overview
Thischapterfocusesontheimportantcardiovascularriskfactorofhypertension.Itincludeshypertensivedefinitions, descriptionsofthepathophysiologiceffectsofhypertensionandpotentialendorgandamage.Itexplainshowthehistoryand physicalexamoftencontaincluestotheetiologyofhypertension,andreviewsthecriticalnonpharmacologicandpharmacologic treatmentsofhypertension.Thefinalsectiondescribeshowtorecognizeandtreatsecondarycausesofhypertension.

Authors
PatrickT.O'Gara,MD,FACC EditorinChief ThomasM.Bashore,MD,FACC AssociateEditor JamesC.Fang,MD,FACC AssociateEditor GlennA.Hirsch,MD,MHS,FACC AssociateEditor JuliaH.Indik,MD,PhD,FACC AssociateEditor DonnaM.Polk,MD,MPH,FACC AssociateEditor SunilV.Rao,MD,FACC AssociateEditor

5.1:Definitions,Prevalence,Etiology,TargetOrgans
Author(s): CliveRosendorff,MD,PhD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeabletohaveexplainthedefinition,prevalence,etiology,andcomplicationsof hypertension,anditscontributiontocardiovascular(CV)risk.

Introduction
CVdisease(CVD),includingstroke,isnowthemostcommoncauseofdeathanddisabilityindevelopedcountries,and israpidlybecomingsoindevelopingcountriesaswell.1 Hypertensionisoneofthemostimportantmodifiablerisk factorsforCVD.Hypertensionaffectsabout25%oftheadultpopulationoftheworld,anditsprevalenceispredictedto increaseby60%to2025,whenatotalofover1.5billionpeoplemaybeaffected.Primaryhypertension(essentialor idiopathichypertension)accountsforabout90%ofallcasesofhypertension.

Definitions
Bloodpressure(BP)inhumanpopulationshasanormaldistribution.Accordingly, thedefinitionsof"normal"BPandofvariousformsofhypertensionarearbitrary,but areneededforpracticalreasonsintheassessmentandtreatmentofpatients. Hypertensionisdefinedasasystolicbloodpressure(SBP)of140mmHgorgreater and/oradiastolicbloodpressure(DBP)of90mmHgorgreaterinpersonsnot takingantihypertensivemedication(Figure1). ThosewithaBPof120139mmHgsystolicand/or8089mmHgdiastolicare classifiedas"prehypertensive,"nowknowntoincreasetheriskofanyCVeventby twotofourfoldcomparedwithanormalBP(<120/80mmHg).2 Olderpersons,in whomhypertensionisbothmoreprevalentandmorelikelytoleadtoCVD complications,aremorelikelytohaveelevationsinSBPinthepresenceofnormal DBP(Figure2).ThepositivecorrelationbetweenBPandriskofCVDmorbidityand mortalityisstrongerforSBPthanforDBP. AgeingisassociatedwithaprogressiveincreaseinsystolicBP,areductionin diastolicBP,andwideningofthepulsepressure.Thisisareflectionofa progressivereductioninthecompliance,orstiffening,oflargeconduitarteries. "Isolatedsystolichypertension"(ISH),thepredominantformofhypertensioninthe elderly,isdefinedasaSBPof140mmHgorgreaterinthepresenceofaDBPof90 mmHgorlower(Figure3).Theaccuracyofdiagnosisandstagingofhypertension ismarkedlyimprovedbyusingSBPratherthanDBPasthedominantcriterion. "Essential,primary,oridiopathichypertension,"definedashighBPdueneitherto secondarycausesnortoaMendelian(monogenetic)disorder,accountsfor90%of allcases.Theterm"primaryhypertension"ispreferred,since"essential hypertension"representsanarchaicmisunderstandingofpathophysiology,namely thathypertensionis"essential"tomaintainbloodflowthroughseverelynarrowed resistancevessels. "Secondaryhypertension"ishighBPcausedbyanidentifiableandpotentially curabledisorder."Refractoryorresistanthypertension"isdefinedasaBPof 140/90mmHgdespitethreedrugsofdifferentclassesatmaximumapproved doses,givenforatleast1month."Spurioushypertension(pseudohypertension)"is artefactuallyelevatedBPobtainedbyindirectcuffmeasurementoverarigid,often calcified,brachialartery. "Whitecoathypertension"describespatientswhoseBPishigh(>140/90mmHg)in anofficeorclinicsetting,withanormaldaytimeambulatorypressure(<135/85mm Hg).Thisisarelativelybenignconditionwithlowriskofmorbideventshowever,the riskmayincreasewithlongtermfollowup(6yearsormore).Antihypertensive medicationinwhitecoathypertensionpatientsmaydecreaseclinicBP,but produceslittleornochangeinambulatoryBPthus,drugtreatmentmaynotconfer substantialbenefit. "Maskedhypertension"isthemirrorimageofwhitecoathypertension.Here,the clinicBPisnormal,butambulatoryorhomemeasurementsarehigh,and associatedwithhighrisk.Althoughtheprevalenceofmaskedhypertensionislow, perhapsonly6%ofthenormotensivepopulation,theabsolutenumberintheUnited Statesmayapproach1518million. Theterm"hypertensivecrisis"encompassesbothhypertensiveurgencyand hypertensiveemergency."Hypertensiveurgency"isdefinedasDBP>120mmHgin theabsenceofacuteorrapidlyworseningtargetorgandamage(Figure3). "Hypertensiveemergency"isdefinedasacuteorrapidlyworseningtargetorgan damageoccurringinahypertensivepatientinassociationwithelevatedBP,but irrespectiveofthespecificBPlevelattained."Malignanthypertension"isa hypertensiveemergencyassociatedwithpapilledema,whereas"accelerated hypertension"isahypertensiveemergencyassociatedwithretinalhemorrhages andexudates. Becauseofthenewdataonlifetimeriskofhypertensionandtheimpressive increaseintheriskofCVDcomplicationsassociatedwithlevelsofBPpreviously

Figure1

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Figure3

consideredtobenormal,theseventhreportoftheJointNationalCommitteeforthe Prevention,Detection,Evaluation,andTreatmentofHighBloodPressure(JNC7) introducedanewclassificationthatincludestheterm"prehypertension"forthose withSBP120139mmHgorDBP8089mmHg(Figure1).3 Individualswhoareprehypertensivearenotcandidatesfordrugtherapyonthebasis oftheirBPaloneandshouldbeadvisedtopracticelifestylemodificationtoreduce theirriskofdevelopinghypertensioninthefuture.However,personswithBPsinthe prehypertensiverangeandhighCVriskshouldbetreatedwithantihypertensive medicationstoatargetof<130/80mmHg. HighCVriskisindicatedbythepresenceofdiabetes,chronickidneydisease, coronaryarterydisease,coronaryarterydiseaseequivalents(stroke,carotid disease,aorticaneurysm,peripheralvasculardisease),orbyaFraminghamrisk scoreof>10%.

ClassificationandManagementofBloodPressureforAdultsAges18YearsorOlder Figure1 ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhReportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

ChangesinSystolicandDiastolicBloodPressureWithAge Figure2 ReproducedwithpermissionfromLippincott,Williams,&Wilkins.BurtVL,WheltonP,RoccellaEJ,etal.PrevalenceofhypertensionintheUSadult population.ResultsfromtheThirdNationalHealthandNutritionExaminationSurvey,19881991.Hypertension199525:30513.

OtherHypertensionDefinitions Figure3 *Themostfrequentcausesofsecondaryhypertensionarerenalparenchymaldisease,renalarterystenosis,pheochromocytoma,primary aldosteronism(Connssyndrome),coarctationoftheaorta,andvasoconstrictordrugs.SeesectiononSecondaryhypertension. OrthodoxdefinitionrequiresadiastolicBPof>120mmHg,butanyelevatedBPmaybeassociatedwithacutetargetorgandamage,justifying managementasahypertensiveemergency. DBP=diastolicbloodpressureHT=hypertensionSBP=systolicbloodpressure.

Prevalence
Approximately76millionAmericanshavehypertension,aboutoneinthreeofthe adultpopulation.4 Inastudyconductedin19992000,40%ofpersonswere normotensive,30%wereprehypertensive,and30%werehypertensive.Therehas beenanincreaseintheprevalenceofhypertensionintheUnitedStatesfrom1988 1994(25%)to20052008(33%),withaconsequentincreaseinhypertension relatedmortality.4,5Theprevalenceofhypertensionincreaseswithage,sothatwell over50%ofthepopulationabovetheageof55yearshashypertension,andinthe 75+agegroup,theprevalenceis7080%. SBPinthepopulationincreaseswithadvancingagethroughoutlife,whereasDBP tendstoplateauorfallafterage60(Figure2).Consequently,inolderpersons,the diagnosisofhypertensionismoreoftenmadeonthebasisofSBPratherthanDBP, andtheprevalenceofISHismuchgreaterintheelderlythaninmiddleagedand youngerindividuals.AhigherpercentageofmenthanwomenhavehighBPuntilage 45.Fromage45toage54,thepercentagesofmenandwomenwithhypertension aresimilar,andafterage55,amuchhigherpercentageofwomenhave hypertensionthandomen.Theprevalenceofhypertensionhasincreased significantly(from25%to30%)sincetheNationalHealthandNutritionExamination Survey(NHANES)of198891inwomenofallagegroups,mostdramaticallyin thoseages60yearsandover. Therearesomeethnicdifferencesintheprevalenceofhypertension.Hypertension ismoreprevalentinnonHispanicblacksthaninnonHispanicwhitesandMexican Americans(Figure4).4,6Overall,AfricanAmericanshaveahigherprevalenceof hypertension(41%)thanwhites(28%)orMexicanAmericans(27%).Inbothsexes, hypertensionwasassociatedwithincreasingage,blackrace/ethnicity,andhigher bodymassindex.

Figure2

Figure4

ChangesinSystolicandDiastolicBloodPressureWithAge Figure2 ReproducedwithpermissionfromLippincott,Williams,&Wilkins.BurtVL,WheltonP,RoccellaEJ,etal.PrevalenceofhypertensionintheUSadult population.ResultsfromtheThirdNationalHealthandNutritionExaminationSurvey,19881991.Hypertension199525:30513.

HypertensionPrevalencebyAgeandRace/EthnicityinMenandWomen Figure4 ReproducedwithpermissionfromHajjarI,KotchenTA.Trendsinprevalence,awareness,treatment,andcontrolofhypertensionintheUnited States,19882000.JAMA2003290:199206.Copyrighted2003,AmericanMedicalAssociation.AllRightsreserved.

HypertensionandCardiovascularRisk
Advancesindiagnosingandtreatinghypertensionhaveplayedamajorroleinthe dramaticdeclinesinCHD(down49%)andstroke(down58%)mortalitythathave occurredinthepast30years.Majorprogresshasbeenmadeinpublicawareness oftheimportanceofhighBPinthepopulation.However,ratesofdeclineofdeath fromCVDhaveslowedinthepastdecade,andmajorcomplicationsof hypertension,includingheartfailureandendstagerenaldisease,haveactually risenoverthattimeperiod.Inadditiontotherapidlyescalatingprevalenceof diabetesandobesity,amajorcontributortothesetrendsisinadequatecontrolofBP inthehypertensivepopulation.Althoughtherehasbeenanimprovementinthepast decade,still<50%ofpatientswithhypertensionhavetheirBPcontrolled(Figure5).4 Intheelderlypopulation,increasedpulsepressure(PP)(generallyaresultof decreasedDBPinthepresenceofelevatedSBP)isapredictorofCVDrisk.SBP shouldbestressedmorethanDBPinthediagnosisandtreatmentofhypertension intheelderlybecauseitplaysamajorroleindeterminingriskofCVDeventsand benefitsoftherapy.CVD,includingstroke,isthemostcommoncauseofdeathand disabilityindevelopedcountries,andhypertensionisoneofthemostimportant modifiableriskfactorsforCVD.1 TherelationshipbetweenBPandCVDmortalityis positive,strong,andcontinuous. Ametaanalysisofobservationalstudiesinvolvingmorethan1millionindividuals withoutpriorhistoriesofstrokeorheartdiseasecarriedoutbytheProspective StudiesTrialists'Collaborationshowedthatdeathfromischemicheartdiseaseand strokeincreasescontinuouslyandlinearlyfromBPlevelsaslowas115mmHg systolicand75mmHgdiastolicupward.7 Anincrementof20mmHginSBPor10mmHginDBPinmiddleagedandelderly personsisassociatedwithatwofoldincreaseinCVD(bothischemicheartdisease andstroke)mortalitythroughouttheentirerangeofBP(Figures6,7).Likewise,a decreaseof20mmHginSBPor10mmHgDBPhalvesCVDmortality. IndividualswithaBPintheprehypertensiverange(SBP120139mmHgorDBP80 89mmHg)alsohaveasignificantlygreaterriskofdevelopingaCVeventthanthose withanormalBP(<120/80mmHg).DatafromtheFraminghamHeartStudyshowed thatthelowerhalfoftheprehypertensionrange(SBP120129mmHgorDBP8084 mmHg)isassociatedwithadoublingofriskofdevelopingaCVevent,andthe upperhalfoftheprehypertensionrange(SBP130139mmHgorDBP8589mm Hg)isassociatedwithathreefoldincreasedrisk,whencomparedtonormalBP. ThisdemonstratesthatBPsevenwithintheprehypertensiverangeof120139/8089 mmHgarefarfrombenign(Figure8).8

Figure5

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Figure8

PrevalenceofHypertension*,PrevalenceofTreatmentandControlofBloodPressureAmongPersonsWithHypertensionNationalHealthand NutritionExaminationSurvey,UnitedStates19992002and20052008 Figure5 Theprevalenceofhypertensiondidnotchangesignificantlyfrom19992002(28.1%)to20052008(30.9%)afteradjustmentforsex,age, race/ethnicity,andpovertyincome. *Averagesystolicbloodpressure140mmHg,averagediastolicbloodpressure90mmHg,orcurrentbloodpressureloweringmedication use. Ananswerofyestothequestion,Areyoucurrentlytakingmedicationtoloweryourbloodpressure?Amongthosewithhypertension (averagesystolicbloodpressure140mmHg,averagediastolicbloodpressure90mmHg,orcurrentmedicationuse).Unadjustedprevalence. Averagetreatedbloodpressure<140/90mmHgonexaminationamongallpersonswithhypertension.Unadjustedprevalence. Testfordifferenceinprevalencestatisticallysignificant(p<0.01)afteradjustmentforsex,agegroup,race/ethnicity,andpovertyincomeratio. ReproducedwithpermissionfromCDC.NationalHealthandNutritionExaminationSurveyData.Hyattsville,MD:USDepartmentofHealthand HumanServices,CDC2010.Availableathttp://www.cdc.gov/nchs/nhanes.htm.AccessedOctober19,2011.

IschemicHeartDiseaseMortalityRateinEachDecadeofAgeVersusUsualBloodPressureattheStartofThatDecade Figure6 Ratesareplottedonafloatingabsolutescale,andeachsquarehasareainverselyproportionaltotheeffectivevarianceofthelogmortalityrate. FordiastolicBP,eachagespecificregressionlineignoresthelefthandpoint(i.e.,atslightlylessthan75mmHg),forwhichtherisklies significantlyabovethefittedregressionline. IHD=IschemicHeartDisease ReproducedwithpermissionfromElsevierScience.LewingtonS,ClarkeR,QizilbashN,PetoR,CollinsR,fortheProspectiveStudies Collaboration.Agespecificrelevanceofusualbloodpressuretovascularmortality:ametaanalysisofindividualdataforonemillionadultsin61 prospectivestudies.Lancet2002360:190313.

StrokeMortalityRateinEachDecadeofAgeVersusUsualBloodPressureattheStartofThatDecade Figure7 Ratesareplottedonafloatingabsolutescale,andeachsquarehasareainverselyproportionaltotheeffectivevarianceofthelogmortalityrate. FordiastolicBP,eachagespecificregressionlineignoresthelefthandpoint(i.e.,atslightlylessthan75mmHg),forwhichtherisklies significantlyabovethefittedregressionline. IHD=IschemicHeartDisease ReproducedwithpermissionfromElsevierScience.LewingtonS,ClarkeR,QizilbashN,PetoR,CollinsR,fortheProspectiveStudies Collaboration.Agespecificrelevanceofusualbloodpressuretovascularmortality:ametaanalysisofindividualdataforonemillionadultsin61 prospectivestudies.Lancet2002360:190313.

ImpactofPrehypertensiononCVRisk Figure8 NormalBP:<120/<80mmHg PreHypertension(1):120129/8084mmHg PreHypertension(2):130139/8589mmHg Prehypertensivebloodpressure(BP)isassociatedwithanincreasedriskforcardiovasculardisease(CVD).Theassociationbetweenbaseline BPandtheincidenceofCVDonfollowupwasinvestigatedin6,859participantsintheFraminghamHeartStudywhowereinitiallyfreeof hypertensionandCVD(Vasanetal.,2001).Astepwiseincreaseincardiovascular(CV)eventrateswasnotedinsubjectswithhigherbaseline BPlevels.The10yearcumulativeincidenceofCVDinsubjectsaged35to64yearswithprehypertension(2)atbaseline(systolicBP:130139 mmHgdiastolicBP8589mmHg)was4%inwomenand8%inmen.Inoldersubjects(ages65to90years),theincidencewas18%inwomen and25%inmen.ComparedwithoptimalBP,prehypertension(2)wasassociatedwithariskfactoradjustedhazardsrationof2.5inwomenand 1.6inmen. ReproducedwithpermissionfromVasanRS,LarsonMG,LeipEP,etal.Impactofhighnormalbloodpressureontheriskofcardiovascular disease.NEnglJMed2001345:12917.

Etiology (1of2)
Primaryhypertension,whichaccountsformorethan90%ofallcasesof hypertension,tendstoclusterinfamilies,andrepresentsacomplexinterplayof polygenicandacquiredetiology.9 Manypathophysiologicfactorshavebeen implicatedinthegenesisofessentialhypertension(Figure9).Theseinclude: Increasedsympatheticnervoussystemactivity. Overproductionofsodiumretaininghormonesandvasoconstrictors (endothelinandthromboxane). Longtermhighsodiumintake. Inadequatedietaryintakeofpotassiumandcalcium. Increasedorinappropriateactivationofthereninangiotensinaldosterone system(RAAS). Deficienciesofvasodilatorssuchasprostaglandinsandnitricoxide. Congenitalabnormalitiesoftheresistancevessels. Diabetesmellitus. Insulinresistance. Obesity. Increasedactivityofvasculargrowthfactors. Alteredcellulariontransport. Theconceptthatstructuralandfunctionalabnormalitiesinthevasculature includingendothelialdysfunction,increasedoxidativestress,vascularremodeling, anddecreasedcompliancemayantedatehypertensionandcontributetoits pathogenesis,hasgainedstrengthinrecentyears.Thisformulationhasimportant implicationsforthetargetingofantihypertensivetherapyinordertoachievebenefits beyondBPlowering. Genetics Hypertensionduetoasinglegenemutationisrare.Inthevastmajorityofcases, multiplegenescontributetohypertension,anditislikelythateachofthegenes makesasmallcontributiontotheincreasedBP,withtheresultanthypertension representingacomplexeffectofmanygenesandenvironmentalinfluences. Improvedtechniquesofgeneticanalysis,especiallygenomewidelinkageanalysis andgeneassociations,haveallowedasearchforgenesthatcontributetothe developmentofprimaryhypertension.Applicationofthesetechniqueshasfound statisticallysignificantlinkageofBPtoseveralchromosomalregions,including regionslinkedtofamilialcombinedhyperlipidemia.Overall,however,identifiable singlegenecausesofhypertensionareuncommon,consistentwithamultifactorial causeofprimaryhypertension.Ultimatelythegoalofgenemappingistoidentify singlenucleotidepolymorphisms(SNPs)thatalterfunctioninsuchawayasto elevateBP. Thecandidategeneapproachtypicallycomparestheprevalenceofhypertensionor thelevelofBPamongindividualsofcontrastinggenotypesatcandidatelociin pathwaysknowntobeinvolvedinBPregulation.Themostpromisingfindingsof suchstudiesrelatetogenesoftheRAAS,suchastheM235Tvariantinthe angiotensinogengene,whichhasbeenassociatedwithincreasedcirculating angiotensinogenlevelsandBPinmanydistinctpopulations,andacommonvariant intheangiotensinconvertingenzyme(ACE)genethathasbeenassociatedinsome studieswithBPvariationinmen.ThesevariantsonlymodestlyaffectBP,andother candidategeneshavenotshownconsistentandreproducibleassociationswithBP orhypertensioninlargerpopulations.Thus,geneticcausesofhypertensionappear tobeuncommoningeneralhypertensivepopulations.Recently,averylarge genomewideassociationstudyofsevencommondiseasesfailedtofindany significantgeneassociationswithhypertension.10 Mutationsinabout15geneshavebeenshowntocauseMendelianformsofhuman hypertensionalloftheseareveryrare,andmostaffectBPbyalteringrenalsalt handling.ThesewillbedescribedmorefullyinthesectiononSecondary Hypertension.

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SodiumandPotassium Sodiumexcessandpotassiumdeficitinthedietarepivotalfactorsinthe pathogenesisofhypertension.11Primaryhypertensionandagerelatedincreasesin BParevirtuallyunknowninpopulationswithasodiumintakeof<50mmol/day.On average,foreach50mmol/dayincreaseinsodiumintake,BPincreasesbyabout 5/3mmHg,andifsodiumintakeislowered,BPgenerallyfalls.Mostprocessed foodshavelargeamountsofsodiumafastfoodhamburgercontainsover1g(over 40mmol)ofsodium.Itisthereforenosurprisethattheaveragesaltintakeinthe UnitedStatesisabout10g/day,equivalenttoabout4gor(180mmol)ofsodiumper day. Incontrast,dietscontainingabundantfruitsandvegetablesaresodiumpoorand potassiumrich.Lowpotassiumdietsalsopredisposetohypertension,and inclusionofpotassiumrichfoodsinthedietlowersBP.Anexampleofthisisthe DASH(DietaryApproachestoStopHypertension)diet,richinfruits,vegetables,and lowfatdairyproducts,whichhasbeenshowntoreduceBPinprehypertensive persons. Figure10depictssomeofthemolecularmechanismsimplicatedintheretentionof sodiumandlossofpotassiumbythekidneysinprimaryhypertension.Other mechanismsmayincludeacongenitalreductioninthenumberofnephrons, diminishedrenalmedullarybloodflow,andacquiredrenalinjuryduetoischemiaor interstitialinflammation. Themainconsequenceofsodiumretentionandpotassiumdepletionisanincrease invasculartoneandBP.Increasedvascularsmoothmuscletoneisgeneratedby changesinthetransmembranedistributionofsodium,bydecreasingthesynthesis ofnitricoxide,andbystimulationofsympatheticoutflowfromthebrain.Theseeffects canbereversedbyadequatepotassiumrepletion,andminimizedbydietarysodium reduction. SympatheticNervousSystem IncreasedsympatheticnervoussystemactivityincreasesBPandcontributestothe developmentandmaintenanceofhypertensionthroughstimulationoftheheart, peripheralvasculature,andkidneys,causingincreasedcardiacoutput,increased vascularresistance,andfluidretention.Autonomicimbalance(increased sympathetictoneaccompaniedbyreducedparasympathetictone)hasalsobeen associatedwithmanymetabolic,hemodynamic,trophic,andrheologic abnormalitiesthatresultinincreasedCVmorbidityandmortality(Figure10). Increasedsympatheticactivityand/orreducedparasympatheticactivityincreases heartrate,strokevolume,cardiacoutput,peripheralresistance,norepinephrine,and epinephrinesecretionbytheadrenalmedulla,andreninsecretionbyactivationof theadrenergicreceptorsonthejuxtaglomerularapparatusofthekidney.Allof theseeffectsraiseBP. ThenormalresponsetoanelevatedBPisactivationofbaroreceptorstoreflexly lowerthepressurethereisevidencethatinhypertensiveindividuals,baroreceptor thresholdsareresetupwardsandbaroreceptorsensitivityreduced,bluntingthe normalresponsetoanelevatedBPandallowingforthemaintenanceofthe hypertension.Thereisalsoaninterestinginterrelationshipbetweenthe sympatheticnervoussystemandsaltandwatermetabolism.Increaseddietarysalt willactivatetheanteriorhypothalamustoincreasecentralnervoussystem sympatheticoutflow.Renalsympatheticnervestimulationisincreasedin hypertensivepatients,inducingrenaltubularNa+andwaterreabsorption,resulting inintravascularvolumeexpansionandincreasedBP. BPinyoungerindividualstendstobemorelabile,withanincreaseincardiacoutput andsystolicBP,suggestinganimportantroleforthesympatheticnervoussystemin theinitiationofhypertension.Thereafter,thereisashifttoanincreasedvascular resistance,alsocontributedtobythesympatheticnervoussystem,withanincrease inDBPandnormalizationofcardiacoutput.Eventually,afterage50or60years,ISH againpredominates,whichisassociatedwithincreasedcentralarterialstiffness. Chronicsympatheticstimulationinducesvascularremodelingandleftventricular (LV)hypertrophy,presumablybyactionsofnorepinephrineonitsreceptors,aswell

asonreleaseofvarioustrophicfactors,includingtransforminggrowthfactor, insulinlikegrowthfactor1,andfibroblastgrowthfactors.Positivecorrelations betweencirculatingnorepinephrinelevels,LVmass,andreducedarterial complianceduetovascularhypertrophyhavebeendemonstrated.Thus, sympatheticmechanismscontributetothedevelopmentoftargetorgandamage,as wellastothepathogenesisofhypertension. VascularReactivity Hypertensivepatientsmanifestgreatervasoconstrictorresponsestoinfused norepinephrinethannormotensivecontrols.Theexpecteddownregulationof noradrenergicreceptorsinresponsetoincreasedcirculatingnorepinephrinelevels doesnotoccurinhypertensivepatients,resultinginenhancedsensitivityto norepinephrine,increasedperipheralvascularresistance,andBPelevation. Vasoconstrictorresponsivenesstonorepinephrineisalsoincreasedin normotensiveoffspringofhypertensiveparentscomparedtocontrolswithouta familyhistoryofhypertension,suggestingthatthehypersensitivitymaybegeneticin originandnotsimplyaconsequenceofelevatedBP.Centrallyactingsympatholytic agentsandandadrenergicantagonistsareeffectiveinreducingBPinpatients withessentialhypertension,thusprovidingindirectclinicalevidenceforthe importanceofsympatheticmechanismsinthemaintenanceofhypertension. Exposuretostressincreasessympatheticoutflow,andrepeatedstressinduced vasoconstrictionmayresultinvascularhypertrophy,leadingtoincreasedperipheral resistanceandBP.Personswithafamilyhistoryofhypertensionhaveaugmented vasoconstrictorandsympatheticresponsestolaboratorystressors,suchascold pressortestingandmentalstress,whichmaypredisposethemtohypertension. VascularRemodeling Inhypertension,theincreaseinperipheralvascularresistancecanbeascribedto bothfunctional(vasoconstriction)andmorphologic(remodeling)effectson precapillarysmallarteriesandarterioles.Therearetwotypesofarterialremodeling inhypertension:1)eutrophicinwardremodeling,and2)hypertrophicinward remodeling.Eutrophicinwardremodelingreferstoadecreaseinlumendiameter withoutachangeinthethicknessofthearterialwall.Incontrast,hypertrophicinward remodelingisdefinedasadecreaseinlumendiameterassociatedwithan increaseinwallthickness.Elevatedperipheralvascularresistanceinhypertensive patientsisrelatedtorarefaction(decreaseinnumberofparallelconnectedvessels) andluminalnarrowingofresistancevessels(Figure11). Mechanismsofhypertrophyandeutrophicremodelingaresimilar,andinclude increasesinintravascularpressure,sympatheticactivity,angiotensinIIand endothelin1levels,andoxidativestress,aswellasnitricoxidedeficiencyand geneticfactors.12Antihypertensivetreatmentwithseveralclassesofagents, includingACEinhibitors(ACEIs),angiotensinreceptorblockers(ARBs),and calciumchannelblockers(CCBs),normalizesresistancevesselstructure.Onthe otherhand,betablockertherapydoesnotreverseresistancevesselremodeling evenwheniteffectivelylowersBP.Inrandomizedclinicaltrials,themajor determinantofoutcomeseemstobeBPreduction,anddiureticsandCCBsseemto havedoneaswellorbetterthanRAASblockers,atleastinhighriskpatients. However,manyauthoritieswouldagreethatthemajordeterminantofCVoutcomes isBPreduction,usingwhateverclassofdrugsiseffective. ArterialStiffness SBPandPPincreasewithadvancingage,mainlyasaresultofreducedelasticity (increasedstiffness)ofthelargeconduitarteries.Increasedstiffnessofthese arteriesresultsfromcollagendepositionandsmoothmusclecellhypertrophy,as wellasthinning,fragmenting,andfractureofelastinfibersinthemedia.The distendingpressureofconduitvesselsisamajordeterminantofstiffness.Thetwo phase(elastinandcollagen)contentofloadbearingelementsinthemediais responsibleforthebehaviorofthesevesselsunderstress:Atlowpressures,stress isbornealmostentirelybythedistensibleelastinlamellae,whileathigher pressures,lessdistensiblecollagenousfibersarerecruited,andthevessel appearsstiffer.Conduitvesselsarerelativelyunaffectedbyneurohumoral vasodilatormechanisms.

Inadditiontothesestructuralabnormalities,endothelialdysfunction,whichdevelops overtimeasaconsequenceofbothagingandhypertension,contributesfunctionally toincreasedarterialstiffnessinelderlypersonswithISH.Otherfactorsthat decreasecentralarterialcompliancebydamagingtheendotheliuminclude:1) diabetes,2)tobaccouse,3)highdietarysaltintake,4)elevatedhomocysteine levels,and5)estrogendeficiency. Reducednitricoxide(NO)synthesisand/orreleaseinthissettingcontributesto increasedwallthicknessofconduitvesselssuchastheaortaandcommoncarotid artery.ThefunctionalsignificanceofNOdeficiencyinISHissupportedbytheability ofNOdonors,suchasnitratesorderivatives,toincreasearterialcomplianceand distensibility,andreduceSBPwithoutdecreasingDBP. IncreasedarterialstiffnesscontributestothewidePPcommonlyseeninelderly hypertensivepatients,inpartbycausingthepulsewavevelocitytoincrease.With eachejectionofbloodfromtheLV,apressure(pulse)waveisgeneratedandtravels fromthehearttotheperipheryatafinitespeedthatdependsontheelastic propertiesoftheconduitarteries.Thepulsewaveisreflectedatanypointof discontinuityinthearterialtree,andreturnstotheaortaandLV.Thetimingofthe wavereflectiondependsonboththeelasticpropertiesandthelengthoftheconduit arteries. Inyoungerpersons(Figure12),pulsewavevelocityissufficientlyslow (approximately5m/sec)sothatthereflectedwavereachestheaorticvalveafter closure,leadingtoahigherDBPandenhancingcoronaryperfusionbyprovidinga "boosting"effect.Inolderpersons,particularlyiftheyarehypertensive,pulsewave velocityisgreatlyincreased(approximately1020m/sec)duetocentralarterial stiffening.Atthisspeed,thereflectedwavereachestheaorticvalvebeforeclosure, mergeswiththeincidentorantegradewave,andproducesahigherSBP(and afterload),PP,andadecreasedDBP. ThisphenomenonaccountsforthehigherSBPandPPandthelowerDBPthatis seenintheelderlypopulationandisexaggeratedinthepresenceofhypertension. TheincreaseinSBPincreasescardiacmetabolicrequirementsandpredisposesto thedevelopmentofLVhypertrophyandheartfailure.PPiscloselyrelatedtoSBPand isclearlylinkedtoadvancedatheroscleroticdiseaseandCVDeventssuchasfatal andnonfatalmyocardialinfarction(MI)andstroke.Withaging,thereisagradualshift intheBPriskrelationshipsfromdiastolictosystolicandPP. Mostantihypertensivedrugsactonperipheralmusculararteriesratherthancentral conduitvessels.TheyreducePPviaindirecteffectsontheamplitudeandtimingof reflectedpulsewaves.Nitroglycerincausesmarkedreductionsinwavereflection, centralSBP,andLVload,withsmallerchangesinSBPorDBPintheperiphery. VasodilatordrugslowerBPbydecreasingarteriolartone,butsomeofthem,like ACEIs,ARBs,andCCBs,alsoreducethestiffnessofconduitarteriesandtherefore pulsewavereflection,contributingtotheirantihypertensiveeffect.

PathophysiologicMechanismsofHypertension Figure9 Redarrowsshowhypertensionpromotingmechanismsgrayarrowsshowhypertensionopposingmechanisms. AME=syndromeofapparentmineralocorticoidexcessAng(17)=angiotensin(17)peptideCGRP=calcitoningenerelatedpeptideCNS= centralnervoussystemGI=gastrointestinalGRA=glucocorticoidremediablealdosteronismNO=nitricoxide. ReproducedwithpermissionfromSaundersElsevier.FrancoV,CalhounDA,OparilS.Pathophysiologyofhypertension.In:Hypertension:A CompaniontoBraunwaldsHeartDisease.BlackHR,ElliottWJ.Philadelphia:SaundersElsevier2007:26.

RenalMechanismsofSodiumRetentionandPotassiumLossinPrimaryHypertension Figure10 Potassiumdepletionstimulatedboththesympatheticnervoussystemandthereninangiotensinaldosteronesystemtoenhancesodiumtransport fromthetubularlumenintorenaltubulatcells,viatheNa+K+exchanger(NHE)intheproximaltubule,andtheNa+Cl'cotransporter(NCC)inthe distaltubule.Inthecollectingduct,theincreaseinaldosteronestimulatedsodiumreabsorptionbyactivatingtheepithelialNa+channel(ENaC). Removalofsodiumfromthetubularlumengeneratesamorenegativeintraluminalmembranevoltage,whichenhancespotassiumexcretion throughtheluminalK+channel.AldosteronealsostimulatestheATPdependentNa+K+pumpontheabluminalmembraneofthetubularcell, enhancingsodiumretentionandpotassiumloss.Excesssodiumupregulatestheformationofanendogenousdigitalislikefactorintheadrenal glandsandbrain,whichmediatesfurthersodiumretentionbyincreasingtheexpressionandactivityoftherenalNa+K+pump. AdaptedwithpermissionfromAdroguHJ,MadiasNE.Sodiumandpotassiuminthepathogenesisofhypertension.NEnglJMed2007356:1966 78.

HowRemodelingCanModifytheCrossSectionsofBloodVessels Figure11 Thestartingpointisthevesselatthecenter.Remodelingcanbehypertrophic(increaseofcrosssectionalarea),eutrophic(nochangeincross sectionalarea),orhypotrophic(decreaseofcrosssectionalarea).Theseformsofremodelingcanbeinward(reductioninlumendiameter)or outward(e.g.,increaseinlumendiameter). ReproducedwithpermissionfromtheAmericanCollegeofPhysicians.OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.Ann InternMed2003139:7616.

ChangeinAorticPressureProfileduetoAgeRelatedVascularStiffeningandIncreasedPulsewaveVelocity(PWV) Figure12 1:Increasedsystolicbloodpressure(SBP)anddecreaseddiastolicbloodpressure(DBP)duetodecreasedaorticdistensibility.2:Increased PWVasaresultofdecreasedaorticdistensibilityandincreaseddistal(arteriolar)resistance.3:Returnofthereflectedprimarypulsetothe centralaortainsystoleratherthanindiastoleduetofasterwavetravel.4:Changeinaorticpulsewaveprofilebecauseofearlywavereflection. NotethesummationofantegradeandretrogradepulsewavestoproducealargeSBP.Thisincreasesleftventricular(LV)strokeworkand thereforemyocardialoxygendemand.Notealsothereductioninthediastolicpressuretime(integratedareaundertheDBPcurve).Thisreduction incoronaryperfusionpressureincreasesthevulnerabilityofthemyocardiumtohypoxia.5:TheenhancedaorticBPresultingfromdecreased aorticdistensibilityandearlyreflectedwaves. ReproducedwithpermissionfromSaundersElsevier.RosendorffC.Ischemicheartdiseaseinhypertension.InHypertension:ACompanionto BraunwaldsHeartDisease,eds.BlackHR,ElliottWJ.Philadelphia:SaundersElsevier,2007:329.

Etiology (2of2)
ReninAngiotensinAldosteroneSystem Figure13summarizesthekeyelementsoftheRAAS.Thekeyreceptorfor angiotensinIIistheAT1receptor.AT1receptorsarefoundinthevasculatureand manyothertissues.TheyactivatecalciumchannelsandtheGprotein, phospholipaseC,diacylglycerolandinositoltrisphophatetransductionpathways, thustriggeringangiotensinIImediatedCVevents,includingconstrictionof resistancevessels,stimulationofaldosteronesynthesisandrelease,renaltubular sodiumreabsorption(directlyandindirectlyviaaldosterone),stimulationofthirst, releaseofantidiuretichormone,andenhancementofsympatheticoutflowfromthe brain.Importantly,angiotensinIIalsoinduceshypertrophyandhyperplasiaof cardiacmyocytesandvascularsmoothmusclecellsdirectlyandindirectlyby stimulatingthereleaseofanumberofgrowthfactorsandcytokines.12 ActivationoftheAT2receptorsubtypestimulatesaphosphatasethatinactivates mitogenactivatedproteinkinase,akeyenzymeinvolvedintransducingsignalsfrom theAT1receptor.Thus,activationoftheAT2receptoropposesthebiologicaleffects ofAT1receptoractivation,leadingtovasodilation,growthinhibition,andcell differentiation(Figure14). ThephysiologicroleoftheAT2receptorinadulthumansisunclear,butitisthought tofunctionunderstressconditions(e.g.,vascularinjury,ischemiareperfusion)and toaccountforsomeofthefavorablevasculareffectsoftheARBs,whichareselective antagonistsofAT1receptors.WhenanARBisadministered,reninisreleasedfrom thekidneyduetoremovaloffeedbackinhibitionbyangiotensinII.Thisleadsto increasedgenerationofangiotensinII,whichisshuntedtotheAT2receptor,favoring vasodilationandattenuationofunfavorablevascularremodeling. LocalproductionofangiotensinIIinavarietyoftissues,includingthebloodvessels, heart,adrenals,andbrain,isunderthecontrolofACEandanumberofother enzymes,includingchymas.TheactivityofthelocalRAASandalternativepathways ofangiotensinIIformationmaymakeanimportantcontributiontotheremodelingof resistancevesselsandthedevelopmentoftargetorgandamage(including atherosclerosis,LVhypertrophy,MI,heartfailure,stroke,endstagerenaldisease, andarterialaneurysm)inhypertensivepersons.NonACEenzymesthatconvert angiotensinItoangiotensinIIareresponsibleforthephenomenonof"angiotensin escape,"wherebytheplasmaandpresumablythetissueconcentrationof angiotensinIIisnevercompletelysuppressedbyACEIs. AngiotensinIIandOxidativeStress Stimulationofreactiveoxygenspeciesproductionisanadditionalmechanismby whichangiotensinIIincreasesCVrisk(Figure15).11Hypertensionassociatedwith angiotensinIIadministrationislinkedtoupregulationofvascularp22phoxmRNA,a componentoftheoxidativeenzymeNAD(P)Hoxidase.AT1receptordependent activationofNAD(P)Hoxidaseisassociatedwithenhancedformationoftheoxidant superoxideanion(O2),whichreactsreadilywithNOtoformtheoxidantperoxynitrite (ONOO).ReductioninNObioavailabilitythusprovidesanadditionalmechanismto explaintheenhancedvasoconstrictorresponsetoangiotensinIIinhypertension. NAD(P)Hoxidasemayalsoplayanimportantroleinthehypertrophicresponseto angiotensinII. OthervasculotoxicresponsestoangiotensinIIthatarelinkedtotheactivationof NAD(P)HoxidaseincludetheoxidationofLDLcholesterolandincreasedmRNA expressionformonocytechemoattractantprotein1(MCP1)andvascularcell adhesionmolecule1(VCAM1).ACEIsandARBslimitoxidativereactionsinthe vasculaturebyblockingangiotensinIIinducedactivationofNAD(P)Hoxidase.This hasledtothehypothesisthatRAASblockershaveclinicallyimportantvasoprotective effectsbeyondBPlowering. Aldosterone
Figure13

Figure14

Figure15

Figure16

Figure17a

Figure17b

Theeffectsofaldosteroneonsodiumandwaterreabsorptioninthedistaltubuleof thekidneyarewellknown,butmanyofthedeleteriouseffectsofaldosteroneonthe CVsystemaremediatedviaactivationofmineralocorticoidreceptorson nonepithelialcellsofthebrain,heart,andbloodvessels(Figure16).Aldosterone hasdirecteffectsonthebrainthatresultinincreasesinsaltappetite,sympathetic outflow,andBPeffectsontheheartthatresultincardiachypertrophyandfibrosis anddirectvasculareffectsthatresultinendothelialdysfunction,renalarteriopathy withproteinuria,andvascularinflammationwithextracellularmatrixdeposition, fibrosis,andincreasedstiffness. Theseinjuriouseffectsofaldosteroneoftenoccurinthesettingofhypertensionall requiresaltfortheirfullexpression.Myocardialfibrosis,includingbothperivascular andinterstitialfibrosis,hasbeendemonstratedinavarietyofrodentmodelsof hypertensionandshowntocorrelatestronglywithcirculatingaldosteronelevels. Importantly,whensaltwaswithheldfromtheseanimals,cardiacfibrosisdidnot occur.Similarly,inhumans,lowsaltdietsincreasealdosteronelevels,buttheseare notassociatedwithcardiacorvascularpathology. Compellingevidenceindicatesthataldosteroneinducedfibrosisisinitiatedby vascularandperivascularinflammation.Thenonselectivealdosteroneantagonist spironolactoneandtheselectivemineralocorticoidreceptorantagonisteplerenone effectivelypreventorreverseexpressionofproinflammatorycytokinesand chemokines,andtheconsequentvascularandperivascularfibrosisinrodent models.Thesefindingsareconsistentwithclinicalevidenceofaninverse relationshipbetweenplasmaaldosteroneandlargearterycompliancein hypertensivepatients. Spironolactonetreatmentofheartfailurepatientshasalsobeenshowntoreduce circulatinglevelsofprocollagentypeIINterminalaminopeptide,providingindirect evidenceofanantifibroticeffectontheheart.Spironolactoneandeplerenone improveoutcomesinheartfailure.13,14 Aldosteroneexcessisamorecommoncauseof,orcontributingfactorto hypertension,particularlytreatmentresistanthypertension,thanpreviouslythought. Manypatientswithprimaryhyperaldosteronismdonotmanifestlowserum potassiumlevels,andserumpotassiumisnotanentirelyreliablescreeningtestfor aldosteroneexcess. Prevalenceratesbetween8%and32%havebeenreportedonthebasisofthe patientpopulationbeingscreened(higherinreferralpractices,wherethepatientmix tendstobeenrichedwithrefractoryhypertension,andlowerinfamilypracticesor communitydatabases).BPinpatientswithaldosteroneexcessrespondswellto treatmentwithamineralocorticoidreceptorantagonist.Additionalclinicalstudies withtheseagentsareneededtoelucidatetheroleofaldosteroneinthe pathogenesisofprimaryandsecondaryhypertensionandrelatedtargetorgan damageinhumanpopulations. Endothelin Theendothelins(ET1,ET2,ET3)areafamilyof21aminoacidpeptideswithpotent biologicalactivities.Theyaresynthesizedinseveraltissues,includingthe endothelium(ET1)andsmoothmusclecells.Theproductionandreleaseof endothelinisstimulatedbymanyfactors,hormonalandmetabolic,andbygrowth factors,hypoxia,andshearstress. ReleasedendothelinbindstotheendothelinreceptorsETAandETB.TheETA receptorsonvascularsmoothmusclecellsmediatevasoconstrictionandtheETB receptorsontheendotheliumarelinkedtonitricoxide(NO)andprostacyclin release,thustendingtopromotevasodilation.TheETAreceptorsactivatethe phospholipaseC,inositoltrisphosphate,diacylglycerolpathway(asdoes angiotensinII),whichthroughanincreaseincytosolicCa2+andproteinkinaseC (PKC)causesvasoconstrictionandstimulationofvascularsmoothmusclegrowth andproliferation.15Thus,acomplexinteractionbetweenET1,angiotensinII, receptoragonists,Ca2+,andothergrowthfactorsparticipatesinthepathogenesisof vascularhypertrophyinhypertension. TheplasmaconcentrationofET1tendstobeincreasedinsevereatherosclerotic

disease,butnotconsistentlyinhypertension.ThereasonforthismaybethatET1is secretedinanabluminaldirectionbyendothelialcellsandactsinaparacrine fashiononunderlyingsmoothmusclecellstocausevasoconstrictionandelevate BPwithoutnecessarilyreachingincreasedlevelsinthesystemiccirculation. ETreceptorantagonistsreduceBPandperipheralvascularresistanceinboth normotensivepersonsandpatientswithmildtomoderateessentialhypertension, supportingtheinterpretationthatET1playsaroleinthecontrolofvasomotortonein normalhumansubjects,aswellasinthepathogenesisofhypertension.However, developmentofthisdrugclassforthetreatmentofsystemichypertensionhasbeen plaguedbytoxicityissues,mainlyhepatotoxicity. TheETreceptorantagonistsbosentan,ambrisentanareFDAapprovedforthe treatmentofpulmonary,butnotsystemicarterialhypertensionintheUnitedStates. InarecentphaseIIIclinicaltrial16inpatientswithresistantsystemichypertension, theETAselectiveantagonistdarusentanfailedtoachieveitscoprimaryefficacy endpointsofachangeinsystolicanddiastolicbloodpressureafter14weeks comparedtoplacebo. EndothelialDysfunction Endothelialdysfunctionhasbeenimplicatedasbothacauseandaconsequenceof hypertensionviamechanismsthatinvolvereducedNOsynthesis,release,and/or bioactivity(Figures17a,b).NOisapotentvasodilator,inhibitorofplateletadhesion andaggregation,andsuppressorofmigrationandproliferationofvascularsmooth musclecells.NOisreleasedbynormalendothelialcellsinresponsetoavarietyof stimuli,includingchangesinBP,shearstress,andpulsatilestretch,andplaysan importantroleinBPregulation,thrombosis,andatherosclerosis.TheCVsystemin normalpersonsisexposedtocontinuousNOdependentvasodilatortone,butNO relatedvascularrelaxationisdiminishedinhypertensivepersons. IthasbeensuggestedthatangiotensinIIatconcentrationsthathaveaminimal effectonBPenhancesformationoftheoxidantsuperoxide.Increasedoxidantstress andthedevelopmentofendothelialdysfunctionmaythuspredisposetothe developmentofhypertension.Theobservationthatinvivodeliveryofsuperoxide dismutase(enzymethatreducessuperoxidetohydrogenperoxide)reducesBPand restoresNObioactivityprovidesfurtherevidencethatsuperoxideinducedoxidant stresscontributestotheinactivationofNOandthedevelopmentofendothelial dysfunctioninhypertensivemodels.

TheReninAngiotensinAldosteroneSystem Figure13 Theenzymerenin,producedmainlyinthejuxtaglomerularcellsofthekidney,cleavesthedecapeptideangiotensinIfromaprecursormolecule, angiotensinogen,alargeglobularproteinderivedmainlyfromtheliver.Angiotensinconvertingenzyme(ACE)isadipeptidylcarboxypeptidase thatconvertsangiotensinItotheoctopeptideangiotensinII,andalsoinactivatesbradykinin,apotentvasodilator.Otherangiotensinmoleculesare angiotensin(17)andangiotensinIV(38),thefunctionsofwhichhavenotyetbeenfullyelucidated. RAS=reninangiotensinsystemACE=angiotensinconvertingenzymeARB=angiotensinIItype1receptorblockersATR=angiotensin receptorEP=endopeptidaseEC=endothelialcells. ReproducedwithpermissionfromStaessenJA,LiY,RichartT.Oralrenininhibitors.Lancet2006368:144956.

TheAngiotensionIITypes1(AT1)and2(AT2)ReceptorsHaveOpposingEffects Figure14 TheAT1receptormediatesvasoconstriction,cellgrowth,andcellproliferationtheAT2receptorhastheoppositeeffect,stimulatingvasodilation, antigrowth,andcelldifferentiation.TheAT1receptorisantinatriuretictheAT2receptorisnatriuretic.TheAT1receptorstimulationcausesfree radicalformationAT2stimulationproducesnitricoxide(NO)thatcanneutralizefreeradicals.TheAT1receptorinducesplasminogenactivator inhibitor1(PAI1)andothergrowthfamilypathwaystheAT2receptordoesnot.Theangiotensinreceptorblockersbindtoandselectivelyblock theAT1receptor,allowingstimulationofthereceptorbyangiotensinII. ReproducedwithpermissionfromtheAmericanCollegeofPhysicians.OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.Ann InternMed2003139:7616.

MechanismsofAngiotensinII(ANGII)Dependent,OxidantMediatedVascularDamage Figure15 ReproducedwithpermissionfromtheAmericanCollegeofPhysicians.OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.Ann InternMed2003139:7616.

DeleteriousEffectsofAldosterone/Salt Figure16 ReproducedwithpermissionfromBenthamSciencePublishers.McMahonEG.Eplerenone,anewselectivealdosteroneblocker.CurrPharmDes 20039:106575.

EndothelialFunctionintheNormalVasculature(1of2) Figure17a Largeconductancevessels(left),forexample,epicardialcoronaryrteries,andresistancearterioles(right),areshown.Innormalconductance arteries,plateletsandmonocytescirculatefreely,andoxidationofLDLispreventedbyapreponderanceofNOformation.Atthelevelofthe smallarterioles,reducedvasculartoneismaintainedbyconstantreleaseofNO.Endothelin1normallyinducesnovasoconstrictionoronly minimalvasoconstrictionthroughstimulationoftypeAendothelinreceptors(ETA)locatedonsmoothmusclecells,andcontributestobasalNO releasebystimulatingtypeBendothelinreceptors(ETB)onendothelialcells. ReproducedwithpermissionfromtheAmericanCollegeofPhysicians.OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.Ann InternMed2003139:7616.

EndothelialFunctionintheHypertensiveVasculature(2of2) Figure17b Inthehypertensivemicrovasculature,decreasedactivityofNOandenhancedETAmediatedvasoconstrictoractivityofendothelin1resultin increasedvasculartoneandmedialhypertrophy,withaconsequentincreaseinsystemicvascularresistance.Atthelevelofconductance arteries,asimilarimbalanceintheactivityofendothelialfactorsleadstoaproatheroscleroticmilieuthatisconducivetotheoxidationofLDL,the adhesionandmigrationofmonocytes,andtheformationoffoamcells.Theseactivitiesultimatelyleadtothedevelopmentofatherosclerotic plaques,theruptureofwhich,inconjunctionwithenhancedplateletaggregationandimpairedfibrinolysis,resultsinacuteintravascular thrombosis,thusexplainingtheincreasedriskforCVeventsinpatientswithhypertension.Thesemechanismsmaybeoperativeinpatientswith highnormalBPandmaycontributetotheirincreasedCVrisk. ReproducedwithpermissionfromtheAmericanCollegeofPhysicians.OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.Ann InternMed2003139:7616.

TargetOrgans (1of2)
HighBPhassignificanceonlyinsofarasitcausesdamagetotargetorgans.Thecommonthemeinmanyofthese effectsisinwardeutrophicremodelingofsmallresistancearteries,increasedlargearterystiffness,andaccelerated atherogenesis.Thereisevidencethatthesevascularchangesmayprecedethedevelopmentofhypertension, suggestingthatthesevasculareffectsmayplayaprimaryroleinthedevelopmentofhypertensionorthattheysharea commonneurohormonaletiologywithhypertension.17Thissectionbrieflysummarizestheorgandamagethatoccursin responsetoprolongedBPelevation,includingeffectsontheventricularmyocardium,brain,arteries,andkidney. HypertensionandtheHeart TheLVinhypertensivesubjectsbecomesprogressivelylessdistensibleinresponsetoanincreasedafterload,andlater willhypertrophy.Theetiologyofthishypertensioninducedcardiacdamageiscomplex,andincludespressureoverload, circulatingandlocalfactorssuchasangiotensinII,catecholamines,andET1,whichpromotevascularandmyocyte growth,increasedconnectivetissuedeposition,andcollagencrosslinking. IncreasedLVstiffnessandhypertrophyhaveseveralconsequences:limitationoftherateatwhichtheLVcanfillduring diastolecausesleftatrial(LA)enlargementandthickening,withthedevelopmentofafourthheartsoundorgallopand theelectrocardiographic(ECG)changesofLAabnormality(broad,notchedPwavesinII,biphasicPwaveinV1 ),andthe characteristicechocardiographicfindingsofLAenlargement. IndividualswithLAenlargementaremorelikelytodevelopatrialfibrillation.LAsizeisimportantinassessingtheeffects ofhypertensionontheheart.Newonsetatrialfibrillationismorelikelytodevelopinhypertensivepatientswithincreased LAsize,andantihypertensivetherapyisprotectiveagainstthisarrhythmia.IncreasedLVstiffnessmayproducethe symptomsandsignsofdiastolicheartfailure.LVhypertrophy(LVH)alsoimposesanincreaseinmyocardialoxygen demand,whichinthepresenceofocclusivecoronaryarterydisease(itselfacceleratedbyhypertension)andimpaired coronaryflowreserve,makestheindividualmoresusceptibletomyocardialischemia,infarction,orheartfailure.ECG evidenceofLVH,strainpatternandprolongedQRSdurationareallmarkersofcardiactargetorgandamageand predictorsofheartfailureinhypertensivepatients.18 Theechocardiogrammayshowinterventricularseptalhypertrophy,hypertrophyoftheLVfreewall,andincreased calculatedLVmass(men225g,women165g)orLVmassindex(men115g/m2 ,women95g/m2 ).19The echocardiographicdiagnosisofLVdiastolicdysfunctionduetodecreasedLVcomplianceismorecomplex,andis discussedinthesectiononLVfailurewithpreservedsystolicfunction. TheprevalenceofLVHinhypertensiveindividualsis2535%.LVHisassociatedwithagradedincreaseintheriskof CVD,proportionaltothedegreeofhypertrophyandoverandabovetheriskofthehypertensionperse.Patientswith hypertensionandLVHareatincreasedriskofacutecoronarysyndromeduetotheincreasedmetabolicdemandofthe hypertrophiedmyocardium,theincreasedoutputimpedanceoftheelevatedaorticBP,theimpairmentofmyocardial perfusionrelatedtocoronaryarterydisease,andtheincreasedresistancetomyocardialbloodflowinthestiffLV. Heartfailure,withorwithoutapreservedsystolicfunction,isanotherfrequentconsequenceofhypertensiveandischemic heartdisease.ManystudieshaveshownsignificantregressionofLVHwhenBPisreduceditisnotclearwhetherthisis simplyafunctionofthedegreeofBPloweringorwhethersomeantihypertensivedrugsarebetterthanothersatdoses thatareequipotentforBPreduction.ACEinhibitors,ARBs,CCBs,anddiureticsallregressLVH,whereasbetablockers arelesseffective. RecentdatahaveshownthatanincreasednocturnalBPonambulatoryBPmonitoring,especiallywhenassociatedwith "nondipping"ofnocturnalBP,hasadditionalpredictivevaluefordevelopmentofcongestiveheartfailurebeyond conventionalofficeBPmeasurement.20 HypertensionandtheBrain Thecentralnervoussystemcomplicationsofhypertensionarestroke,hypertensiveencephalopathy,anddementia. Stroke Hypertensionisthemostprevalentriskfactorforcerebrovasculardisease,andcontributessubstantiallytostroke.This maybeduetolipohyalinosisorfibrinoidnecrosiswithassociatedfocaldamagetosmallresistancevessels,whichmay occlude,causinglacunarinfarcts,orrupture,causinghemorrhagicstrokes.Hypertensionmayexacerbate atherosclerosisoflargervessels,whichifoccluded,willcauseischemicstroke,orifruptured,hemorrhagicstroke.Other mechanismsofstrokeincludeembolizationofthrombusfromhypertensionrelatedatheromainthecarotidarteriesor ascendingaorta,orfromhypertensionrelatedheartdisease,suchasatrialfibrillation,MI,ventriculardyskinesiaor aneurysm,andrarely,paradoxicalembolithroughapatentforamenovale.

Moststrokeshaveacentralcoreofseverebloodflowreductionwithpermanentinfarctionandasurroundingpenumbraof ischemic,butsalvageabletissue.Thepurposeofprompttherapywithanticoagulants,fibrinolytics,andneuroprotective therapiesistoimproveflowtotheischemicpenumbra.Themanagementofhypertensioninthepatientwithacutestroke iscontroversial.Cerebrovascularautoregulationisimpairedorabolishedintheischemicpenumbrabecauseoflocal hypoxiaandacidosis,resultinginapassivepressureflowrelationshipinthatregion.Thus,ahighperfusionpressure (i.e.,ahighBP)isanadvantageinacuteischemicstroke. CurrentstrokeguidelinesfromtheAmericanHeartAssociationandAmericanStrokeAssociationreflectthisconcept.21 TheysuggestthatantihypertensivemedicationsbewithheldunlesstheBPisveryhigh,>220mmHgsystolic,orBP>120 mmHgdiastolic.However,onestudy,CHHIPS(ControllingHypertensionandHypotensionImmediatelyPostStroke),22 hasshownimprovedstrokeoutcomes(lowermortalityandlesspoststrokedependency)iftheBPisloweredtoaSBPof 145155mmHgacutely.Inthelongerterm,thereisampleevidencefrommanyclinicaltrialsthatBPloweringis importantfortheprimarypreventionofstroke.Inpatientswithpreviousstroke,treatmentofhypertensiondoesreducethe riskofrecurrence.23 Althoughnumerousstudieshavestronglysupportedthetreatmentofhypertensiontopreventstroke,twolargestudieson thesecondarypreventionofstrokehaveproducedmixedresults.ThePROGRESS(PerindoprilProtectionAgainst RecurrentStrokeStudy)trial,23showedthatloweringBP(meanreduction12.3/5.0mmHg)withperindopriland indapamideinapopulationwithahistoryofstroke,decreasedtheriskofstrokerecurrenceby28%over4years. Ontheotherhand,thePRoFESS(PreventionRegimenforEffectivelyAvoidingSecondStrokes)trial,24showednobenefit oftelmisartaninthesecondarypreventionofstroke.Thismaybeexplainedonthebasisthat,comparedto thePROGRESScohort,thesubjectsenrolledinPRoFESShadlowerbaselineBPs(144/84mmHgvs.147/86mmHg), andalesserBPloweringduringthestudy(4.9/2.8mmHgvs.12.3/5.0mmHg).TheneedtolowerBPtotargetvaluesin hypertensivepatientswhohavehadastrokeremainsstrong.

TargetOrgans (2of2)
AcuteHypertensiveEncephalopathy AcutehypertensiveencephalopathyisamedicalemergencycharacterizedbyaveryhighBP(hypertensivecrisis),severe headache,andotherneurologicsymptoms(suchasagitation,visualblurringorblindness,drowsiness,confusion, seizures).Papilledema(malignanthypertension)isoften,butnotalwayspresent.Inthissituation,theBPinpostcapillary venulesexceedstheupperlimitofcerebrovascularautoregulation,causingpressurerelateddilatationwithdisruptionof thebloodbrainbarrierandfocalcerebraledema. Factorswhichmayfacilitatethe"breakthrough"ofautoregulationincludeactivationofpotassiumchannelsandof parasympatheticnervestocerebralvessels.Hypertensiveencephalopathyisahypertensiveemergency:Patientsshould beadmittedtoanintensivecareunitforparenteralantihypertensivetherapy. MildCognitiveImpairmentandDementia SBPisastrongpredictorofmildcognitiveimpairmentandfrankdementia,bothvasculardementia(VD)andAlzheimer's disease(AD).VDandADhavedifferentpathogenesesVDproducessmallinfarcts,arteriosclerosis,particularlymedial necrosisofsmallpenetratingarterioles(Binswanger'sdiseaseorsubcorticalarterioscleroticencephalopathy),and subcorticaldemyelination.ThehallmarklesionofADisthedepositionofextracellularamyloidplaquesandintracellular neurofibrillarytangles.VDandADareoftennoteasytodifferentiateclinicallyorbycurrentimagingtechniques,andare oftenfoundinthesamepatient.GoodBPcontrolhasbeenshownincontrolledclinicaltrialstosubstantiallyreducethe riskofmildcognitiveimpairmentanddementia. Hypertensionwithchronickidneydisease(CKD)isdefinedasthepresenceoflongstandinginjurytothekidney, confirmedbykidneybiopsyoraglomerularfiltrationrate(GFR)of<60ml/min/1.73m2 forlongerthan3months.The clinicalassociationsareaserumcreatinineof1.2mg/dlinwomenand1.4mg/dlinmen,andmicroalbuminuria(30 300mg/day)oralbuminuria(>300mg/day).Diabetesandhypertensionaccountforthebulkofpatientswithendstage renalfailure. Thekeycomponentsofhypertensioninpatientswithkidneydiseaseinclude:1)inappropriatelyelevatedsympathetic nervousactivity,2)activationoftheRAAS,and3)impairedsodiumandwaterexcretionbythekidney.Bothsympathetic overactivityandangiotensinIIselectivelyconstricttheefferentarteriolesofthekidney,increasingglomerularfiltration pressureandthereforefiltrationfraction.Asaconsequence,thecolloidosmoticpressureofthefluidleavingthe glomerularcapillarytoentertheperitubularnetworkofcapillariesisincreased,resultingingreatersodiumreabsorption throughthetubules.BoththesympatheticnervoussystemandtheRAASalsoaredirectvasoconstrictorsofsystemic resistancearterioles.Sympatheticnervesalsostimulatereninreleasethroughactivationofreceptors,resultinginan increaseinangiotensinII. Anotherstimulustoreninreleaseisthelowsodiumconcentrationinthedistalnephron,aconsequenceofthegreater sodiumreabsorptionintheproximalrenaltubule.OthermechanismsincludeadirecteffectofangiotensinIItoenhance thesodium/hydrogenantiporter,oftheproximaltubulecellstoincreasesodiumreabsorption,andtheangiotensinII mediatedreleaseofthemineralocorticoidhormone,aldosterone.AngiotensinIIalsocausesmorphologicchangesinthe kidney,mesangialcellproliferation,andtheactivationandreleaseofproinflammatorycytokinesintherenal parenchyma. HypertensionisbothacauseandcomplicationofCKD,andloweringBPslowstheprogressionofrenaldisease. PatientswithCKDareatincreasedriskofCVevents.TheBPgoalinpatientswithCKDis<130/80mmHg.Achievement ofthislevelofBPcontrolinpatientswithCKDisoftendifficult,andmostpatientswillrequire24antihypertensivedrugsin moderatetohighdoses. BoththeJNC7andtheClinicalPracticeGuidelinesonHypertensionandAntihypertensiveAgentsinChronicKidney Disease(K/DOQIBP)guidelines(http://www.kidney.org/professionals/kdoqi/guidelines_bp/index.htm)clearlystatethat compellingandspecificindicationsexistfortheuseofACEIsorARBstolowerBPinpatientswitheitherdiabetesor CKD.3 EveniftheBPisnormal,itisreasonabletotreatdiabeticpatientswithanACEIorARB,toreduce microalbuminuriaandpreventthedevelopmentofdiabeticnephropathy,25aswellastoslowtherateofdeclineofrenal functionandpreventCVeventsinestablisheddiabeticnephropathy.26,27TheevidenceforrenoprotectionofACEIsor ARBsisnotasstrongforhypertensionasitisfordiabetes,buttheuseoftheseclassesofdrugsareappropriateforthe firstlinetreatmentofhypertensioninpatientswithmicroalbuminuriaorfranknephropathy. ItshouldbeborneinmindthatRAASblockersreduceangiotensinIIdependentefferentarteriolartone,thusreducing glomerularfiltrationpressureandthereforeGFR.Theresultingincreaseinserumcreatinineisnotanindicationto discontinuetheACEIortheARB.Iftheserumcreatininelevelincreasesbymorethan30%,orifitcontinuestoriseafter3 monthsoftherapy,thenvolumedepletion,unsuspectedLVsystolicdysfunctionwithareducedcardiacoutput,orrenal

arterystenosisshouldbesuspectedandtheRAASblockershouldbewithhelduntiltheunderlyingconditioncanbe diagnosedandcorrected. Similarly,ariseinserumpotassiumshouldbeexpectedwithACEIorARBtherapythisshouldbeaconcernonlyifthe serumpotassiumrises0.5mEq/Lormorefromabaselinelevelof>5.0mEq/L.Otherwisetheriseinserumpotassium canbemanagedbyeducatingthepatienttoreducetheintakeofpotassium.

KeyPoints
Hypertensionisverycommoninnearlyallpopulations,andisamajorindependentriskfactorforCVD. ThereisagradedrelationshipbetweenBPandCVrisk,withnoapparentlowerlimit. BPtargetsare<130/80mmHgforthosewithdiabetes,kidneydisease,andcoronaryarterydisease. Theetiologyofhypertensionismultifactorialmonogeneticformsarerare.Keyelementsintheetiologyare activationofneurohormonalsystems(sympatheticnervoussystem,RAAS,ET)increasedoxidativestressaltered cellulariontransportofsodium,potassium,andcalciumandabnormalitiesofendothelialfunctionandvascular reactivity,largearterycompliance,andsmallartery/arteriolarresistance. ThemaintargetorganeffectsandresultantCVDeventsareatheroscleroticvasculardiseaseMI,LVhypertrophy, atrialfibrillation,heartfailurestroke,encephalopathy,dementia,andrenalfailure.

References
1. WorldHealthOrganization.TheWorldHealthReport,2008.PrimaryHealthCare.Geneva,Switzerland:World HealthOrganization.Availableat:www.who.int/whr/2008/whr08_en.pdf.Accessed12/19/2011. 2. HsiaJ,MargolisKL,EatonCB,etal.fortheWomen'sHealthInitiativeInvestigators.Prehypertensionand cardiovasculardiseaseriskintheWomen'sHealthInitiative.Circulation2007115:85560. 3. ChobanianAV,BakrisGL,BlackHR,etal.TheSeventhReportontheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7Report.JAMA2003289:256072. 4. CentersforDiseaseControlandPrevention.NationalHealthandNutritionExaminationSurveyData.Hyattsville, MD:USDepartmentofHealthandHumanServices2010.Availableat:http://www.cdc.gov/nchs/nhanes.htm. Accessed12/19/2011. 5. RogerVL,GoAS,LloydJonesDM,etal.,onbehalfoftheAmericanHeartAssociationStatisticsCommitteeand StrokeStatisticsSubcommittee.Heartdiseaseandstrokestatistics2011update:areportfromtheAmerican HeartAssociation.Circulation2011123:e18. 6. OngKL,CheungBM,ManYB,LauCP,LamKS.Prevalence,awareness,treatment,andcontrolofhypertension amongUnitedStatesadults,19992004.Hypertension200749:6975. 7. LewingtonS,ClarkeR,QizilbashN,PetoR,CollinsR,onbehalfoftheProspectiveStudiesCollaboration.Age specificrelevanceofusualbloodpressuretovascularmortality:ametaanalysisofindividualdataforonemillion adultsin61prospectivestudies.Lancet2002360:190313. 8. VasanRS,LarsonMG,LeipEP,etal.Impactofhighnormalbloodpressureontheriskofcardiovasculardisease. NEnglJMed2001345:12917. 9. OparilS,ZamanMA,CalhounDA.Pathogenesisofhypertension.AnnInternMed2003139:76176. 10. TheWellcomeTrustCaseControlConsortium.Genomewideassociationstudyof14,000casesofseven commondiseasesand3,000sharedcontrols.Nature2007447:66178. 11. AdroguHJ,MadiasNE.Sodiumandpotassiuminthepathogenesisofhypertension.NEnglJMed 2007356:196678. 12. RosendorffC.Thereninangiotensinsystemandvascularhypertrophy.JAmCollCardiol199628:80312. 13. PittB,ZannadWF,RemmeWJ,etal.Theeffectofspironolactoneonmorbidityandmortalityinpatientswith severeheartfailure.RandomizedAldactoneEvaluationStudyInvestigators.NEnglJMed1999341:70917. 14. PittB,RemmeW,ZannadWF,etal.Eplerenone,aselectivealdosteroneblocker,inpatientswithleftventricular dysfunctionaftermyocardialinfarction.NEnglJMed2003348:130921. 15. RosendorffC.Endothelin,vascularhypertrophy,andhypertension.CardiovascDrugsTher199710:795802. 16. BakrisGL,LindholmLH,BlackHR,etal.Divergentresultsusingclinicandambulatorybloodpressures:reportof adarusentanresistanthypertensiontrial.Hypertension201056:82430. 17. YambeM,TomiyamaH,YamadaJ,etal.ArterialstiffnessandprogressiontohypertensioninJapanesemale subjectswithhighnormalbloodpressure.JHypertens200724:8793. 18. DhingraR,PencinaMJ,WangTJ,etal.ElectrocardiographicQRSdurationandtheriskofcongestiveheartfailure: theFraminghamHeartstudy.Hypertension200647:8617. 19. LangRM,BierigM,DevereuxRB,etal.Recommendationsforchamberquantification:areportfromtheAmerican SocietyofEchocardiography'sGuidelinesandStandardsCommitteeandtheChamberQuantificationWriting Group,developedinconjunctionwiththeEuropeanAssociationofEchocardiography.JAmSocEchocardiogr 200518:144063. 20. IngelssonE,BjorklundBodegardK,LindL,ArnlovJ,SundstromJ.Diurnalbloodpressurepatternandriskof congestiveheartfailure.JAMA2006295:285966. 21. AdamsHPJr,delZoppoG,AlbertsMJ,etal.Guidelinesfortheearlymanagementofadultswithischemicstroke: aguidelinefromtheAmericanHeartAssociation/AmericanStrokeAssociationStrokeCouncil,ClinicalCardiology Council,CardiovascularRadiologyandInterventionCouncil,andtheAtheroscleroticPeripheralVascularDisease andQualityofCareOutcomesinResearchInterdisciplinaryWorkingGroups.Stroke200738:1655711. 22. PotterJ,RobinsonTG,FordGA,etal.Controllinghypertensionandhypotensionimmediatelypoststroke (CHHIPS):arandomized,placebocontrolled,doubleblindpilottrial.LancetNeurol20098:4856. 23. PROGRESSCollaborativeGroup.Randomisedtrialofaperindoprilbasedbloodpressureloweringregimen among6,105individualswithpreviousstrokeortransientischaemicattack.Lancet2001358:103341. 24. YusufS,DienerHC,SaccoRL,etal.,onbehalfofthePRoFESSStudyGroup.Telmisartantopreventrecurrent strokeandcardiovascularevents.NEnglJMed2008359:122537. 25. ParvingHH,LehnertH,BrochnerMortensenJ,GomisR,AndersenS,ArnerP,onbehalfoftheIrbesartanin PatientswithType2DiabetesandMicroalbuminuriaStudyGroup.Theeffectofirbesartanonthedevelopmentof diabeticnephropathyinpatientswithtype2diabetes.NEnglJMed2001345:8708. 26. BrennerBM,CooperME,deZeeuwD,etal.,onbehalfoftheRENAALStudyInvestigators.Effectsoflosartanon renalandcardiovascularoutcomesinpatientswithtype2diabetesandnephropathy.NEnglJMed2001345:861 9. 27. LewisEJ,HunsickerLG,ClarkeWR,etal.Renoprotectiveeffectoftheangiotensinreceptorantagonistirbesartan inpatientswithnephropathyduetotype2diabetes.NEnglJMed2001345:85160.

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5.2:DiagnosisandManagementofHypertension
Author(s): CliveRosendorff,MD,PhD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeabletoimplementcurrentguidelinesforthediagnosisandtreatmentof hypertensivepatients,includingmultipleriskfactormodification.

DiagnosisofHypertension
Hypertensionshouldbediagnosedandtreatedinthecontextofreducingoverall cardiovascular(CV)riskandpreventingmorbidityandmortalityfromCVdisease (CVD).Inmosthypertensivepatients,therearemultipleriskfactorsfor atheroscleroticdisease.Therefore,comprehensiveassessmentandtreatmentofall riskfactorsareessentialforeffectiveintervention.AllmodifiableCVriskfactors(i.e., hypertension,hyperlipidemia,alcoholandtobaccouse,obesity,sedentarylifestyle, glucoseintolerance,andinsulinresistance)shouldbeincludedintheinitial assessment(Figure1),andaddressedbythetreatmentplan.Inaddition,theinitial evaluationshouldincludeanaccuratemeasurementofbloodpressure(BP), screeningforsecondarycausesofhypertension,andassessmentoftargetorgan damage.

Figure1

CardiovascularAssessmentintheHypertensivePatient Figure1 ReproducedwithpermissionfromHajjarI,KotchenTA.Trendsinprevalence,awareness,treatment,andcontrolofhypertensionintheUnited States,19882000.JAMA2003290:199206.Copyrighted2003,AmericanMedicalAssociation.AllRightsreserved.

BloodPressureMeasurement
InOfficeBloodPressureMeasurement ExceptincasesofextremeBPelevationwithsystolicBP(SBP)>210mmHg,and/or diastolicBP(DBP)>120mmHg(hypertensiveurgency),orelevatedBPwith evidenceofongoingtargetorgandamage(hypertensiveemergency),hypertension shouldnotbediagnosedonthebasisofmeasurementsmadeonasingle occasion.Hypertensionisdiagnosedwhenatleasttwoseparatereadingsobtained atleast12weeksapartaverage140/90mmHg.1 Procedurestoensureaccurate measurementofBPintheofficesettingareoutlinedinFigure2. Patientsshouldabstainfromtobaccouseandcaffeineingestionforatleast30 minutesbeforetheBPmeasurementistaken.Thearmshouldbeexposedandfree ofconstrictingclothing.Patientsshouldbeaskedtositquietlyfor5minutesbefore theBPismeasured.Useofanappropriatelysizedcuff,inwhichthebladder encirclesatleast80%ofthearm,isessentialbecauseacuffthatistoolargeortoo smallwillresultinfalselyloworfalselyhighreadings,respectively.Acommonerror istousearegularcuffonalargerarmthiswilloverestimatethetrueBP.DuringBP measurement,thearmshouldbesupportedwiththecuffatapproximatelyheart level. DeterminingBPaccuratelycanbedifficultinelderlypatientsbecauseofstiffeningof arterialwalls.ThelossofarterialwallcompliancecanresultinfalselyelevatedBP measurementswhenastandardsphygmomanometerisused. Pseudohypertension,afalselyelevatedBPobtainedbyindirectcuffmeasurement secondarytolossofarterialcomplianceorevencalcification,shouldbesuspected inelderlypatientsdiagnosedashavinghypertension,butwithoutevidenceoftarget organdamage. Osler'smaneuvercansometimesbeusedtoidentifythisphenomenon.Inflatethe BPcuffabovetheleveloftheSBPifthepulselessradialorbrachialarteryremains palpable,stiffeningofthearterymayfalselyelevatetheBPmeasurement.Direct intraarterialBPdeterminationsmaybenecessarytoaccuratelydiagnose hypertensioninthissetting. ItisnowknownthatsomeclassesofBPloweringdrugs,suchasbetablockers, maylowerbrachialarterysystolicBPmorethancentralaorticsystolicBP,andthat thecentralaorticsystolicBPmaybeabetterpredictorofCVoutcomes.2 The noninvasivemeasurementofcentralaorticBPinvolvesthetranslationofthebrachial orradialpulsewaveformstoacentralaorticwaveformusinganexperimentally derivedtransferfunction.Thisrequiresspecialequipment,asitisnotlikelytobe adoptedforgeneralusesoon. OutofOfficeBloodPressureMeasurement HomeBPmeasurementorautomatedambulatoryBPmonitoringoftenhelpsto verifythediagnosisandassesstheseverityofhypertension.BPvaluesobtained outsidetheclinicsettingaregenerallylowerandcorrelatebetterwithtargetorgan damageandoutcomesthanBPmeasurementsobtainedbyhealthcarepersonnel intheclinic. TheutilityofhomeorworkplaceBPmeasurementsdependsontheuseofaccurate andcalibratedBPmonitorsandcarefulrepeatedinstructioningoodBP measurementtechnique.Normalmean24hourambulatoryBPis<125/75mmHg, withameanof<130/85mmHgduringthedayand<110/70mmHgatnight.3 There isnormallyanocturnal"dip"inBP,which,ifabsent,signalsanincreasedriskofCV events.Obstructivesleepapnea(OSA)isassociatedwithhypertension,andBPcan beloweredinpatientswithOSAbytheuseofcontinuouspositiveairwaypressure (CPAP)duringsleep. "Whitecoateffect"referstothefairlycommonsituationinwhichtheclinicorofficeBP ishigherthanthatathome."Whitecoathypertension,"inwhichapatient'sBPisin thehypertensionrangewhenmeasuredbyhealthcarepersonnelbutisnormalat home,occursinapproximately20%ofhypertensivepatients.Itisprobablyananxiety
Figure3 Figure2

Figure4a

Figure4b

Figure4c

Figure4d

Figure5

responsethatmaybeamplifiedthroughpatientphysicianinteractions. Whitecoathypertensionisassociatedwithothercoronaryriskfactors,andis generallythoughttobeassociatedwithincreasedCVDrisk,butnottothelevel observedinfixedhypertension.Intheabsenceofreliableprognosticdataand withoutprospectiverandomizedoutcometrialsofantihypertensivedrugtreatmentin whitecoathypertension,ataminimum,lifestylemodificationshouldbeemployed forBPcontrol,andconcomitantCVDriskfactorsshouldbetreatedaggressively. Somehypertensionauthoritiesadvocateantihypertensivedrugtherapyforthese patients. Insomepatients,officeBPmaybesignificantlylowerthanambulatoryBP("masked hypertension"or"reversewhitecoathypertension").Thismayleadtoafalselylow estimateofdailyBPandpossibleundertreatmentofsomepatients.Patientswith maskedhypertensionareatincreasedriskofCVD,andboththeirBPandtheir concomitantriskfactorsshouldbemanagedaggressively.4 History Thepurposeofthehistoryandphysicalexaminationis:1)todeterminetheneedfor andguideapossibleevaluationofsecondarycausesofhypertension,2)to determinethepresenceandseverityoftargetorgandamage,and3)toassess overallCVriskandidentifyallmodifiableCVriskfactors(Figure3).Patientsshould alsobequestionedaboutthedurationandseverityoftheirhypertension,prior workupofpossiblesecondarycausesofhypertension,andtheefficacyandadverse effectsofprevioustherapies. Cluestosecondarycausesofhypertension(Figures4a,b,c,d)shouldbesought, includingtheonsetofseverehypertensionatanearlyage,particularlyinthe absenceofapositivefamilyhistoryofhypertension,andanabruptworseninginthe severityofhypertensioninanolderpatient.Patientswithresistanthypertensionthat remainsuncontrolledinthepresenceofanaggressivemultidrugregimenshould alsobeworkedupforsecondaryhypertension. Targetorgandamagemustbedocumentedbyhistoryandphysicalexamination.A historyofcoronaryheartdisease(CHD),cerebrovasculardisease,peripheral vasculardisease,orchronickidneydisease(CKD)suggestslongstanding,poorly controlledhypertension.Inaddition,priordiagnosisandtreatmentofotherCVrisk factors(hyperlipidemia,diabetes,smoking,obesity,orsedentarylifestyle)mustbe establishedtoguidemanagementdecisions. Riskfactorsforprimaryhypertension,suchasapositivefamilyhistoryorpregnancy relatedhypertension,shouldbeidentified.Relevantlifestylecharacteristics,suchas weightgain,sedentarylifestyle,highdietarysaltingestion,andexcessivealcohol consumptionshouldbereviewed. PhysicalExamination ThephysicalexaminationshouldaccuratelydeterminetheBP,identifysignsof secondarycausesofhypertension,anddocumentthepresenceanddegreeof targetorgandamage.TheBPdeterminationshouldbetheaverageofaminimumof twoBPreadingsobtained23minutesapart.Initially,theBPshouldbemeasuredin botharms.Althoughthereareoftensmallvariationsbetweenarms,large differencessuggestsubclavianarteryobstruction.Ingeneral,theBPmeasurement shouldbeobtainedfromthearmthatyieldsthehigherreadings.StandingBPlevels shouldbecheckedduringtheinitialevaluationandafterdrugtitrationstoexclude significantorthostasis. LaboratoryEvaluation Laboratoryevaluationshoulddocumenttargetorgandamage(Figure5).Bloodurea nitrogen(BUN)andserumcreatininelevelsshouldbeobtainedtoquantifyrenal function.Serumcreatininecanbesupplementedasanindexofrenalfunctionwith thecalculationofestimatedglomerularfiltrationrate(eGFR),whichisderivedfrom anequationthatincludestermsforgender,race,andage.5 Urineshouldbe analyzedformicroalbuminuria,oneoftheearliestsignsofendothelialdysfunction andgeneralizedvasculardisease.

CKDisbothacauseandacomplicationofhypertension,andisdefinedaseither:1) reducedexcretoryfunctionwithaneGFR<60ml/min/1.73m2 (approximately correspondingtoaserumcreatinineof>1.5mg/dlinmenor>1.3mg/dlinwomen), or2)thepresenceofalbuminuria(>300mg/dayor>300mgalbumin/gcreatinine).1 Urinaryalbuminexcretionhasdiagnosticandprognosticvalueequivalenttoreduced eGFR.Albuminexcretioncanbemostconvenientlyassessedbymeasuringthe albumin:creatinineratioonaspoturinesample:Aratioof30300mgalbumin/g creatininesignifiesmicroalbuminuria>300mgalbumin/gcreatininesignifiesCKD. Arecenttrendistoabandonthetermmicroalbuminuriaandtoregardalllevelsof albuminexcretionabove30mg/gcreatinineassignifyingCKD.Serumpotassium shouldbemeasuredtoruleouthypokalemiasuggestiveofhyperaldosteronism,or thehyperkalemiaofrenalfailure. Fastingserumglucoseshouldbeassessedtoexcludeimpairedglucosetolerance, whichoccursinasmanyas50%ofhypertensivepatients,orfrankdiabetes. Glycosylatedhemoglobincanbeusedtoconfirmthediagnosisofdiabetes.A fastinglipidprofileshouldbeobtainedtodiagnosedyslipidemia,whichisalso commoninhypertensivepatients.Anelectrocardiogram(ECG)shouldbeobtained tolookforevidenceofischemicheartdisease,leftventricular(LV)hypertrophy,or both.

BloodPressureMeasurement Figure2

EvaluationofthePatientWithElevatedBloodPressure Figure3

EvidenceofSecondaryHypertension(1of4) Figure4a

CausesofSecondaryHypertension(2of4) Figure4b ReproducedwithpermissionfromOparilS,CalhounD(2000).Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.New York:ScientificAmerican.

CausesofSecondaryHypertension(3of4) Figure4c ReproducedwithpermissionfromOparilS,CalhounD(2000).Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.New York:ScientificAmerican.

CausesofSecondaryHypertension(4of4) Figure4d ReproducedwithpermissionfromOparilS,CalhounD(2000).Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.New York:ScientificAmerican.

BaselineLaboratoryTests Figure5

BenefitsofPharmacologicTreatment
ReducingBPbypharmacologicmeansreducesCVmorbidityandmortality.In clinicaltrials,antihypertensivetherapyhasbeenassociatedwithreductionsin strokeincidenceof3540%,inmyocardialinfarction(MI)of2025%,andinthe developmentofcongestiveheartfailure(CHF)of>50%. Metaanalysesofrandomizedcontrolledtrialsofantihypertensivetherapyhave shownoutcomebenefitswiththemajorclassesofantihypertensivedrugs,including angiotensinconvertingenzyme(ACE)inhibitors,angiotensinreceptorblockers,and calciumchannelblockers.6,7Theevidenceforbetablockersandthiazidetype diureticsforCVprotectioninuncomplicatedhypertensioniscontroversial,andwill bedescribedinthemoduleonPharmacologicTreatmentofHypertensioninthis chapter. Antihypertensivedrugtreatmentalsoslowsprogressiontomoresevere hypertension,developmentofLVhypertrophy,progressionofrenaldiseaseand CHF,andreducesallcausemortality.Clinicaltrialsinelderlypatients,particularly thosewithISH,haveshownevengreaterbenefitthaninyoungerpersons. TreatmentThresholdsandGoals TheultimategoalofantihypertensivetherapyistoreduceoverallCVriskandthus CVmorbidityandmortality.Thus,inadditiontoBPreduction,treatmentofother modifiableCVriskfactorsshouldbeaddressed.Basedonevidencefrommultiple clinicaltrials,theseventhreportoftheJointNationalCommitteeforthePrevention, Detection,Evaluation,andTreatmentofHighBloodPressure(JNC7),1 recommendsthatthethresholdforthepharmacologictreatmentofhypertension shouldbeaBPof140/90mmHg,exceptinthepresenceofdiabetesorCKDwhen patientsshouldbestartedonappropriatedrugtherapywithagoalBPof<130/80 mmHg(Figures6,7). AScientificStatementfromtheAmericanHeartAssociationrecommendsthat therapybeinitiatedwithagoalof<130/80mmHgforhypertensivepatientswho havecoronaryarterydisease(CAD),CADequivalents(carotidarterydisease,aortic aneurysm,andperipheralarterydisease),orwhohaveaFraminghamriskscoreof 10%(Figures8a,b,9).8 Lifestylemodificationshouldbeusedasadjunctivetherapyforallpatientsreceiving pharmacologictreatment,andforprimarytherapyof"prehypertensive"persons(120 129/8089mmHg)whodonothaveclinicalindicationsforpharmacologictreatment. AnidealBP,basedonepidemiologicdata,wouldappeartobe115/75mmHg.9 Thishaspromptedmanytoadvocatea"goaslowasthepatientwilltolerate" strategyofantihypertensivetreatment.Expertcommitteesandtreatmentguidelines havenotembracedsucharadicalapproach,sinceevidencefromrandomized controlledoutcometrialswithverylowBPtargetsissparse.Itisnotclearthat "optimal"BPachievedbypharmacologicmeanshasariskprofilesimilartonaturally occurring"optimal"BP.Further,therisksassociatedwithantihypertensivedrug therapyinthehighdosesneededtoreduceBPto"optimal"levelsareuncertain,as isthecostofthisapproach. Intherecentstudy,ACCORDBP(ActiontoControlCardiovascularRiskinDiabetes BloodPressureTrial),10inpatientswithtype2diabetesathighriskforCVevents, targetingasystolicBPof<120mmHg,ascomparedwith<140mmHg,didnot reducetherateofacompositeoutcomeoffatalandnonfatalCVevents.Anew NationalInstitutesofHealthsponsoredtrialnowunderway,SPRINT(SystolicBlood PressureInterventionTrial),willtest,innondiabeticsubjects,theeffectsofintensive BPlowering(to<120mmHgvs.<140mmHg)onthepreventionofCVD, progressionofrenaldisease,andcognitivedeclineover46years. Forpatientswithwhitecoathypertensionwhohavenoevidenceoftargetorgan damage,pharmacologictherapyislikelytobeunnecessary,butthisiscontroversial. If,however,targetorgandamageispresentparticularlyifitisprogressive

Figure6

Figure7

Figure8a

Figure8b

Figure9

pharmacologictherapyshouldbeadministered.HomeBPmeasurementor24hour ambulatoryBPmonitoring(ABPM)isusefultoavoidovertreatmentofthesepatients. Antihypertensivetreatmentisindicatedinisolatedsystolichypertensionbecause SBPisabetterpredictorofevents(CHD,CVD,CHF,stroke,endstagerenal disease,andallcausemortality)thanisDBP,especiallyamongolderpersons. Elevatedpulsepressure,anindicatorofreducedcomplianceinlargevessels,isa bettermarkerofincreasedCVriskthanisSBPorDBPalone,particularlyinelderly individuals.PharmacologictherapyinpatientswithISHiswelltoleratedandeffective inbothloweringBPandreducingCVmorbidityandmortality,particularlythrough reductionsinstroke.ThegoaloftreatmentinpatientswithISHistolowerSBPto <140mmHg,andto<130mmHginpatientswithdiabetes,CKD,CAD,CAD equivalents,andwithaFraminghamriskscore10%,asdefinedpreviously. Note,however,fromFigure9,thatoldermenarenearlyallathighriskforMI,and shouldbetreatediftheirBPis130/80mmHg.However,ifthereisevidenceof myocardialischemia,andtheDBPishightobeginwith,theBPshouldbelowered slowly,andcautionisadvisedininducingfallsofDBPbelow60mmHgifthepatient hasdiabetesmellitus(andisthereforemorelikelytohavesignificantCAD)orisover theageof60years.Inolderhypertensiveindividualswithwidepulsepressures, loweringSBPmaycauseverylowDBPvalues(<60mmHg).Thisshouldalertthe cliniciantoassesscarefullyanyuntowardsignsorsymptoms,especiallythosedue tomyocardialischemia.8

ClassificationandManagementofBloodPressureforAdultsAges18YearsorOlder Figure6 ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhReportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

AlgorithmforTreatmentofHypertension Figure7 ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

Calculationofa10YearRiskforCoronaryHeartDiseaseUsingtheFraminghamPointScore(1of2)Men Figure8a ReproducedfromtheNationalHeart,Lung,andBloodInstituteaspartoftheNationalInstitutesofHealthandtheUSDepartmentofHealthand HumanServices.Availableat:http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm.Accessed11/30/2011.

Calculationofa10YearRiskforCoronaryHeartDiseaseUsingtheFraminghamPointScore(2of2)Women Figure8b ReproducedfromtheNationalHeart,Lung,andBloodInstituteaspartoftheNationalInstitutesofHealthandtheUSDepartmentofHealthand HumanServices.Availableat:http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm.Accessed11/30/2011.

DataFromtheFraminghamHeartStudyExperience Figure9 Muchoftheyoungandmiddleagedpopulationhasalowtointermediateriskforhardcoronaryheartdisease(CHD)events(myocardial infarctionorCHDdeath).Evenuptoage80years,morethanthreequartersofwomenexperiencea10yearriskofCHDthatfallsbelow10%. Therisksarehigherformen,andbyage60themajorityofmenareathighrisk(>10%per10years)forCHD.Nearlyallmeninthe7079year agegroupareathighrisk. OriginalfigurecourtesyofPeterW.F.Wilson,MD,FraminghamHeartStudy(unpublisheddata).ModifiedwithpermissionfromPasternakRC, AbramsJ,GreenlandP,etal.Taskforce#1identificationofcoronaryheartdiseaserisk:isthereadetectiongap?JAmCollCardiol 200341:186374.

LifestyleModification
AllpatientswithhighBPshouldreceiveadviceregardinglifestylemodification (Figure10)aseitherdefinitivetherapyorasanadjuncttopharmacologictreatment. WhilelifestylemodificationhasnotbeenshowntoreduceCVmorbidityand mortality,ithasbeenshowninrandomizedcontrolledtrialstolowerBPinboth hypertensiveandhighriskprehypertensivepersons,andcanpreventhypertension inthelattergroup.Inaddition,lifestylemodificationcanpotentiallyreducethe numberanddosageofantihypertensivemedicationsneededtocontrolapatient's highBP. Adviceonlifestylemodificationshouldbetailoredtoeachpatient'sneeds.For example,emphasisshouldbeplacedonweightlossandincreasedphysicalactivity forobesepatients.Allhypertensivepatientsshouldbeadvisedtoadoptthefollowing lifestylemodifications:1)eatawellbalanceddietrichinfruits,vegetables,andlow fatdairyproducts2)loseweightifnotatidealbodyweight3)pursueregular physicalexercise4)decreasealcoholconsumptiontolessthan23standard drinksadayforthosewhodrink5)reducedietarysodiumand6)stopsmoking. Diet TheDASHCollaborativeResearchGrouphasprovidedstrongevidencethattotal dietismoreimportantthanindividualmicronutrientssuchassodiumindetermining BP.11TheydemonstratedthattheDASHeatingplan,adiethighinfruits,vegetables, andlowfatdairyproductsandlowinsaturatedandtotalfat,loweredBPby3.5/2.1 mmHginnormotensiveindividuals,andby11.4/5.5mmHginhypertensives,even thoughsodiumintakeandweightwereheldconstant. Importantly,theDASHeatingplanwasparticularlyeffectiveinreducingBPinthe blackstudyparticipants(Figures11a,b).TheBPreductioninhypertensiveblacks was13.6/6.1mmHg,aneffectcomparabletothatachievedwithmanysingle antihypertensivedrugs.TheDASHdietcanbeapproximatedbytakingfourservings offruit,fourservingsofvegetables,andthreeservingsoflowfatdairyproductsper day(Figure12). WeightLoss Weightlossispotentiallythemosteffectivelifestylemodificationforthosewithhigh BP.TheBPloweringeffectofweightlossisindependentofsodiumrestriction,and isseeninbothobeseandnonobesehypertensiveindividuals.Clinicaltrialevidence suggeststhatweightlossinterventionsproduceBPbenefitsthatpersistevenafter cessationofactivetherapy.Inaddition,weightlossdecreasesinsulinresistance, theincidenceandseverityofdiabetes,serumcholesterol,andtheprevalenceofLV hypertrophy.TheseeffectsreduceoverallCVriskindependentofBP.Bodymass indexshouldbemaintainedbetween18.5and24.9kg/m2 . Becausesustainedweightreductionisextremelydifficulttoachieve,emphasis shouldbeplacedonpreventionofweightgain,particularlyinyoungerindividuals withprehypertensionandinfamilieswithahighprevalenceofhypertension.When prescribingweightlossregimens,theclinicianshouldavoidappetitesuppressants thatcontainsubstancesknowntoraiseBP. PhysicalActivity Regularphysicalactivitypromotesweightlossandgeneralgoodhealth.Exercise withagoalofachieving4060%ofmaximumO2consumption(3045minutesof briskwalkingformostdaysoftheweekisrecommended)hasbeenshownto decreaseSBPby49mmHginbothnormotensivesandhypertensives.Inaddition, regularphysicalactivitypromotesasenseofwellbeinganddecreasesCVrisk, morbidity,andmortality.Exercisealsoreducesoverallmortalityandhasbeneficial effectsonserumlipidprofiles. Prescriptionsforexerciseshould,asotherlifestylemodifications,betailoredtoeach individualpatient'sconditionandpreference.Personswithadvancedorunstable CVDmayrequireamedicalevaluationbeforeinitiationofexerciseand/ora

Figure10

Figure11a

Figure11b

Figure12

medicallysupervisedexerciseprogram.Youngerpersonscanpursuevigorous activities,whileelderlypatientsbenefitfrombriskwalkingforabout20minutesevery day.Aerobicexercisessuchaswalking,jogging,biking,andswimmingare preferredoverisometricexercisessuchasweightlifting,asthelattercanraiseBP levels. Alcohol DrinkingalcoholicbeveragesincreasesBPbothacutelyandchronically.Beyonda thresholdpoint,theBPelevationisproportionaltotheamountofalcoholconsumed. Further,excessivealcoholuseisafrequentcauseofresistancetoantihypertensive therapy,andshouldbeinvestigatedinallpatientsfailingtorespondtoBPlowering medications. Reasonablerecommendationsarefornondrinkersnottobeginconsumingalcohol andforthosewhododrinktolimitdailyintaketo1ounce(30ml)ofethanol equivalentto2ounces(60ml)of100proofalcohol,8ounces(240ml)ofwine,or24 ounces(720ml)ofbeerinmenandonehalfthatamountinwomenandsmaller men.Theadjustmentforgenderandsizeisnecessarybecausewomenabsorb alcoholmorerapidlyandmetabolizealcoholmoreslowlythanmen,andtheeffects ofalcoholareinverselyproportionaltobodymass.Bingedrinkingshouldbeavoided becauseofanassociationwithincreasedriskofstroke. SodiumReduction HighsodiumintakehasgenerallybeenrelatedtoBPelevation,particularlyin hypertensiveindividuals,andthiseffectappearstobeaugmentedbyconcomitant lowpotassiumintake.WhensodiumrestrictionwasaddedtotheDASHdietin theDASH(DietaryApproachestoStopHypertension)trial,thereductioninsodium intakefromthehigh(150mmol/day)totheintermediate(100mmol/day)level reducedSBPby2.1mmHgwhenparticipantswereona"usualAmericandiet,"and by1.3mmHgontheDASHdiet.Reducingthesodiumintakefromtheintermediate tothelow(50mmol/day)levelcausedadditionalreductionsof4.6mmHgonthe usualdiet,and1.7mmHgontheDASHdiet. ThelargestBPeffectwasobservedwiththecombinationofDASHdietandlow sodiumintake.WhiledietarysodiumreductionclearlylowersBPinmany antihypertensiveindividuals,evidencethatitcanreduceCVeventsissparseand hasbeenchallengedbyobservationaldatademonstratingadirectrelationship betweendietarysaltintakeandlifeexpectancy.Onlyonestudyhasshowna reductioninCVeventsinbothhypertensiveandnormotensiveindividualswhohad participatedinaclinicaltrialofdietarysodiumreduction/weightreductionmany yearsbefore.12 BasedontheseobservationsandthesmallbutconsistentBPloweringeffects observedinotherclinicaltrialsofdietarysodiumreductioninhypertensivepersons, avoidingexcessivesodiumintakeisrecommendedforthesepatients.1,13Additional benefitsofsodiumreductioninclude:1)reduceddiureticinducedhypokalemiaand greatereaseofBPcontrolwithdiuretictherapy,2)protectionfromosteoporosisand fracturesbyreducingurinarycalciumexcretion,and3)favorableeffectsonLV hypertrophy. TheJNC7recommendsareductionindailyconsumptionofsodiumchlorideto<6g andofsodiumto<2.4g.Thiscanbeachievedbyavoidingobviouslysaltyfoods,not addingsaltatthetable,andeatingmoremealscookedfromnaturalingredients. Avoidingprocessedfoodswithexcessivesodiumcontentand/orreducingthe sodiumcontentofthosefoodsareadditionalstrategiesforreducingsodiumintake.

LifestyleModificationstoManageHypertension Figure10 ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportontheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

EffectofDASHDietonBloodPressurebyRaceandHypertensionStatus(1of2)SystolicBloodPressure Figure11a ReproducedwithpermissionfromSvetkeyLP,SimonsMortonD,VollmerWM,etal.Effectsofdietarypatternsonbloodpressure:subgroup analysisoftheDietaryApproachestoStopHypertension(DASH)randomizedclinicaltrial.ArchInternMed1999159:28593.Copyrighted 1999,AmericanMedicalAssociation.AllRightsreserved.

EffectofDASHDietonBloodPressurebyRaceandHypertensionStatus(2of2)DiastolicBloodPressure Figure11b ReproducedwithpermissionfromSvetkeyLP,SimonsMortonD,VollmerWM,etal.Effectsofdietarypatternsonbloodpressure:subgroup analysisoftheDietaryApproachestoStopHypertension(DASH)randomizedclinicaltrial.ArchInternMed1999159:28593.Copyrighted 1999,AmericanMedicalAssociation.AllRightsreserved.

DASHDiet Figure12 TipsoneatingtheDASHDietway: Startsmall.Makegradualchangesinyoureatinghabits. Centeryourmealaroundcarbohydratessuchaspasta,rice,beans,andvegetables. Treatmeatasonepartofthewholemeal,insteadofthefocus. Usefruit,orlowfat,lowenergyfoodssuchassugarfreegelatinfordessertsorsnacks.

KeyPoints
TherearedistinctadvantagesanddisadvantagesofmeasuringBPathomeversustheclinicoroffice. Whitecoathypertensionisnotbenign,andshouldprobablybetreatedwithaggressivelifestylemodification,and possiblywithpharmacologictherapy. Inallpatients,acarefulhistoryandphysicalexaminationshouldbedirectedtothefollowingobjectives:1)to identifysecondarycausesofhypertension,2)toestablishthepresenceandseverityofhypertensivetargetorgan damage,and3)todevelopacomprehensiveCVriskprofile. Laboratoryevaluationshouldbetailoredtothesameobjectives,andshouldincludeserumsodium,potassium, BUN,creatinine,eGFR,fastingglucoseandlipidprofile,urinalysis,andmeasurementofthealbumin:creatinine ratioinaspoturinesample. Thethresholdforpharmacologictreatmentis140/90mmHg,exceptinpatientswithdiabetes,CKD,CAD,CAD equivalents(cerebrovasculardisease,carotidarterydisease,aorticaneurysm,peripheralvasculardisease)and thosewithaFraminghamriskscoreof=10%,inwhomthethresholdis130/80mmHg. Thereisclearevidencefromclinicaltrialsthatchangesinlifestyle,includingweightlossandmaintenanceof normalbodyweightincreasedphysicalactivitydietarymodificationtoincludemorefruits,vegetables,andlowfat dairyproductsmoderationofalcoholintakeandsodiumreductioninsaltsensitiveindividuals,canlowerBPin bothhypertensiveandprehypertensivepersons,andcanpreventhypertensioninthelattergroup. MaintenanceoradoptionofahealthylifestyleisrecommendedforallpersonsirrespectiveofBP,andisan importantadjuncttopharmacologictherapyinpatientswithhypertension.

References
1. ChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure.Hypertension200342:120652. 2. WilliamsB,LacyPS,ThomSM,etal.,onbehalfoftheCAFInvestigatorsAngloScandinavianCardiacOutcomes TrialInvestigatorsCAFSteeringCommitteeandWritingCommittee.Differentialimpactofbloodpressure loweringdrugsoncentralaorticpressureandclinicaloutcomes:principalresultsoftheConduitArteryFunction Evaluation(CAFE)study.Circulation2006113:121325. 3. KikuyaM,HansenTW,ThijsL,etal.Diagnosticthresholdsforambulatorybloodpressuremonitoringbasedon 10yearcardiovascularrisk.Circulation2007115:214552. 4. HaraA,OhkuboT,KikuyaM,etal.Detectionofcarotidatherosclerosisinindividualswithmaskedhypertension andwhitecoathypertensionbyselfmeasuredbloodpressureathome:theOhasamastudy.JHypertens 200725:3217. 5. KidneyDiseaseOutcomesQualityInitiative(K/DOQI).K/DOQIclinicalpracticeguidelinesonhypertensionand antihypertensiveagentsinchronickidneydisease.AmJKidneyDis200443(5Suppl1):S1290. 6. TurnbullF,onbehalfoftheBloodPressureLoweringTreatmentTrialistsCollaboration.Effectsofdifferentblood pressureloweringregimensonmajorcardiovascularevents:resultsofprospectivelydesignedoverviewsof randomisedtrials.BloodPressureLoweringTreatmentTrialistsCollaboration.Lancet2003362:152735. 7. NealB,MacMahonS,ChapmanN,onbehalfoftheBloodPressureLoweringTreatmentTrialists'Collaboration. EffectsofACEinhibitors,calciumantagonists,andotherbloodpressureloweringdrugs:resultsofprospectively designedoverviewsofrandomisedtrials.BloodPressureLoweringTreatmentTrialists'Collaboration.Lancet 2000356:195564. 8. RosendorffC,BlackHR,CannonCP,etal.Treatmentofhypertensioninthepreventionandmanagementof ischemicheartdisease:ascientificstatementfromtheAmericanHeartAssociationCouncilforHighBlood PressureResearchandtheCouncilsonClinicalCardiologyandEpidemiologyand.Circulation2007115:2761 88. 9. LewingtonS,ClarkeR,QizilbashN,PetoR,CollinsR,onbehalfoftheProspectiveStudiesCollaboration.Age specificrelevanceofusualbloodpressuretovascularmortality:ametaanalysisofindividualdataforonemillion adultsin61prospectivestudies.Lancet2002360:190313. 10. ACCORDStudyGroup.Effectsofintensivebloodpressurecontrolintype2diabetesmellitus.NEnglJMed 2010362:157585. 11. AppelLJ,BrandsMW,DanielsSR,KaranjaN,ElmerPJ,SacksFM.Dietaryapproachestopreventionand treatmentofhypertension:ascientificstatementfromtheAmericanHeartAssociation.Hypertension200647:296 308. 12. CookNR,CutlerJA,ObarzanekE,etal.Longtermeffectsofdietarysodiumreductiononcardiovasculardisease outcomes:observationalfollowupoftrialsofhypertensiveprevention(TOHP).BMJ2007334:8858. 13. ManciaG,DeBackerG,DominiczakA,etal.2007GuidelinesfortheManagementofArterialHypertension:The TaskForcefortheManagementofArterialHypertensionoftheEuropeanSocietyofHypertension(ESH)andofthe EuropeanSocietyofCardiology(ESC).JHypertens200725:110587.

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5.3:PharmacologicTreatmentofHypertension
Author(s): CliveRosendorff,MD,PhD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeabletoidentifythepharmacologicoptionsfortreatinghypertensivepatients, includingthosewithcomorbidconditions.

PharmacologicTreatment
GeneralConsiderations Abundantclinicaltrialdataindicatethatloweringbloodpressure(BP)with antihypertensivedrugseffectivelyreducestheriskofavarietyofcardiovascular disease(CVD)outcomes,includingCVdeath,aswellastotalmortality.Outcome benefitshavebeenseenwithtreatmentbasedondiuretics,betablockers, angiotensinconvertingenzymeinhibitors(ACEIs),angiotensinreceptorblockers (ARBs),andcalciumchannelblockers(CCBs).1,2 Mosthypertensivepatientsrequiremorethanonedrug,sotheemphasisshouldbe onthechoiceofcompatiblecombinationsandcorrectdoses,ratherthanindividual drugchoices.Itshouldbenoted,also,thattheeighthreportoftheJointNational CommitteeonPrevention,Detection,Evaluation,andTreatmentofHighBlood Pressure(JNC8)isinpreparationatthetimeofthiswriting,andthe recommendationscontainedinthismodulemaychangeasaresultofJNC8. ItisamatterofcontroversywhetherreductionofCVDriskissimplyafunctionofBP lowering,orwhethersomeclassesofantihypertensivedrugshaveadditional vasoprotectivepropertieswhichmakethemmoreappropriatethanothers.Some authoritieshaveclaimedthat,foroutcomesotherthanHF,differencesinachieved systolicBP(SBP)loweringarelinearlyrelatedtotheextentofriskreduction(Figure 1),and,therefore,BPreductioniseverything.Ontheotherhand,trialssuchasLIFE (LosartanInterventionForEndpointreductioninhypertension),3 ACCOMPLISH (AvoidingCardiovascularEventsthroughCombinationTherapyinPatientsLiving withSystolicHypertension),4 andASCOTBPLA(AngloScandinavianCardiac OutcomesTrialBloodPressureLoweringArm)5 havedemonstratedmajor treatmentadvantagesofonetreatmentoveranotherwithoutassociateddifferences inBPreductionorinattainedBP.Itisclearthat,forhypertensivepatientsoverall,BP reductionisthefirstpriority,butalsothatprovidersshouldbemorediscriminatingin theirchoiceofantihypertensivedrug,totakeadvantageofdrugpropertiesthatare additionaltoBPloweringalone. TheseventhreportoftheJointNationalCommitteeforthePrevention,Detection, Evaluation,andTreatmentofHighBloodPressure(JNC7),publishedin2003, focuseditsantihypertensivetreatmentapproachonthepresenceorabsenceof "compellingindications,"thatis,highriskcomorbidconditionsforwhichclinical trialshavedemonstratedbenefitofspecificclassesofantihypertensivedrugs (Figures2,3).6 Forhypertensivepersonswithcompellingindications,drug selectionsaredictatedbythecomorbidconditionaswellastheBP.Intheabsence ofcompellingindications,JNC7recommendsthatmostpatientsbetreatedwitha thiazidetypediuretic,eitheraloneorincombinationwithotherclassesofdrugs (ACEIs,ARBs,CCBs,orbetablockers)thathavebeenshowntobebeneficialin randomizedcontrolledoutcometrials.ThelatestEuropeanguidelineshavealso takentheviewthatthesefiveclassesofdrugsaresuitablefortheinitiationand maintenanceofantihypertensivetreatment,aloneandincombination,exceptthat betablockers,especiallyincombinationwiththiazidediuretics,shouldnotbeused inpatientswiththemetabolicsyndromeorathighriskofincidentdiabetes.7 AngiotensinConvertingEnzymeInhibitorsandAngiotensinReceptorBlockers ACEIsarerecommendedasfirstlinetherapyforhypertensioninthosepatientswho haveleftventricular(LV)dysfunction,andshouldbeincludedinthetherapyof patientswithcoronaryarterydisease(CAD)orwhoareathighriskforCAD.Although theevidenceforrenoprotectioninpatientswithdiabeticnephropathyisstrongestfor ARBs,itisnotunreasonabletouseACEIsinthissituation.8 Byextrapolation,ACEIs shouldalsobeconsideredforhypertensiontreatmentinpatientswithhypertensive nephropathy,andindiabeteswithoutnephropathy.Ifpatientsdevelopintoleranceto ACEIs,suchasdrycoughorangioedema,thenanARBshouldbesubstituted. TheONTARGET(OngoingTelmisartanAloneandinCombinationWithRamipril GlobalEndpointTrial)study9 showedthattheARBtelmisartanwasnotinferiortothe
Figure1

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Figure4

Figure5a

Figure5b

Figure6

Figure7

ACEIramiprilinthepreventionofCVeventsinapopulationofpatientsathighriskfor CVD.Thus,ingeneral,anARBcanbeconsideredabettertolerated,equivalent,and suitablealternativetoanACEI.Surprisingly,althoughtheBPwasevenlowerwitha combinationoframiprilandtelmisartantogether,therewasnofurtherimprovement withregardtotheprimaryoutcome,andthereweremoresideeffects. Thecombinationofareninangiotensinsystem(RAS)blocker(ACEIorARB)witha diureticisalogicalchoiceforinitialtherapyinawidevarietyofpatients.TheALLHAT (AntihypertensiveandLipidLoweringTreatmenttoPreventHeartAttackTrial) study10showedequalbenefitbetweenchlorthalidone,amlodipine,andlisinoprilin preventingfatalCADeventsandnonfatalmyocardialinfarction(MI)inover30,000 patientswithhypertension,followedforameanofjustunder5years. AnotherappropriatefirstlinecombinationisaRASblockerwithaCCB. TheACCOMPLISH(AvoidingCardiovascularEventsthroughCombinationTherapyin PatientsLivingwithSystolicHypertension)trial11comparedthecombinationofan ACEI(benazepril)withaCCB(amlodipine)versusthesameACEI(benazepril)plus hydrochlorothiazide.Thisstudy,inover11,000highriskhypertensivepatients,had astheprimaryoutcomeacompositeofdeathfromCVcauses,nonfatalMI,stroke, hospitalizationforangina,suddencardiacarrest,andcoronaryrevascularization. TheachievedBPwasthesameinbothtreatmentgroups,buttherewasarelative riskreductionofabout20%intheACEI/CCBgroupcomparedtothe ACEI/hydrochlorothiazidegroup. TheapparentdiscrepancybetweenALLHAT(inwhichchlorthalidonewasasgood asamlodipine)andACCOMPLISH(inwhichhydrochlorothiazidewasnotasgoodas amlodipine)canberesolvedbytheobservationthatthesearetwodifferentdiuretics. Hydrochlorothiazideisathiazidediuretic,whereaschlorthalidoneisnot.Thisis discussedfurtherlaterinthismodule. Allofthesestudiestogetherwouldsupporttwoexcellentoptionstocombinewitha RASblocker,namelyadiuretic,oraCCB,orperhapsbothforpatientswithresistant hypertension. BetaBlockers Severalmetaanalysesofdatafromrandomizedcontrolledtrialshaveshownthat treatmentwithbetablockersalone,orincombinationwithotherdrugclasses,isnot aseffectiveinreducingCVDeventsordeathasthosebasedonotherdrugclasses orplacebo.12,13Theresultisthatbetablockershavelosttheirattractivenessas firstlinetherapyforuncomplicatedhypertension.Thecaveattothisisthatnearlyall oftheoutcomestudiesofbetablockersinhypertensionusedatenolol.Itisnot knownwhetherthenewerbetablockerscarvedilol,metoprolol,bisoprolol,and nebivololwhichallimproveoutcomesinpatientswithimpairedLVfunction,willturn outtobemoreeffectivethanatenololinreducingotherCVoutcomesinpatientswith hypertension.InpatientswithCAD,betablockersmovefromtherapeuticlimboto centerstagetheyarethedrugsoffirstchoiceforthetreatmentofhypertensionin patientswithstableanginaandpostMI.14 ThiazideDiuretics Thebasisforthesomewhatcontroversialrecommendationofpreferredstatusfor thiazidediureticsbyJNC7isthefavorableexperiencewithchlorthalidonein ALLHAT,10aswellasthefactthatthiazidediureticsenhancetheantihypertensive efficacyofmostotherdrugclasses,andtheirlowcost.Further,volumeoverload relatedtoinadequateorabsentdiuretictherapyisacommoncauseofresistanceto BPcontrol. Atthesametime,thereareconsiderableproblemswiththeuseofthiazidediuretics asfirstlinetherapyinhypertension.Theantihypertensiveefficacyof hydrochlorothiazideinitsdailydoseof12.525mg,asmeasuredbyheadtohead studiesbyambulatoryBPmeasurement,isconsistentlyinferiortothatofotherdrug classes.15Inaddition,therearesignificantsideeffects,includingadecreasein insulinsensitivityandahigherincidenceofnewonsetdiabetesmellitus,16andan increaseinlowdensitylipoproteincholesterolandtriglycerides.17

TheapparentparadoxbetweenthefavorableresultsofALLHATwithchlorthalidone andtheknownadversemetaboliceffectsofhydrochlorothiazideandotherthiazide diureticsisresolvedbythelittleknownfactthatchlorthalidoneisnotathiazide diuretic.18Thisgrowingrealizationhasledtoanincreasingutilizationof chlorthalidoneinpreferencetohydrochlorothiazideasthediureticofchoiceinthe treatmentofhypertension. InitiationofTherapy ForpersonswithBP>20/10mmHgabovegoal(stage2hypertension),initial treatmentwithtwodrugs,usuallyincludingathiazidetypediuretic,isrecommended byJNC7becauseofthehighriskofthispatientgroup.Randomizedcontrolledtrials haveshownthatsingledrugtreatmentisnotusuallyadequatetoachievegoalBPs inmosthypertensivepatients,particularlythosewithmainlysystolicorstage2 hypertension.Forexample,intheverylargeALLHATtrial(n=42,418),fewerthan 30%ofparticipantsachievedgoalBP(<140/90mmHg)onmonotherapy.19 DataaresimilarfortheLIFE,3 CONVINCE(ControlledOnsetVerapamilInvestigation ofCardiovascularEndPoints),20INVEST(InternationalVerapamilTrandolapril Study),21andASCOT5 trials,inwhichaminorityofparticipantswereon monotherapyattheendofthefollowupperiod.Inthesetrials,asecond,third,and evenfourthdrugwasaddedinordertoattaingoalBPsandassureequalizationof BPsbetweenoramongtreatmentarms.Thesecond,third,andfourthlineactive studymedicationscouldcomefromadrugclassotherthanthatofaprimarystudy drug. Initiatingtherapywithmorethanoneagentoffersthepotentialadvantagesof achievingBPcontrolmorerapidlyandavoidingdoserelatedadverseeffectsof individualdrugsbyproducinggreaterBPreductionatlowerdosesofthecomponent agents.Inaddition,fixeddosecombinationsmaybemoreconvenient,simplerto take,andlesscostlythantheindividualcomponentsprescribedseparately(Figure 4).Theloweststartingdoseofmostfixeddosecombinationsisbelowdosesused inclinicaloutcometrials,anddosesoftheseagentsshouldbetitratedupwardto achievegoalBPbeforeaddingotherdrugs. Themostcommonlyusedindividualantihypertensivedrugsandfixeddose combinationsarelistedinFigures5a,b,andFigure6.Commonadverseeffectsare summarizedinFigure7.Severaladditionalkeypointsshouldbeconsideredwhen initiatingtreatmentwithantihypertensivemedication.First,treatmentshouldalways includelifestylemodification.Longacting,onceadayagentsarepreferreddueto improvedpatientadherenceandmoresustainedeffectsonBP.ContinuousBP controlisespeciallyimportantinpreventingsuddencardiacdeath,MI,andstroke precipitatedbymorningsurgesinBP.Thepresenceofspecificcontraindications and/orcomorbidconditionsoftendictatestheappropriatemedicationforapatient, since5070%ofthosewithessentialhypertensionhavecomorbidconditions (compellingindications)callingforspecificagents(Figure3).6 Aftertherapyhasbeeninitiated,patientsshouldbeseenevery12weeks (dependingontheseverityofhypertension)totitrateantihypertensivedrugdosage, andevery34monthsonceBPcontrolisachieved.Patientsshouldbeencouraged tomeasureandrecordtheirownBPsathomeorintheworkplace,asanaidto adherenceandimprovedBPcontrol.

AssociationsofBloodPressureDifferencesBetweenGroupsWithRisksofMajorVascularOutcomesandDeath Figure1 ReproducedwithpermissionfromElsevierScience.TurnbullF,fortheBloodPressureLoweringTreatmentTrialistsCollaboration.Effectsof differentbloodpressureloweringregimensonmajorcardiovascularevents:resultsofprospectivelydesignedoverviewsofrandomisedtrials. Lancet2003362:152735.

AlgorithmforTreatmentofHypertension Figure2 ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

HighRiskConditionsWithCompellingIndications Figure3 ReproducedwithpermissionfromLippincott,Williams&Wilkins.FrancoV,OparilS,CarreteroOA.HypertensiontherapyPart2.Circulation 2004109:30818.

AdvantagesofFixedDoseCombinationTherapy Figure4

OralAntihypertensiveDrugs(1of2) Figure5a Footnote:TheFDAapprovedlabelshouldbeconsultedbeforeanydrugisprescribed. ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

OralAntihypertensiveDrugs(2of2) Figure5b Footnote:TheFDAapprovedlabelshouldbeconsultedbeforeanydrugisprescribed. ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

CombinationDrugsforHypertension Figure6 Footnote:TheFDAapprovedlabelshouldbeconsultedbeforeanydrugisprescribed. ReproducedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.TheSeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7(Express)Report.JAMA2003289:256072.Copyrighted2003, AmericanMedicalAssociation.AllRightsreserved.

CommonAdverseEffectsofAntihypertensiveDrugs Figure7 ReproducedwithpermissionfromOparilS,WeberM,eds.Hypertension,CompaniontoBrennerandRectors,TheKidney.Philadelphia,PA:W.B. SaundersCompany,200066274.

ResistantHypertension

Hypertensionisresistantorrefractorytousualmedicalmanagementin approximately10%ofcases.RefractoryorresistanthypertensionisdefinedasaBP thatremainsabovegoal(130/80mmHginpatientswithdiabetes,chronickidney disease(CKD),CAD,coronaryarteryequivalents,andaFraminghamriskscoreof 10%otherwise140/90mmHg)despitetheconcurrentuseofthree antihypertensiveagentsofdifferentclasses.22Allagentsshouldbeprescribedat optimaldoseamounts.Causesofresistancetoantihypertensivetreatmentinclude secondaryhypertension(tobedescribedlater),inadequatetherapy,nonadherence totherapy,otherpatientrelatedfactors,andinappropriatetherapy(Figure8). InadequatetherapyisacommoncauseofuncontrolledBP,whetherornotthehigh BPistrulytreatmentresistant.Inadequateuseofdiuretictherapyasanaddonisa commonculprithere,sinceafrequentcauseofresistanthypertensioninthose adherenttomedicaltherapyisvolumeoverload.Inonestudy,hypertension specialistswereabletocontrolBPin50%ofthosepatientswhoseregimenshad beenconsideredsuboptimalbyaddingadiuretic,increasingthedoseofdiuretic,or changingthediuretictotheappropriateclassforthepatient'srenalfunction. Upto50%ofresistanthypertensioniscausedbynonadherencetoprescribed therapy.Cluestononadherenceinclude:1)missedappointments,2)failureto manifestexpectedbiologicaleffectsofmedicationsuchasdecreasedheartrate withbetablockertreatment,and3)thepresenceofsubstanceabuse.Various substances,includingdecongestants,brochodilators,corticosteroids,and nonsteroidalantiinflammatorydrugs(NSAIDs),includingaspirin,contributeto refractoryhypertensionbydirectlyraisingtheBP,interferingwiththeactionsof antihypertensivemedications,orboth(Figure8).Forexample,NSAIDscanraiseBP byinhibitingnatriuresisandcausingvolumeexpansion,aswellasbyinterfering withtheactionsofagentssuchasACEIs. HeavyalcoholusecanincreaseBPandmakeitmoredifficulttocontrol,ascanillicit drugssuchascocaineandamphetamines.Abuseofalcoholandothersubstances alsocontributestononadherencetotherapy.Caffeineandnicotinecancause transientrefractoryhypertensionthroughtheirabilitytotemporarilyraiseBP. Patientrelatedfactorssuchasobesity,hyperinsulinemia,andobstructivesleep apneaarealsoassociatedwithrefractoryhypertension.Obesepatients(bodymass index[BMI]>30kg/m2 )mayrequiremoreantihypertensivemedicationstoachieve BPcontrolthanleanerpatients,andthemedicationrequirementincreasesin proportiontotheelevationinBMI. Whitecoathypertensionorspurioushypertension(pseudohypertension)canleadto aninappropriatediagnosisofresistanthypertension.Whitecoathypertensionhas beenreportedin2040%ofpatientswithuntreatedhypertension.Whitecoat hypertensionshouldbesuspectedinthoseresistanttotherapy,butwithout evidenceoftargetorgandamage.ThesepatientsreporthomeBPvaluesthatare normalandmuchlower(<135/85mmHg)thanthoseobtainedintheclinicsetting (>140/90mmHg).AmbulatoryandhomeBPmeasurementsarehighlyusefulin diagnosingandmanagingwhitecoathypertension. Patientswithsuspectedwhitecoathypertensionshouldbemonitoredcarefullyfor targetorgandamageandthepresenceofotherCVDriskfactors,asthepresenceor absenceoftheseplaysamajorroleindecidingwhethertotreat.Ingeneral, however,whitecoathypertensionhasamorebenignprognosisthantrue hypertension,andthereisthuslessneedtoinitiateantihypertensivemedicationin patientswithwhitecoathypertensionthanpatientswithtruehypertension. Nevertheless,thesepatientsshouldhaveaggressivelifestylemodification,andif theofficeBPremainselevated,drugtherapyshouldbeconsidered. Spurioushypertension(pseudohypertension)mostoftenoccursintheelderlydueto stiff,sometimescalcifiedarteries.Ithasbeenestimatedthat57%ofelderlypatients havespurioushypertension.Thediagnosisisdifficulttomake,astheclassic physicaldiagnosistest,theOslermaneuver,whichconsistsofpalpatingapulsein theradialorbrachialarterywhiletheBPcuffisinflatedabovetheauscultatedSBP, hasquestionableaccuracyandusefulness.Betterassessmentcanbemadewith anintraarterialBPmeasurement,butthisisobviouslyunsuitableforroutineuse.

Figure8

CausesofRefractoryHypertension Figure8

BarrierstoBloodPressureControl
Physicians'patternsofpracticeclearlycontributetothepoorcontrolofhypertension. Anationalsurveyhasshownthatonethirdofprimarycarephysiciansdonot recommendtreatmentforpatientswithadiastolicBP(DBP)of90100mmHg,and anevenhigherproportiondonotinitiateorintensifytreatmentinpatientswithaSBP of140160mmHg.Otherstudieshaveshownthatphysiciansareunlikelyto diagnoseisolatedsystolichypertensionortreatitaggressively.IntheVeterans AffairsHospitals,theproblemhasbeenaggressivelytackled,withBP<140/90mm Hg,and<130/80mmHgindiabetics,specifiedasperformancemeasures.This hasresultedintreatmentsuccessratesofover75%,incontrasttotheNational HealthandNutritionExaminationSurvey(NHANES)dataforcontrolratesinthe generalpopulationof<40%.23 Asecondmajorcontributortopoorcontrolofhypertensionisthehighrateof discontinuanceofmedicationsbyhypertensivepatients:5070%ofnewtreatments arediscontinuedwithinthefirst6monthsinmostpractices.Thesehigh discontinuanceratesreflectacombinationofadversedrugeffects,costofdrugs, poorefficacy,changesinprovider,dissatisfactionwithotheraspectsofcare,and lackofunderstandingoftherisksoftargetorgandamage.Dealingwiththese barrierstoadherencetoprescribedtherapyisthekeytothesuccessfultreatmentof hypertensivepatients.Maximizingadherenceisclearlymoreimportantthan choosingaspecificdrugorregimeninachievingthedesiredoutcome.Suggestions foroptimizingpatientadherencetoantihypertensivetherapyaresummarizedin Figure9. MonotherapywithmostantihypertensivedrugscontrolsBPinfewerthan50%of patients.RandomizedcontrolledtrialsinwhichBPhasbeensuccessfullyloweredto aggressivegoalshaveshownthatthreeorfourantihypertensivedrugsarefrequently required(Figure10).Thisisparticularlytrueforhighriskpatientssuchasthosewith diabetes,renalinsufficiency,orCAD.Surveyshaveshownthatpracticingphysicians commonlyunderprescribeantihypertensivemedication:70%ofprescriptionsfor antihypertensivedrugsareforthestartingdose,indicatingfailuretouptitratedoses ofindividualagents.Thistendency,combinedwithreluctancetoprescribemultiple antihypertensivedrugsatuptomaximumdosesatfrequentintervalsinordertotreat togoal,aswellasfrequentdrugdiscontinuationsbypatients,contributetopoorBP controlinpractice. CompellingIndications Compellingindicationsforspecificantihypertensivedrugtherapyincludehighrisk conditionsthatcanbedirectsequelaeofhypertension(heartfailure[HF],CAD, stroke,andCKD),orcommonlyassociatedwithhypertension(diabetes,highCAD risk).Therapeuticdecisionsinsuchindividualsshouldbedirectedatboththe compellingindicationandBPlowering(Figure3).6,14

Figure9

Figure10

Figure3

SuggestionsforIncreasingPatientAdherencetoAntihypertensiveTherapy Figure9 References: 1. BakrisGL,WilliamsM,DworkinL,etal.Preservingrenalfunctioninadultswithhypertensionanddiabetes:aconsensusapproach. NationalKidneyFoundationHypertensionandDiabetesExecutiveCommitteesWorkingGroup.AmJKidneyDis200036:64661. 2. CushmanWC,FordCE,CutlerJA,etal.,fortheALLHATCollaborativeResearchGroup.Successandpredictorsofbloodpressure controlindiverseNorthAmericansettings:theAntihypertensiveLipidLoweringTreatmenttoPreventHeartAttackTrial(ALLHAT).JClin Hypertens20024:393404.

AverageNumberofAntihypertensiveAgentsNeededtoAchieveBPGoals Figure10

HighRiskConditionsWithCompellingIndications Figure3 ReproducedwithpermissionfromLippincott,Williams&Wilkins.FrancoV,OparilS,CarreteroOA.HypertensiontherapyPart2.Circulation 2004109:30818.

IschemicHeartDisease (1of3)
BPGoals Generally,inpatientswithischemicheartdisease,14orwhohavecoronaryartery equivalents,orwhoareatahighriskfordevelopingCAD(Framinghamriskscore >10%)thetargetBPis<130/80mmHg.Ifventriculardysfunctionispresent, considerationshouldbegiventoloweringtheBPevenfurther,to<120/80mmHg.14 InpatientswithestablishedCAD,theBPshouldbeloweredslowly,andcautionis advisedininducingfallsofDBPbelow60mmHg.Inolderhypertensiveindividuals withwidepulsepressures,loweringSBPmaycauseverylowDBPvalues(<60mm Hg).Thisshouldalertthecliniciantoassesscarefullyanyuntowardsignsor symptoms,especiallythoseduetomyocardialischemia. HighCoronaryDiseaseRisk FortheprimarypreventionofCVevents,renalfailure,andothercomplicationsof hypertension,aggressiveBPloweringisappropriate,withatargetBPof<130/80 mmHginindividualswithanyofthefollowing:diabetesmellituschronicrenal diseasepriorstrokeortransientischemicattack,CADCADriskequivalents (carotidarterydisease[carotidbruit,orabnormalcarotidultrasoundorangiography, peripheralarterialdisease,abdominalaorticaneurysm),andthosewitha10year Framinghamriskscoreof10%.AtargetBPof<140/90mmHgisappropriatefor hypertensiveindividualswithnoneoftheaboveconcomitantconditions(Figure11). InpatientswithanelevatedDBPandCADwithevidenceofmyocardialischemia,the BPshouldbeloweredslowly,andcautionisadvisedininducingreductionsinDBP tobelow60mmHgifthepatienthasdiabetesmellitusorisovertheageof60 years.Inolderhypertensiveindividualswithwidepulsepressures,loweringSBP maycauseverylowDBPvalues(<60mmHg).Thisshouldalerttheclinicianto assesscarefullyanyuntowardsignsorsymptoms,especiallythosedueto myocardialischemia. Intheveryold,thoseover80yearsofage,antihypertensivetherapyiseffectivein reducingtotalmortality,stroke,andHFwithoutmajortreatmentrelatedadverse effects.24Nevertheless,cautionshouldbeusedintreatingveryelderlypatientswith orthostaticsymptoms,cognitiveimpairment,orpoorfunctionalstatus,asthese individualswereexcludedfromtheclinicaltrialthatdemonstratedtreatmentbenefit. Thechoiceofdrugsremainscontroversial.Thereisageneralconsensusthatthe amountofBPreduction,ratherthanthechoiceofantihypertensivedrug,isthemajor determinantofreductionofCVriskhowever,thereissufficientevidenceinthe comparativeclinicaltrialstosupporttheuseofanACEinhibitor(orARB),CCB,or chlorthalidoneasfirstlinetherapy,supplementedbyaseconddrugifBPcontrolis notachievedbymonotherapy.Mostpatientswillrequiretwoormoredrugstoreach goal,andwhentheBPis>20/10mmHgabovegoal,twodrugsshouldusuallybe usedfromtheoutseteitherasseparateprescriptionsorinfixeddosecombinations. Traditionalbetablockersshouldnotbeusedasfirstlinetherapyinuncomplicated hypertensionsincerandomizedcontrolledtrialshavedemonstratedthattheyarenot asgoodascomparatordrugsandarenotsuperiortoplaceboinpreventingdeath andCVevents,includingstroke.11,12However,betablockersareindicatedin patientswithCADforbothsymptomreliefandBPcontrol,andthebetablockers carvedilol,nebivolol,metoprolol,andbisoprololhaveimprovedoutcomesinpatients withHF.Thenewervasodilatingbetablockerslikenebivololandcarvedilolalso havebetterhemodynamicandmetaboliceffectsthantheolderagents.Inthe asymptomaticpostMIpatient,abetablockerisamoreappropriatechoicefor secondarypreventionaftertheinfarction,andisthedrugoffirstchoiceifthepatient hasanginapectoris. Onceantihypertensivedrugtherapyisinitiated,mostpatientsshouldreturnfor followupandadjustmentofmedicationsatapproximately1to2weekintervalsuntil theBPgoalisreached.Morefrequentvisitswillalsobenecessaryforpatientswith
Figure11

stage2hypertensionorwithcomplicatingcomorbidconditions.Serumpotassium andcreatinineshouldbemonitoredatleast12timesperyear.AfterBPisatgoal andstable,followupvisitscanusuallybeat3to6monthintervals.Comorbidities suchasHF,associateddiseasessuchasdiabetes,andtheneedforlaboratory testsinfluencethefrequencyofvisits. StableAnginaandSilentIschemia Patientswithhypertensionandchronicstableangina,14,25shouldbetreatedwitha regimenthatincludesabetablocker.Inaddition,anACEIorARBshouldbe prescribed,especiallyinpatientswithahistoryofprioracutecoronarysyndromeor LVdysfunction.Ifnecessary,otherdrugscanbeaddedtoachievetargetBP.The combinationofabetablockerandACEIorARBshouldalsobeconsideredevenin theabsenceofapriorMI,diabetesmellitus,orLVsystolicdysfunction(Figure11). Ifbetablockersarecontraindicatedorproduceintolerablesideeffects,a nondihydropyridineCCB(suchasdiltiazemorverapamil)canbesubstituted,butnot ifthereisLVdysfunction.Ifeithertheanginaorthehypertensionremains uncontrolled,eitherchlorthalidoneoralongactingdihydropyridineCCBcanbe addedtothebasicregimenofbetablockerandACEIorARB.Thecombinationofa betablockerandeitherofthenondihydropyridineCCBs(diltiazemorverapamil) shouldbeusedwithcautioninpatientswithsymptomaticCADandhypertension becauseoftheincreasedriskofsignificantbradyarrhythmiasandHF. Asisusuallyindicated,thepatientsshouldalsoreceivenitrates,antiplateletor anticoagulantdrugs,andlipidloweringagentsforthemanagementofanginaand thepreventionofcoronaryevents.Inuncontrolledseverehypertensioninpatients whoaretakingantiplateletoranticoagulantdrugs,BPshouldbeloweredwithout delaytoreducetheriskofhemorrhagicstroke.

TreatmentofHypertensioninthePreventionandManagementofIschemicHeartDisease:SummaryoftheMainRecommendations Figure11 Beforemakinganymanagementdecisions,youarestronglyurgedtoreadthefulltextoftherelevantsectionoftheScientificStatement. *Diabetesmellitus,chronickidneydisease,knownCADorCADequivalent(carotidarterydisease,peripheralarterialdisease,abdominalaortic aneurysm),or10yearFraminghamriskscore10%. Weightlossifappropriate,healthydiet(includingsodiumrestriction),exercise,smokingcessation,andalcoholmoderation. EvidencesupportsACEI(orARB),CCB,orthiazidediureticasfirstlinetherapy. IfanteriorMIispresent,ifhypertensionpersists,ifLVdysfunctionorHFispresent,orifthepatienthasdiabetesmellitus. IfsevereHFispresent(NewYorkHeartAssociationclassIIIorIV,orLVEF<40%andclinicalHF). ACEI=angiotensinconvertingenzymeinhibitorARB=angiotensinreceptorblockerBP=bloodpressureCAD=coronaryarterydiseaseCCB =calciumchannelblockerDBP=diastolicbloodpressureLVD=leftventriculardysfunctionNSTEMI=nonSTelevationmyocardialinfarction SBP=systolicbloodpressureSTEMI=STelevationmyocardialinfarctionUA=unstableangina. ReproducedwithpermissionfromLippincott,WilliamsandWilkins.RosendorffC,BlackHR,CannonCP,etal.Treatmentofhypertensioninthe preventionandmanagementofischemicheartdisease:ascientificstatementfromtheAmericanHeartAssociationCouncilforHighBlood PressureResearchandtheCouncilsonClinicalCardiologyandEpidemiologyandPrevention.Circulation2007115:27618.www.lww.com

IschemicHeartDisease (2of3)
UnstableAnginaandNonSTSegmentElevationMyocardialInfarction ForunstableanginaornonSTelevationmyocardialinfarction(NSTEMI),14,26the initialtherapyofhypertensionshouldincludeanoralbeta1selectivebetablocker withoutintrinsicsympathomimeticactivity,inadditiontonitrates,forsymptom control.Ifthepatientishemodynamicallyunstable,whichismorecommonlyan issueinSTEMIthaninunstableanginaandNSTEMI,theinitiationofbetablocker therapyshouldbedelayeduntilstabilizationofHForshockhasbeenachieved. DiureticscanbeaddedforBPcontrolandforthemanagementofHF(Figure11). Ifthereisacontraindicationtotheuseofabetablocker,orifthepatientdevelops intolerablesideeffectsofabetablocker,thenanondihydropyridineCCB,suchas verapamilordiltiazem,maybesubstituted,butnotifthereisLVdysfunction.Ifthe anginaorthehypertensionisnotcontrolledwithabetablockeralone,thenalonger actingdihydropyridineCCBmaybeadded.ChlorthalidonecanalsobeaddedforBP control. Ifthepatientishemodynamicallystable,anACEIorARBshouldbeaddedifthe patienthasananteriorMI,ifhypertensionpersists,ifthepatienthasevidenceofLV dysfunctionorHF,orifthepatienthasdiabetesmellitus. Inaddition,nitrates,anticoagulants,antiplateletdrugs,andlipidloweringagents shouldbeused,asindicated,forthemanagementofacutecoronarysyndromes.BP shouldbeloweredwithoutdelayinpatientswithuncontrolledhypertensionwhoare takingantiplateletoranticoagulantdrugs,toreducetheriskofhemorrhagicstroke. STSegmentElevationMyocardialInfarction ForSTEMI,14,27,28theprinciplesoftherapyforhypertensionaresimilartothosefor unstableanginaandNSTEMIasdescribedearlier,withsomeexceptions.Initial therapyofhypertensioncanincludeshortactingbeta1selectivebetablocker withoutintrinsicsympathomimeticactivity,usuallyorallybutintravenouslyifthereis tachycardiaorsustainedhypertensioninadditiontonitratesforsymptomcontrol. However,ifthepatientishemodynamicallyunstable,theinitiationofbetablocker therapyshouldbedelayeduntilstabilizationofHForshockhasbeenachieved. DiureticscanbeaddedforBPcontrolandformanagementofHF. AnACEIorARBshouldbeadministeredearlyinpatientswithSTEMIand hypertension,particularlyinanteriorMI,orifhypertensionpersistsorthereisLV dysfunction,HF,ordiabetesmellitus.ACEinhibitionhasbeenfoundtobe particularlybeneficialinpatientsinwhomtheinfarctislargeand/orthereisahistory ofpreviousinfarction,HF,andtachycardia.ACEIsandARBsshouldnotbegiven togetherbecausethereisanincreaseintheincidenceofadverseeventswithout improvingsurvival. AldosteroneantagonistsmaybeusefulinthemanagementofSTEMIwithLV dysfunctionandHFandmayhaveanadditiveBPloweringeffect.Serumpotassium levelsmustbemonitored.Theseagentsshouldbeavoidedinpatientswithelevated serumcreatininelevels(2.0mg/dlinmen,1.8mg/dlinwomen),creatinine clearanceof<50ml/min,orelevatedpotassiumlevels(5.5mEq/L). CCBsdonotreducemortalityratesinthesettingofacuteSTEMIandcanincrease mortalityifthereisdepressedLVfunctionand/orpulmonaryedema.Longacting dihydropyridineCCBscanbeusedwhenbetablockersarecontraindicatedor inadequatetocontrolangina,orasadjuncttherapyforBPcontrol. NondihydropyridineCCBsmaybeusedforthetreatmentofpatientswith supraventriculartachycardia,butshouldnotbeusedinpatientswith bradyarrhythmiasorimpairedLVfunction. Patientsshouldalsoreceivenitrates,anticoagulantandantiplateletdrugs,andlipid loweringagents,forthemanagementofSTEMI.Uncontrolledhypertensionisa contraindicationtofibrinolytictherapybecauseoftheriskofhemorrhagicstroke.For
Figure11

Figure3

thesamereason,BPshouldbeloweredwithoutdelayinpatientswithuncontrolled hypertensionwhoaretakingantiplateletorantiplateletoranticoagulantdrugs. HeartFailure HypertensionprecedesthedevelopmentofcongestiveHF(CHF)inapproximately 90%ofpatients,andincreasestheriskforCHFbytwofoldinmenandthreefoldin women.Accordingly,aggressivetreatmentofhypertensionplaysanimportantrolein preventingandmanagingCHF.14Therearecompellingindicationsfortheuseofall ofthemajorclassesofantihypertensivedrugsinCHF,withtheexceptionofthe CCBs(Figure3).BPgoalsinCHFhavenotbeenspecificallydefinedbasedon clinicaltrialdata.However,reducingSBPtotherangeof110130mmHgappearsto bebeneficial.SomeexpertsevenadvocateloweringSBPto<100mmHgoraslow astolerated,inpartbasedonresultsoftheCOPERNICUS(CarvedilolProspective RandomizedCumulativeSurvival)trial.29 ThetreatmentofhypertensioninpatientswithHFshouldincludebehavioral modification,suchassodiumreduction,andacloselymonitoredexerciseprogram. OthernonpharmacologicapproachesarethesameasforpatientswithoutHF. DrugsthathavebeenshowntoimproveoutcomesforpatientswithHFgenerally alsolowerBP.Patientsshouldbetreatedwithdiuretics,ACEIs(orARBs),beta blockers,andaldosteronereceptorantagonists.Chlorthalidoneisagoodchoiceof diureticforBPcontrolandtoreversevolumeoverloadandassociatedsymptoms.In severeHF,orinpatientswithsevererenalimpairment,loopdiureticsshouldbe usedforvolumecontrol,butthesearelesseffectivethanthiazidediureticsand chlorthalidoneinloweringBP.DiureticsshouldbeusedtogetherwithanACEIor ARBandabetablocker. StudieshaveshownequivalenceofbenefitofACEIsandtheARBscandesartanor valsartaninHF.EitherclassofagentsiseffectiveinloweringBP.Drugsfromeach classcanbeusedtogether,providedthatthepatientishemodynamicallystableand notintheimmediatepostMIperiod.Amongthebetablockers,carvedilol,nebivolol, metoprololsuccinate,andbisoprololimproveoutcomesinHFandareeffectivein loweringBP. Thealdosteronereceptorantagonistsspironolactoneandeplerenonehavebeen showntobebeneficialinHFandshouldbeincludedintheregimenifthereis severeHF(NewYorkHeartAssociationclassIIIorIV,orLVejectionfraction<40% andclinicalHF).Oneortheothermaybeprescribedinadditiontoathiazidediuretic orchlorthalidoneinpatientsrequiringapotassiumsparingagent.Ifanaldosterone receptorantagonistisadministeredwithanACEIoranARBorinthepresenceof renalinsufficiency,theserumpotassiumshouldbemonitoredfrequently.These drugsshouldnotbeused,iftheserumcreatininelevelis2.5mg/dlinmenor2.0 mg/dlinwomen,oriftheserumpotassiumlevelis5.0mEq/L.Spironolactoneor eplerenonemaybeusedtogetherwithathiazidediuretic,particularlyinpatientswith refractoryhypertension. Theadditionofhydralazine/isosorbidedinitratetotheregimenofdiuretic,ACEIor ARB,andbetablockerinAfricanAmericanpatientswithNewYorkHeartAssociation classIIIorIVHFshouldbeconsidered.Othersmaybenefitsimilarly,butthishasnot yetbeentested. DrugstoavoidinpatientswithHFandhypertensionarenondihydropyridineCCBs (suchasverapamilanddiltiazem),clonidine,andmoxonidine.Alphaadrenergic blockers,suchasdoxazosin,shouldbeusedonlyifotherdrugsforthe managementofhypertensionandHFareinadequatetoachieveBPcontrolat maximumtolerateddoses.

TreatmentofHypertensioninthePreventionandManagementofIschemicHeartDisease:SummaryoftheMainRecommendations Figure11 Beforemakinganymanagementdecisions,youarestronglyurgedtoreadthefulltextoftherelevantsectionoftheScientificStatement. *Diabetesmellitus,chronickidneydisease,knownCADorCADequivalent(carotidarterydisease,peripheralarterialdisease,abdominalaortic aneurysm),or10yearFraminghamriskscore10%. Weightlossifappropriate,healthydiet(includingsodiumrestriction),exercise,smokingcessation,andalcoholmoderation. EvidencesupportsACEI(orARB),CCB,orthiazidediureticasfirstlinetherapy. IfanteriorMIispresent,ifhypertensionpersists,ifLVdysfunctionorHFispresent,orifthepatienthasdiabetesmellitus. IfsevereHFispresent(NewYorkHeartAssociationclassIIIorIV,orLVEF<40%andclinicalHF). ACEI=angiotensinconvertingenzymeinhibitorARB=angiotensinreceptorblockerBP=bloodpressureCAD=coronaryarterydiseaseCCB =calciumchannelblockerDBP=diastolicbloodpressureLVD=leftventriculardysfunctionNSTEMI=nonSTelevationmyocardialinfarction SBP=systolicbloodpressureSTEMI=STelevationmyocardialinfarctionUA=unstableangina. ReproducedwithpermissionfromLippincott,WilliamsandWilkins.RosendorffC,BlackHR,CannonCP,etal.Treatmentofhypertensioninthe preventionandmanagementofischemicheartdisease:ascientificstatementfromtheAmericanHeartAssociationCouncilforHighBlood PressureResearchandtheCouncilsonClinicalCardiologyandEpidemiologyandPrevention.Circulation2007115:27618.www.lww.com

HighRiskConditionsWithCompellingIndications Figure3 ReproducedwithpermissionfromLippincott,Williams&Wilkins.FrancoV,OparilS,CarreteroOA.HypertensiontherapyPart2.Circulation 2004109:30818.

IschemicHeartDisease (3of3)
Diabetes DiabetesisanindependentriskfactorforCVD(coronaryheartdisease[CHD]andstroke),andthecauseofdeathin approximatelytwothirdsofpersonswithdiabetes.Diabetesisalsothemostcommoncauseofendstagerenaldisease intheUnitedStates.Hypertensioniscommonandcarriesaworseprognosisindiabetics.30Randomizedcontrolled clinicaltrialshaveshownthatrigoroustreatmentofBPinpatientswithdiabetesreducesmacrovascularand microvasculardisease,andthatdiabeticpatientsareparticularlysensitivetosmallreductionsinBP.TheBPgoal recommendedbyJNC7in2003andtheAmericanDiabetesAssociation(ADA)in2010is<130/80mmHg.6,30 TheADAguidelinessuggestthatpatientswithanSBPof130139mmHgoraDBPof8089mmHgshouldbegivena trialoflifestyle/behavioraltherapyalone,andthen,iftargetsarenotachieved,shouldalsobetreatedwithpharmacologic agents.Patientswithhypertension(SBP140mmHgorDBP90mmHg)shouldreceivedrugtherapyfromtheoutsetin additiontolifestyle/behavioraltherapy. TheBPtargetof<130/90mmHghasrecentlycomeintoquestionwiththepublicationoftheresultsoftheACCORDBP (ActiontoControlCardiovascularRiskinDiabetesBloodPressure)studyin2010.31Thetrialshowedthat,inpatients withtype2diabetesathighriskforCVevents,targetinganSBPof<120mmHg,ascomparedwith<140mmHg,didnot reducetherateofacompositeoutcomeoffatalandnonfatalmajorCVevents.TheconditionsoftheACCORDstudywere suchthattherewasexcellentglycemicandlipidcontrol(glycatedhemoglobinmeanvalueswere7.6%and7.5%inthe intensiveandstandardtherapygroupslowdensitylipoproteincholesterolvalueswere98.7and96.8mg/dlandmedian triglycerideswere138and131mg/dl).Thisqualityofglycemicandlipidcontrol,whichisunfortunatelynotcommonin generalclinicalpractice,maybethereasonwhythedifferenceinBPsdidnothaveasignificantimpactonoutcomes.For thevastgeneralpopulationofdiabeticpatients,withagreatvariationinglycemicandlipidcontrol,itisnotunreasonable toretainthe<130/80mmHgBPgoal. The2010ADAguidelines32suggestthatallpatientswithdiabetesandhypertensionshouldbetreatedwitharegimen thatincludeseitheranACEIoranARB.AthiazidediureticshouldbeaddedtoachieveBPtargetsinpatientswithan estimatedglomerularfiltrationrate(eGFR)30ml/min/1.73m2 andaloopdiureticinthosewithalowereGFR.The NationalKidneyFoundation(NKF)KidneyDiseaseOutcomesQualityInitiative(KDOQI)2007guidelines33gofurtherthey recommendanACEIoranARBinnormotensivepeoplewithdiabetes,whohavemicroormacroalbuminuria. OtherdrugclassesthathavebeenshowntoreduceCVeventsinpatientswithdiabetes(betablockersandCCBs)can beaddedasneededtoachieveBPtargets.However,metaanalyseshaveshownpooreroutcomeswithtraditionalbeta blockers,particularlyatenolol,asinitialtherapyforpatientswithoutCAD.12,13IfACEIs,ARB,ordiureticsareused, monitorrenalfunction(serumcreatinine,bloodureanitrogen,eGFR)andserumpotassiumlevelsforthefirst3months. Ifstable,followupcouldoccurevery6monthsthereafter. Inpatientswithtype2diabetes,hypertension,andmicroalbuminuria,ACEIsandARBshavebeenshowntodelaythe progressiontomacroalbuminuria.34Inpatientswithovertdiabeticnephropathy,ARBsslowthedeclineinGFRanddelay thedevelopmentofendstagerenaldisease.35,36Inthosewithtype2diabetes,hypertension,macroalbuminuria(>300 mg/day),nephropathy,orrenalinsufficiency,anACEIoranARBisindicatedasfirstchoiceantihypertensivetherapy.If oneclassisnottolerated,theothershouldbesubstituted. ChronicKidneyDisease CVDisthemostcommoncauseofdeathinpersonswithCKD,37itselfanindependentriskfactorforCVD.Personswith eGFR<60ml/minhaveanapproximately16%increaseinCVDmortality,andthosewitheGFR<30ml/minhavea30% increase.CVDriskexhibitsacontinuousrelationshipwithalbuminuria:thepresenceofmicroalbuminuriaconfersa50% increaseinrisk,andthepresenceofmacroalbuminuriaconfersa350%increase.37 CKDisdefinedaskidneydamage,asconfirmedbykidneybiopsyormarkersofdamage,orGFR<60ml/min/1.73m2 for 3months.37,38Usingthisdefinition,theNHANESIIIdatabaseandtheUSRenalDataSystem(USRDS)estimatethat approximately11%ofadultsintheUnitedStateshaveCKD. HypertensionisbothacauseandaconsequenceofCKD.Thereisastrong,consistentrelationshipofhigherlevelsof BPtofasterkidneydiseaseprogression.Inpart,thismaybeduetodeleteriouseffectsofhigherintraglomerularpressure (PGC),resultinginanelevatedsinglenephronGFR,whichintheshorttermmayleadtostabilizationorevenincreased GFR,butinthelongtermisfollowedbyproteinuria,glomerularsclerosis,andkidneyfailure. HypertensionisalsoacommoncomplicationofCKD,whichincreasestheriskforthetwomainoutcomesofCKD:loss

ofkidneyfunction,sometimesleadingtokidneyfailure,andCVD,bothassociatedwithincreasedmortality.Appropriate evaluationandmanagementofhypertensionanduseofantihypertensiveagentsinCKDofferstheopportunitytoslowthe progressionofkidneydiseaseandreducetheriskofCVD.AGFRof<60ml/min/1.73m2 ormicroalbuminuria(both criteriaforthedefinitionofCKD)areindependentriskfactorsforCVD,andthedesignationofCKDisa"compelling indication"forantihypertensivetherapyatalowerBPthresholdwithalowerBPtarget(<130/80mmHg). DietaryandothertherapeuticlifestylemodificationsarerecommendedaspartofacomprehensivestrategytolowerBP andreduceCVDriskinCKD.Adietarysodiumintakeof<2.4g/d(<100mmol/d)shouldberecommendedformostadults withCKDandhypertension.OtherdietaryrecommendationsforadultsshouldbemodifiedaccordingtothestageofCKD, withtheDASH(DietaryApproachestoStopHypertension)dietmodifiedwithproteinintake0.60.8g/kg/d,phosphorus 0.81.0g/d,andpotassium24g/dforstage34CKD.OtherlifestylemodificationsincludeweightmaintenanceifBMIis <25kg/m2 ,weightlossifoverweightorobese,moderationofalcoholintake,andsmokingcessation. AllantihypertensiveagentscanbeusedtolowerBPinCKD.Multidrugregimenswillbenecessaryinmostpatientswith CKDtoachievetherapeuticgoals.PatientswithspecificcausesofkidneydiseaseandCVDwillbenefitfromspecific classesofagents.TargetBPforCVDriskreductioninCKDshouldbe<130/80mmHg. SinceangiotensinIIdamagesthekidneysbystimulatingmesangialcellproliferation,ACEIsandARBsarethepreferred agentsfordiabetickidneydiseaseandnondiabetickidneydiseasewithspoturinetotalproteintocreatinineratiosof 200mg/g.Theyshouldbeusedatmoderatetohighdoses,asusedinclinicaltrials.Theycanbeusedincombination tolowerBPorreduceproteinuria.PatientstreatedwithACEIsorARBsshouldbemonitoredforhypotension,decreased GFR,andhyperkalemia.Thefirstagenttobeaddedthereaftershouldbeadiuretic. SupportforthekeyroleofACEIsandARBshascomefromseveralclinicaltrials.TheAASK(AfricanAmericanStudyof KidneyDiseaseandHypertension)studyof1,094nondiabetichypertensiveAfricanAmericanindividualswithCKD demonstratedthatthedeclineinGFRwasslowerintheACEI(ramipril)groupthanintheBB(metoprolol)ortheCCB (amlodipine)groups,irrespectiveofthedegreeofproteinuria.39 IRMA2(IrbesartaninPatientsWithType2DiabetesandMicroalbuminuria),34atrialconductedinpatientswithtype2 diabetesmellitusandmicroalbuminuria,demonstratedthattheARBirbesartanreducedtherateofprogressionto proteinuriaanddiabeticnephropathywhencomparedtousualtherapy,withoutloweringBP.TheRENAAL(Reductionof EndpointsinNIDDMwiththeAngiotensinIIAntagonistLosartan)35andIDNT(IrbesartanDiabeticNephropathyTrial)36 studieswereconductedintype2diabeticswithovertnephropathy,hypertension,andserumcreatinineof13mg/dl.In bothtrials,addinganARBreducedtheincidenceofadoublingofserumcreatinine,comparedwithconventional antihypertensivetreatment,withnearlyequalBPloweringinbothtreatmentarms.IntheRENAALstudy,theincidenceof endstagerenaldiseasewasalsolowerinthelosartangroupcomparedtothoseonconventionalhypertensivetherapy. TheresultsofthesetrialsstronglysupporttheuseofACEIsandARBstopreventthedeteriorationinrenalfunctionand progressionofproteinuria,whicharealmostinevitableinthepatientwithuntreateddiabeticnephropathy. TheclinicianshouldexpectsomeinitialtransientdeclineinGFR,withanincreaseinserumcreatinine,oninitiationof therapywithanACEIorARB.ThisisbecauseangiotensinIIconstrictstheefferentarteriolesofthekidneymorethanthe afferentarteriolesinhibitionofthisactionbyanACEIorARBwilldecreaseefferentarteriolartonemorethatafferent arteriolartone,resultinginadecreaseinglomerularfiltrationpressure,andadeclineinGFR.Thisistheshorttermprice topayforthelongertermrenoprotectiveactionofdrugs,whichblocktheRAS. Inmostpatients,theACEIorARBcanbecontinuedif:1)theeGFRdeclineortheincreaseinserumcreatinineover4 monthsis<35%fromthebaselinevalueor2)serumpotassiumis<5.5mEq/L.Thereisnocutoffvalueforserum creatinineatwhichACEIorARBtreatmentisinappropriate.Creatinineandpotassiumshouldbemeasured24weeks afterstartingtherapywithanACEIorARB:ifstable,themeasurementsshouldberepeatedat6monthsandevery6 monthsthereafter.Ifthereisanexcessiveincreaseinserumcreatinine,theACEIorARBshouldbediscontinued,andthe patientshouldbeevaluatedtoassesshydration,hemodynamicstatus,andqueryuseofnephrotoxicmedications. Considerationshouldalsobegiventothediagnosisofrenalarterystenosisinthissituation.Furthermore,inkidney transplantrecipients,ACEIsandARBsmayexacerbatehyperkalemiacausedbycyclosporineortacrolimus.Thus, treatmentofpatientswithCKDwithACEIsandARBsrequiresknowledgeoftheexpectedbenefitsandrisksoftherapy andcarefulattentiontoBP,renalandcardiacfunction,electrolytebalance,andpossibledruginteractions. Inmostcases,adiureticshouldbethesecondagentandaCCBthethird.Thiazidediureticsorchlorthalidonegivenonce adayarerecommendedinpatientswithaGFR30ml/min/1.732 ,andloopdiureticsinpatientswithaGFR<30 ml/min/1.73m2 .Loopdiureticsmaybegivenincombinationwiththiazidediureticsorchlorthalidoneforpatientswith extracellularfluid(ECF)volumeexpansionandedema.Potassiumsparingdiureticsshouldbeusedwithcautionin patientswithaGFR<30ml/min/1.732 inpatientsreceivingconcomitanttherapywithACEIs,ARBs,orsupplemental potassiumandinpatientswithadditionalriskfactorsforhyperkalemia.Patientstreatedwithdiureticsshouldbe monitoredforvolumedepletion,manifestedbyhypotensionordecreasedGFR,hypokalemia,orotherelectrolyte abnormalities.

KeyPoints
Oncehypertensiondevelops,pharmacologictreatmentisneededtoreduceBPandpreventCVDoutcomes. ClinicaltrialdataindicatethatloweringBPwithantihypertensivedrugseffectivelyreducesCVDoutcomes, includingstroke,CHD,CHF,andCVdeath,aswellastotalmortality. OutcomebenefitshavebeenseenparticularlywithantihypertensiveregimensbasedonACEIs,ARBs,CCBs,and diuretics(suchaschlorthalidone).Metaanalysesofdatafromrandomizedcontrolledtrialshavenotshown significantdifferencesintotalmajorCVeventsbetweenregimensbasedonACEIs,ARBs,orCCBs,anddiuretics, withtraditionalbetablockersbeinglesseffective. ForoutcomesotherthanCHF,differencesinachievedSBPreductionhavebeenshowninsomeanalysestobe relatedtotheextentofriskreduction,independentoftreatmentassignment.Therefore,somewouldarguethat,for hypertensivepatientsasawhole,reductionofBP(especiallySBP)ispossiblymoreimportantthanchoiceof antihypertensivedrug(s)forreducingCVDrisk.However,thisremainscontroversial. Clinicaltrialshaveshownthatinmostpatients,twoormoreantihypertensivemedicationsarerequiredtoachieve goalBP,namely<140/90mmHginmost<130/80mmHginthosewithdiabetes,CKD,CAD,CADequivalents, andhighriskpatients,i.e.,thosewithaFraminghamriskscoreof10%.Accordingly,initiationoftherapywithtwo agents(inindividualtabletsorfixeddosecombination)shouldbestartedinthosewithBP>20/10mmHgabove goal. JNC7guidelinesrecommendusingthiazidetypediureticsasfirstlinetreatmentinmosthypertensives,andin combinationwithotherdrugclasseswheremultipledrugsarerequired.ThisdiffersfromEuropeanguidelines,in whichantihypertensivedrugchoicesareleftuptothehealthcareprovider. TheAmericanHeartAssociation(AHA)ScientificStatement14onhypertensionandCADhasemphasizedACEIs, ARBs,andCCBsasthemostappropriateagents,withadiuretic.Therationaleforthepreferredstatusofthe diureticssuchaschlorthalidoneincludes:1)thefavorableoutcometrialdatadelineatingtheirbenefits,2)their abilitytoenhancetheantihypertensiveefficacyofmostotherdrugclasses,and3)theirlowcost.Theirbiochemical adverseeffects(i.e.,hypokalemia,reducedinsulinsensitivity)anddiabetesareaconcern,andmayinthelonger termnegatetheshorttermbenefitseenintheclinicaltrials. Ahypertensivepatientmayalsohaveahighriskcondition(e.g.,CAD,diabetes,CKD)thatconstitutesa compellingindicationforuseofotherantihypertensivedrugclasses.Inthatcase,initialtreatmentshouldbe dictatedbythecompellingindication,bearinginmindthatBPcontrolisparamount.Treatmentguidelinesfrom JNC7,aswellastheAHA,AmericanCollegeofCardiology,ADA,andtheNKFconcuronthedrugclasschoices foreachcompellingindication. RASagentshavebeenshowntobebeneficialinpatientswithCAD,diabetes,orCKD.Inaddition,betablockers areindicatedinestablishedCAD,andCCBscanbeusedinpatientswithhighCHDriskordiabetesbasedon outcomesdata. MetaanalyseshaveshownthattreatmentregimensbasedonACEIs,ARBs,andCCBsaresuperiortothose basedonthiazidediureticsortraditionalbetablockers.Thecaveatisthatmostofthesestudiesused hydrochlorothiazideasthediureticandatenololasthebetablocker.Chlorthalidone,whichisnotathiazideperse, hasbeenshowntobeeffective,andislikelytosupplanthydrochlorothiazideasthediureticofchoice. Newerbetablockers(carvedilol,metoprolol,bucindolol,nebivolol),lowerBPandarealsoeffectiveinimproving outcomesinpatientswithimpairedLVfunction. CVDistheleadingcauseofmorbidityandmortalityindevelopedcountries,andaggressiveriskfactor modificationisneededtocontrolthisburgeoningpublichealthproblem.TightBPcontrolisfundamentalfor primaryandsecondarypreventionofCVD.

References
1. TurnbullF,NealB,AlgertC,etal.,onbehalfoftheBloodPressureLoweringTreatmentTrialists'Collaboration. Effectsofdifferentbloodpressureloweringregimensonmajorcardiovasculareventsinindividualswithand withoutdiabetesmellitus:resultsofprospectivelydesignedoverviewsofrandomizedtrials.ArchInternMed 2005165:14109. 2. NealB,MacMahonS,ChapmanN,onbehalfoftheBloodPressureLoweringTreatmentTrialists'Collaboration. EffectsofACEinhibitors,calciumantagonists,andotherbloodpressureloweringdrugs:resultsofprospectively designedoverviewsofrandomisedtrials.BloodPressureLoweringTreatmentTrialists'Collaboration.Lancet 2000356:195564. 3. DahlfB,DevereuxRB,KjeldsenSE,etal.,onbehalfoftheLIFEStudyGroup.Cardiovascularmorbidityand mortalityintheLosartanInterventionForEndpointreductioninhypertensionstudy(LIFE):arandomisedtrial againstatenolol.Lancet2002359:9951003. 4. JamersonKA,WeberMA,BakrisGL,etal.,onbehalfoftheACCOMPLISHInvestigators.Benazeprilplus amlodipineorhydrochlorothiazideforhypertensioninhighriskpatients.NEnglJMed2008359:241728. 5. DahlfB,SeverPS,PoulterNR,etal.,onbehalfoftheASCOTInvestigators.Preventionofcardiovascularevents withanantihypertensiveregimenofamlodipineaddingperindoprilasrequiredversusatenololadding bendroflumethiazideasrequired,intheAngloScandinavianCardiacOutcomesTrialBloodPressureLowering Arm(ASCOTBPLA)amulticentrerandomisedcontrolledtrial.Lancet2005366:895906. 6. ChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure.Hypertension200342:120652. 7. ManciaG,DeBackerG,DominiczakA,etal.2007ESHESCPracticeGuidelinesfortheManagementofArterial Hypertension.EuropeanSocietyofHypertensionEuropeanSocietyofCardiologyTaskForceontheManagement ofArterialHypertension.JHypertens200725:175162. 8. KarallieddeJ,VibertiG.Evidenceforrenoprotectionbyblockadeofthereninangiotensinaldosteronesystemin hypertensionanddiabetes.JHumHypertens200620:23953. 9. ONTARGETStudyInvestigators.Telmisartan,ramipril,orbothinpatientsathighriskforvascularevents.NEnglJ Med2008358:154759. 10. TheALLHATOfficersandCoordinatorsfortheALLHATCollaborativeResearchGroup.Majoroutcomesinhigh riskhypertensivepatientsrandomizedtoangiotensinconvertingenzymeinhibitororcalciumchannelblockervs diuretic:TheAntihypertensiveandLipidLoweringTreatmenttoPreventHeartAttackTrial(ALLHAT).JAMA 2002288:298197. 11. JamersonK,WeberMA,BakrisGL,etal.,onbehalfoftheACCOMPLISHTrialInvestigators.Benazeprilplus amlodipineorhydrochlorothiazideforhypertensioninhighriskpatients.NEnglJMed2008359:241728. 12. LindholmLH,CarlbergB,SammuelssonO.Shouldbetablockersremainfirstchoiceinthetreatmentofprimary hypertension?Ametaanalysis.Lancet2005366:154553. 13. BangaloreS,MesserliFH,KostisJB,PepineCJ.Cardiovascularprotectionusingbetablockers:acriticalreview oftheevidence.JAmCollCardiol200750:56372. 14. RosendorffC,BlackHR,CannonCP,etal.Treatmentofhypertensioninthepreventionandmanagementof ischemicheartdisease:ascientificstatementfromtheAmericanHeartAssociationCouncilforHighBlood PressureResearchandtheCouncilsonClinicalCardiologyandEpidemiologyandPrevention.Circulation 2007115276188. 15. MesserliFH,MakaniH,BenjoA,RomeroJ,AlviarC,BangaloreS.Antihypertensiveefficacyofhydrochlorothiazide asevaluatedbyambulatorybloodpressuremonitoring:ametaanalysisofrandomizedtrials.JAmCollCardiol 201157:590600. 16. ElliottWJ,MeyerPM.Incidentdiabetesinclinicaltrialsofantihypertensivedrugs:anetworkmetaanalysis.Lancet 2007369:2017. 17. KasiskeBL,MaJZ,KalilRS,LouisTA.Effectsofantihypertensivetherapyonserumlipids.AnnInternMed 1995122:13341. 18. KurtzTW.Chlorthalidone:don'tcallit"thiazidelike"anymore.Hypertension201056:3357. 19. CushmanWC,FordCE,CutlerJA,etal.,onbehalfoftheALLHATCollaborativeResearchGroup.Successand predictorsofbloodpressurecontrolindiverseNorthAmericansettings:theAntihypertensiveLipidLowering TreatmenttoPreventHeartAttackTrial(ALLHAT).JClinHypertens(Greenwich)20024:393404. 20. BlackHR,ElliottWJ,GranditsG,etal.,onbehalfoftheCONVINCEResearchGroup.Principalresultsofthe ControlledOnsetVerapamilInvestigationofCardiovascularEndPoints(CONVINCE)trial.JAMA2003289:2073 82. 21. PepineCJ,HandbergEM,CooperDeHoffRM,etal.,fortheINVESTInvestigators.Acalciumantagonistvsanon calciumantagonisthypertensiontreatmentstrategyforpatientswithcoronaryarterydisease.TheInternational VerapamilTrandolaprilStudy(INVEST):arandomizedcontrolledtrial.JAMA2003290:280516. 22. CalhounDA,JonesD,TextorS,etal.Resistanthypertension:diagnosis,evaluation,andtreatment.AScientific StatementfromtheAmericanHeartAssociationProfessionalEducationCommitteeoftheCouncilforHighBlood PressureResearch.Hypertension200851:140319. 23. CentersforDiseaseControlandPrevention.NationalHealthandNutritionExaminationSurveydata.Hyattsville,

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MD:NationalCenterforHealthStatistics,2010.Availableat:http://www.cdc.gov/nchs/nhanes.htm.Accessed 12/26/2011. BeckettNS,PetersR,FletcherAE,etal.,onbehalfoftheHYVETStudyGroup.Treatmentofhypertensionin patients80yearsofageorolder.NEnglJMed2008358:188798. FrakerTDJr,FihnSD2002ChronicStableAnginaWritingCommitteeAmericanCollegeofCardiologyAmerican HeartAssociationGibbonsRJ,AbramsJ,ChatterjeeK,etal.2007chronicanginafocusedupdateofthe ACC/AHA2002guidelinesforthemanagementofpatientswithchronicstableangina:areportoftheAmerican CollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelinesWritingGrouptoDevelop theFocusedUpdateofthe2002guidelinesforthemanagementofpatientswithchronicstableangina.JAmColl Cardiol200750:226474. AndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/American HeartAssociationTaskForceonPracticeGuidelines(WritingCommitteetorevisethe2002Guidelinesforthe ManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction)developedincollaboration withtheAmericanCollegeofEmergencyPhysicianstheSocietyforCardiovascularAngiographyand Interventions,andtheSocietyofThoracicSurgeons,andendorsedbytheAmericanAssociationofCardovascular andPulmonaryRehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1 157. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(WritingCommitteetoRevisethe1999Guidelinesforthe ManagementofPatientsWithAcuteMyocardialInfarction).JAmCollCardiol200444:671719. AntmanEM,HandM,ArmstrongPW,etal.2007focusedupdateoftheACC/AHA2004guidelinesforthe managementofpatientswithSTelevationmyocardialinfarction:areportoftheAmericanCollegeof Cardiology/AmericanheartAssociationTaskForceonPracticeGuidelines.JAmCollCardiol200851:21047. PackerM,CoatsAJ,FowlerMB,etal.,onbehalfoftheCarvedilolProspectiveRandomizedCumulativeSurvival StudyGroup.Effectofcarvedilolonsurvivalinseverechronicheartfailure.NEnglJMed2001344:16518. BuseJB,GinsbergHN,BakrisGL,etal.Primarypreventionofcardiovasculardiseasesinpeoplewithdiabetes mellitus:ascientificstatementfromtheAmericanHeartAssociationandtheAmericanDiabetesAssociation. Circulation2007115:11426. ACCORDStudyGroup.Effectsofintensivebloodpressurecontrolintype2diabetesmellitus.NEnglJMed 2010362:157585. AmericanDiabetesAssociation.Standardsofmedicalcareindiabetes2010.DiabetesCare201033Suppl 1:S1161. KidneyDiseaseOutcomesQualityInitiative.KDOQIClinicalpracticeguidelinesandclinicalpractice recommendationsfordiabetesandchronickidneydisease.AmJKidneyDis200749:S12154. ParvingHH,LehnertH,BrochnerMortensenJ,GomisR,AndersenS,ArnerP,onbehalfoftheIrbesartanin PatientswithType2DiabetesandMicroalbuminuriaStudyGroup.Theeffectofirbesartanonthedevelopmentof diabeticnephropathyinpatientswithtype2diabetes.NEnglJMed2001345:8708. BrennerBM,CooperME,deZeeuwD,etal.,onbehalfoftheRENAALStudyInvestigators.Effectsoflosartanon renalandcardiovascularoutcomesinpatientswithtype2diabetesandnephropathy.NEnglJMed2001345:861 9. LewisEJ,HunsickerLG,ClarkeWR,etal.Renoprotectiveeffectoftheangiotensinreceptorantagonistirbesartan inpatientswithnephropathyduetotype2diabetes.NEnglJMed2001345:85160. KidneyDiseaseOutcomesQualityInitiative(K/DOQI).K/DOQIclinicalpracticeguidelinesonhypertensionand antihypertensiveagentsinchronickidneydisease.AmJKidneyDis200443(5Suppl1):S1290. Hypertension,Dialysis,andClinicalNephrologywebsite.GFR/1.73M2byMDRD.Availableat: http://www.hdcn.com.Accessed12/26/2011. WrightJTJr,BakrisG,GreeneT,etal.,onbehalfoftheAfricanAmericanStudyofKidneyDiseaseand HypertensionStudyGroup.Effectofbloodpressureloweringandantihypertensivedrugclassonprogressionof kidneydisease:resultsfromtheAASKtrial.JAMA2002288:242131.

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5.4:OtherSpecialSituations
Author(s): CliveRosendorff,MD,PhD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeabletoidentifythepharmacologicoptionsfortreatingspecialpatient populationswithcommoncomorbidconditions,hypertensivecrisis,andthemorecommonformsofsecondaryhypertension.

SpecialPatientPopulationsandCommonComorbidConditions ThatInfluenceDrugSelection
Commoncomorbidconditionsinmiddleagedandelderlyhypertensivepatientsthat mayinfluencedrugselection,eitherpositivelyornegatively,aresummarized inFigures1and2.Agentsthathaveaddedbenefitforpatientswiththeseconditions shouldbeincludedaspartofthetreatmentprogram,althoughadditionaldrugsmay beneededtobringbloodpressure(BP)undercontrol.Agentsthathaveadverse effectsonthesecomorbidconditionsshouldnotbeselectedasfirstorsecondline therapy,butmayoccasionallybeneededtocontrolBPinpatientswithresistant hypertension. Otherspecialsituationsthataffectantihypertensivedrugchoicesorintensityof treatmentinclude:1)race/ethnicity,2)obesityorthemetabolicsyndrome,3)left ventricular(LV)hypertrophy,4)peripheralarterialdisease,5)oldage,6)orthostatic hypotension,7)impairedcognitivefunctionanddementia,8)erectiledysfunction,9) pregnancy,and10)childhood/adolescence.Thesespecialsituationsaredescribed indetailinthecompleteversionoftheseventhreportoftheJointNational CommitteeforthePrevention,Detection,Evaluation,andTreatmentofHighBlood Pressure(JNC7).1

Figure1

Figure2

AntihypertensiveDrugTherapyWithPotentialFavorableEffectsforSpecialPatientPopulations/ComorbidConditions Figure1

AntihypertensiveDrugTherapyWithPotentialUnfavorableEffectsforSpecialPatientPopulations/ComorbidConditions Figure2

SevereHypertension
Theterminologyhasnotbeenstandardized,sothefollowingapproachis recommended.A"hypertensivecrisis"isdefinedasdiastolicBP(DBP)>120mm Hg.Ifthecrisisisassociatedwithacuteorrapidlyworseningtargetorgandamage, itisa"hypertensiveemergency"ifnot,itisreferredtoasa"hypertensiveurgency." JNC7guidelinesusedaBPof>120mmHgdiastolicwithimpendingor progressivetargetorgandysfunctionasthedefinitionof"hypertensiveemergency." However,manyhypertensionexpertswoulddefinehypertensiveemergencyasthe situationinahypertensivepatientwithelevatedBPinwhichthereisrapidly worseningtargetorgandamage,suchasacuteLVfailurewithpulmonaryedema, acutecoronarysyndrome,strokeortransientischemicattack,encephalopathy,renal failure,aorticaneurysm,orseverepreeclampsia,irrespectiveoftheBPlevel. "Malignanthypertension"isahypertensiveemergencyassociatedwithpapilledema, whereas"acceleratedhypertension"isahypertensiveemergencyassociatedwith retinalhemorrhagesandexudates.2 TherateofriseinBPismoreimportantthantheabsoluteBPrecordedin determiningwhetherthepatientwithseverehypertensionorhypertensiveurgency needsemergencytreatment.Patientswithchronichypertensioncantoleratemuch higherBPsthanpreviouslynormotensivepersons.Encephalopathy,forexample, rarelydevelopsinpatientswithlongstandinghypertensionuntiltheDBPis150 mmHg.Conversely,ayoungwomanwithpreeclampsiamaybecome encephalopathicwithaDBP100mmHg. Severehypertensionoccursmostcommonlyinpatientswhoarenoncompliantwith theirprescribedantihypertensivemedicationsorhavebeenundermedicated.Inthis setting,risingBPisthoughttocauseendothelialdamage,duetothereleaseof vasoconstrictorsubstancessuchasnorepinephrine,endothelin,andangiotensinII. Aviciouscircleofreleaseofadditionalvasoconstrictorsubstancesandfurther increasesinperipheralresistanceisinitiated,whichcanresultinlifethreatening targetorgandamage. Thehistory,physical,andlaboratoryevaluationofapatientwithseverelyelevatedBP shouldbedirectedtowardidentifyingtargetorgandamageandpossiblesecondary causesoftheBPelevation(Figure3).Patientswithhypertensiveemergency,thatis withevidenceofacutetargetorgandamage,requireimmediateBPreduction, generallywithintravenoustherapyintheintensivecaresetting.BPshouldbe reducedpromptly,butgraduallybecauseprecipitousreductionsinBPto normotensivelevelsmayprovoketargetorganischemiaorinfarction.Reductionsin meanarterialpressuregenerallyshouldnotexceed20%inthefirst12hours. Furtherreductionsshouldbeachievedgraduallyovertheensuing2448hours. Sodiumnitroprussideisthedrugofchoicefortreatmentinmosthypertensive emergenciesbecauseofitsimmediateonsetofactionandveryshorthalflife,which allowforeffectiveminutebyminutetitration.Careshouldbetakentoavoid overshoothypotension.Becausesodiumnitroprussideisbothanarteriolarand venodilator,thereisatendencytoovershoothypotensionasaresultofabrupt loweringofthevenousfillingpressureoftherightventricle,resultinginalower cardiacoutput,especiallyinpatientswhoarehypovolemicfromlargedosesofloop diuretics.Thehypotensionmayalsocausereflextachycardia,whichisvery undesirableifthepatienthasmyocardialischemia. Othersideeffectsincludemetabolicacidosis,andtoxicityfromthiocyanateand cyanide(metabolitesofnitroprusside),especiallyinpatientswithrenalorhepatic insufficiency.Specifichypertensiveemergenciesthatrequirespecializedevaluation andtreatmentaresummarizedinFigures4,and5aandb.Specificparenteraldrugs fortreatmentofhypertensiveemergenciesaresummarizedinFigures6aandb. Patientswhohaveahypertensivecrisisaremorelikelytohavesecondary hypertensionthanthosewhodonot.Iftheinitialevaluationisnotrevealing,amore extensiveworkupshouldbeperformedoncetheBPisstabilized. PatientswithseverelyelevatedBPwithoutevidenceoftargetorgandamage (hypertensiveurgency)aremorelikelytobeharmedthanhelpedbyacute,

Figure3

Figure4

Figure5a

Figure5b

Figure6a

Figure6b

aggressiveBPreduction.Inparticular,parenteralantihypertensives,oreven sublingualororaladministrationofshortactingnifedipine,whichcaninduce dramaticBPlowering,arestronglydiscouraged.Allowingapatientwithseverely elevatedBPtositfor2030minutesinaquietareawilloftenresultinasignificant BPreduction.Oralantihypertensivetherapyshouldthenbeinitiatedinthepreviously untreatedpatient,resumedinthenoncompliantpatient,oradjustedinthe undermedicatedpatient.Followupshouldbewithin24hourstoensurecompliance andensurethattheBPisnotworsening.Thereafter,followupshouldbeindaysor weeks,notmonths,untiltheBPgoalisreached.

SymptomsandSignsAssociatedWithAcuteTargetOrganComplicationsinHypertensiveCrisis Figure3

DiagnosticEvaluationofSpecificHypertensiveEmergencies Figure4 BNP=BtypenatriureticpeptideBP=bloodpressureCT=computedtomographyeGFR=estimatedglomerularfiltrationrateJVD=jugular venousdistentionMRI=magneticresonanceimagingTEE=transesophagealechocardiography.

TreatmentRecommendationsforSpecificHypertensiveEmergencies(1of2) Figure5a

TreatmentRecommendationsforSpecificHypertensiveEmergencies(2of2) Figure5b

ParenteralDrugsforTreatmentofHypertensiveEmergencies(1of2) Figure6a ModifiedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeonprevention,detection, evaluation,andtreatmentofhighbloodpressure:JNC7completereport.Hypertension200342:120652.

ParenteralDrugsforTreatmentofHypertensiveEmergencies(2of2) Figure6b ModifiedwithpermissionfromChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeonprevention,detection, evaluation,andtreatmentofhighbloodpressure:JNC7completereport.Hypertension200342:120652.

SecondaryHypertension (1of2)
Secondaryhypertension,highBPcausedbyaspecific,potentiallycurabledisorder, accountsforapproximately10%ofallcasesofhypertension(Figures7a,b,c,d).A briefdescriptionofthediagnosisandtreatmentofthemostcommonformsof secondaryhypertensionfollows.Theremainingcausesofsecondaryhypertension arerareandaredescribedinstandardtextbooksofhypertension.35 PrimaryAldosteronism Primaryaldosteronism(PA),alsocalledConn'ssyndrome,isahypertensive syndromethatresultsfromincreasedproductionofaldosterone,andmayaccount forasmanyas515%ofallcasesofhypertension,andthusappearstobethemost prevalentformofsecondaryhypertension.Aldosteroneexcessgenerallyresultsin suppressedplasmareninactivity,metabolicalkalosis,apotassiumlosing diathesis(sometimesleadingtohypokalemia3.5mEq/L),andhypertension,but thesefindingsarevariable.TheincreaseinBPcanbesevereandresistantto conventionalantihypertensivetherapy. ItisimportanttodiagnoseandtreatPAearlybecausethesepatientsmaybeat higherriskthanotherhypertensivepersonsfortargetorgandamageoftheheart andkidney.Further,targetedpharmacologictherapywithspironolactoneorthe selectivemineralocorticoidreceptorantagonisteplerenone,orsurgery(most commonlylaparoscopicunilateraladrenalectomy)ishighlyeffectiveinloweringBP andpreventingtargetorgandamageinthesepatients.
Figure7d Figure7b

Figure7a

Figure7c

Allpatientswithsevereorresistanthypertension(BPnotattargetinapatienton threeormoreantihypertensivemedicationsinadequatedoses)withnoother obvioussecondarycauseshouldbeconsideredforscreening(Figure8). Inparticular,patientswithspontaneoushypokalemia(serumpotassiumof3.5 mEq/L)orinappropriatehypokalemia(serumpotassiumof3.0mEq/L)whileon conventionaldosesofdiureticsorwhorequireexcessivedosesofpotassium replacementtherapy,patientswithresistantorseverehypertension,aswellas patientswithincidentallydiagnosedadrenaltumors,shouldbescreenedforPA.It shouldbenoted,however,thathypokalemiaisnotauniversalfindinginpatients withPA. Themorningplasmaaldosteroneconcentrationtoplasmareninactivityratio (PAC/PRA)isthescreeningtestofchoiceforPA(Figure8).Aratio>20withaPACof atleast12ng/dlshouldpromptconfirmatorytesting.Aratio>70withaPACof15 ng/dlandaPRA1ng/ml/hisvirtuallydiagnosticofPA.Thetestcanbeperformedin patientstakingallantihypertensivemedicationsexceptspironolactoneor eplerenone. Ifthescreeningtestispositive,thenthenextstepisanaldosteronesuppression test.Afterhypokalemiaiscorrected,patientsaregivenahighsodiumdiet(46g/das tablets)for3daysonday3,a24hoururinespecimeniscollectedformeasurement ofaldosterone,sodium,andpotassium.A24hoururinarysodiumexcretion>200 mgisconsideredadequatedocumentationofsodiumrepletion.Urinaryaldosterone excretion>12mcg/24hoursinthissettingisdiagnosticofaldosteroneexcess. Theremainderofthediagnosticalgorithmisdirectedtowardconfirmingthe existenceofaldosteroneexcessandidentifyingtheresponsiblelesion(Figure9). ThetwomostcommoncausesofPA,aldosteroneproducingadenomaandbilateral adrenalhyperplasia,canbedistinguishedbyhighresolutioncomputedtomography (CT)oftheadrenalglands.Asolitarytumor>1cmindiameterinayoungerpatientis anindicationforsurgery,butmedicaltherapyisalsoarealisticoption,inpart becausealdosteroneproducingadenomasveryrarelyundergomalignant degeneration,andbecausepostproceduralpersistenceofhypertensioniscommon. Ifthereismicronodularityorbilateralmasses,bilateraladrenalvenoussampling(if available)mayhelptodeterminewhetherthealdosteroneexcessoriginatesfrom oneorfrombothadrenals.

Figure8

Figure9

Figure10

Figure11

Nonfunctioningunilateraladrenaladenomasarenotuncommoninolderpatients, sothemerepresenceofalesioninthissettingwithoutevidenceof hyperaldosteronism("incidentaloma")isnotanindicationforadrenalectomy. Treatmentforalateralizingpositivestudyinyoungerindividualscanbesurgical spironolactoneoreplerenoneisthetreatmentofchoiceforanonlateralizingstudy suchasbilateraladrenalhyperplasiaorbilateraladenomas. Patientswithatypicalfeaturesorwhofailtorespondtoaldosteroneantagonistsmay haveoneoftherarerformsofPA,suchasglucocorticoidremediablealdosteronism oradrenalcarcinoma,andshouldbereferredtoaspecializedcenterforevaluation andtreatment. RenalArteryStenosis Renalarterystenosis(RAS)mayresultinhypertensionand/orischemic nephropathy,eventuallyleadingtoendstagerenaldisease(ESRD).AlthoughRAS affects<5%ofhypertensivepatients,ischemicnephropathyaccountsfor1020%of theESRDpopulation.Therefore,diagnosisandtreatmentofRAShaveimportant implicationsforbothBPcontrolandpreservationofrenalfunction.6 RASisduetoatherosclerosisin7090%ofcases,andusuallyinvolvestheostium andproximalthirdofthemainrenalarteryandtheperirenalaorta(Figure10). Segmentalanddiffuseintrarenalatherosclerosisoccurslessfrequentlyandusually representsadvanceddisease.AtheroscleroticRAS,similartootheratherosclerotic disease,occursinmiddleageandbeyond,andismostcommoninpatientswith aortoiliacocclusivedisease,diabetes,coronaryheartdisease,and/ortobaccouse. Theremaining10%orsoofRASiscausedbyfibromusculardysplasia,atypeof vasculitisthataffectsoneormorelayersoftherenalartery,usuallyincludingthe media.IncontrasttoatheroscleroticRAS,fibromusculardysplasiamoreoften affectsyoungerpersons,particularlywomen,andinvolvesthedistaltwothirdsofthe renalartery(Figure10,PanelA).Fibromusculardysplasiaislesslikelytoprogress thanatheroscleroticRAS,althoughtheremaysometimesbedissectionand thrombosis. ClinicalfeaturestraditionallyassociatedwithhypertensionduetoRASare summarizedinFigure11.Ingeneral,themostpowerfulpredictorsofthepresence ofRASare:age,atheroscleroticcardiovasculardiseaseelsewhere,thepresenceof anabdominalbruit,recentonsetofhypertensionorrecentlossofBPcontrol, unilateralsmallkidney,alargeincreaseinserumcreatinineafterinitiationofan angiotensinconvertingenzyme(ACE)inhibitororangiotensinreceptorblocker (ARB),hypercholesterolemia,cigarettesmoking,andtheabsenceofafamilyhistory ofhypertension. AworkupforRASshouldbedoneonlyifthereisresistanthypertensionorifthereis worseningrenalfunction,andifthereisnocontraindicationtoaninvasiveprocedure (percutaneousrenalangioplasty,withorwithoutstenting,orrevascularization surgery),andifthepatientiswillingtoacceptamoreaggressiveapproach. Otherwise,onlymedicalmanagementisadvised. Measurementsofactivationofthereninangiotensinaldosteronesystem(RAAS), suchasperipheralvenousplasmareninactivity(PRA)atrestorfollowing stimulationwithanACEinhibitor,lackthesensitivityandspecificitytobeusefulin screeningforRAS.Moreover,inthechronicstagesofhypertension,PRAmaybe suppressedduetovolumeoverload,andthehypertensionmaynotbeangiotensin dependent.

CausesofSecondaryHypertension(1of4) Figure7a ReproducedwithpermissionfromOparilS,CalhounD.Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.NewYork: ScientificAmerican2000.

CausesofSecondaryHypertension(2of4) Figure7b ReproducedwithpermissionfromOparilS,CalhounD.Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.NewYork: ScientificAmerican2000.

CausesofSecondaryHypertension(3of4) Figure7c ReproducedwithpermissionfromOparilS,CalhounD.Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.NewYork: ScientificAmerican2000.

CausesofSecondaryHypertension(4of4) Figure7d ReproducedwithpermissionfromOparilS,CalhounD.Highbloodpressure.ScientificAmericanMedicine,vol.1,part3,pp.116.NewYork: ScientificAmerican2000.

UseofthePlasmaAldosteroneConcentrationtoPlasmaReninActivityRatiotoScreenforPrimaryAldosteronism Figure8

SubtypeEvaluationofPrimaryAldosteronism Figure9

AngiographicAppearanceoftheTwoMostCommonFormsofRenalArteryStenosis Figure10 PanelA:Thetypicalbeaded,aneurysmalappearanceofthedistalrightrenalarteryinapatientwithrefractoryhypertensionandfibromuscular dysplasia. PanelB:ThesamepatientasinPanelA,afterangioplasty.Therewasimprovementintheangiographicappearanceandresolutionof hypertension. PanelC:Thetypicalappearanceofatheroscleroticrenalarterystenosis,involvingtheostiumandproximalthirdoftheleftrenalartery(arrows). PanelD:ThesamepatientasinPanelC,afterangioplasty.Therewasresidualstenosis,dissection,andapressuregradient. PanelE:WhichresolvedaftertheplacementofaPalmazstent(seearrows). ReproducedwithpermissionfromSafianRD,TextorSE.Renalarterystenosis.NEnglJMed2001344:43142.Copyright2001,Massachusetts MedicalSociety.Allrightsreserved.

ClinicalFeaturesSuggestiveofRenovascularHypertension Figure11 ACEI=angiotensinconvertingenzymeinhibitorARBs=angiotensinreceptorblockersBP=bloodpressure.

SecondaryHypertension (2of2)
UsefulnoninvasivetestsforRASinclude:radioisotopescanningwithACEinhibition (captoprilscintigraphy),Dopplerultrasound,magneticresonanceangiography (MRA),andCTangiography(CTA)(Figure12).Thesensitivityoftheseimaging techniquesvariesfrom8095%underoptimalconditions,buteachhasits advantagesandlimitations.Captoprilscintigraphyisnoninvasiveandrelatively inexpensive,butislessaccurateinbilateraldiseaseoradvancedrenalfailure becauseitdependsonadifferenceinisotopeuptakebetweenthetwosides. Dopplerultrasoundishighlyoperatordependent,andtechnicallydifficulttoperform, especiallyinthepresenceofabdominalobesityandbowelgas.MRAandCTA produceexcellentimagequality,butareexpensive.MRAproducespoorimageswith stentsordistalstenoses(asinfibromusculardysplasia),andCTArequirescontrast medium,oftencontraindicatedinrenalinsufficiency. RenalarteriographyisthedefinitivediagnostictestforRAS,revealinginadditionthe extentofintrarenalandassociatedaorticvasculardiseaseandthedimensionsof thekidneys.IftheclinicalindexofsuspicionofRASishighandinterventionis contemplatedbecauseofresistanthypertensionordeterioratingrenalfunction, renalarteriographymaybeindicatedinlieuofscreeningtestsorregardlessofthe outcomeofscreeningtests. ThegoalsofRAStreatmentareBPcontrolandpreservationofrenalfunction.BP controlcanbeattemptedwithmedicaltherapyalone,withpercutaneousrenal angioplasty(withorwithoutstenting),orsurgery.Thechoiceoftherapyisdictatedby: 1)whetherthelesionisatheroscleroticorfibromuscular,2)itsproximitytotherenal ostium,3)theextentofrenalarterialinvolvement,4)thepatient'scomorbidmedical condition(s),5)theeaseordifficultyincontrollinghypertensionandpreventing progressiverenalinsufficiencywithdrugsalone,and5)theinherentrisks,aswell astheskillofavailableoperatorsinperforminginterventionalprocedures.Anoverall approachtothetherapyofrenovascularhypertensionisoutlinedinFigures13and 14. ControlofBPinrenovascularhypertensionmaybeachievedin>90%ofcaseswith medicaltherapyalone,usuallywithacombinationofantihypertensivedrugs.All classesofthesedrugsmaybeused,butbecausethehypertensionisoftenthe resultofactivationoftheRAAS,drugsthatinhibitangiotensinIIproductionorblock itsreceptorareparticularlyeffective.Thisshouldbeaugmentedwith antiatheroscleroticandantithromboticmeasuressuchasstatintherapy,smoking cessation,andaspirin. ItshouldberememberedthatangiotensinIIhasagreatervasoconstrictoreffecton theefferentarteriolethanontheafferentarterioleand,thus,contributestothe maintenanceofglomerularfiltrationpressure,andthusglomerularfiltrationrate (GFR).ACEinhibitorsandARBs,bydilatingtheefferentarteriole,willcauseafallin glomerularfiltrationpressureandGFRand,thus,anincreaseintheserum creatinine.Thisisanormalresponsetothesedrugs,andisnotanindicationto discontinuethem,unlessthefallinGFRortheincreaseinserumcreatinineis >35%frombaseline(ifthebaselinecreatinineis3mg/dl).Inrarecases,acute (usuallyreversible)renalfailuremayoccur,suggestingthepresenceofahighgrade renalarterystenosis,RASaccompaniedbysevererenalparenchymaldisease,or volumecontraction.RenalfunctionshouldbecarefullymonitoredwheneverACE inhibitorsorARBsareusedinpatientswithRAS,particularlywhencombinedwitha diuretic. MostpatientswithatheroscleroticRASrequiremedicalantihypertensivetherapyas eitherprimarytreatmentorfollowingrenalarteryangioplasty,becausethe revascularizationaloneisseldomsufficienttocontrolBPinmiddleagedorelderly patientswithRAS.Thereasonforthismayberesidualischemicnephropathyinthe affectedkidney,maintainingtherenalhypertension,restenosisoftheaffected kidney,orprogressionofatheroscleroticdiseaseinthecontralateralkidney.In contrast,angioplastyisthetreatmentofchoiceforpatientswithfibromuscular dysplasia,andhasatechnicalsuccessrateof87100%,afavorableeffectonBPof

Figure12

Figure13

Figure14

Figure15

90%,arestenosisrateofonly10%,anda10yearsuccessrateof90%. Surgicalrevascularizationofthekidneyisseldomindicatedinfibromuscular hyperplasiabecauseangioplastyissosuccessfulinthiscondition.Surgeryisalso notrecommendedasinitialtherapyforcontrolofBPinpatientswithatherosclerotic RASbecauseofhighratesofmorbidity/mortalityassociatedwiththeprocedurein thesepatients,andbecausemodernmedicalantihypertensivetherapyisso successful.Age,coexistentatheroscleroticdisease,andbaselinerenalfunctionare themajordeterminantsofoutcome.Surgicalrevascularizationshouldbereserved forpatientswithaorticdiseaseorfailedangioplastywithorwithoutstenting,for preservationofrenalfunctionandforBPcontrol. Thesuccessofsurgical(andcatheterbased)revascularizationinpreservingrenal functiondependsontheadequacyofthevasculaturedistaltothesiteofthearterial lesion,thelevelofrenalfunctionatthetimeofintervention,andtherateatwhich renalfunctionhasdeterioratedpriortointervention.Bestresultsareachievedwhen theserumcreatinineis<3.0mg/dl.Risksofsurgicalrevascularizationoutweighthe benefitsinpatientswithmoreadvancedrenalfailure(serumcreatinine>4.0mg/dl) becausesuchpatientshavesignificantunderlyingirreversiblerenalparenchymal disease. Insummary(Figures13,14),thetreatmentofchoiceforhypertensioninpatients withRASduetofibromusculardysplasiaisrevascularizationwithangioplastyif possible,orwithsurgeryifangioplastyisunsuccessfulortechnicallynotfeasible. Thiswillobviatelifelongmedicaltherapyintheseyoungpatients.Incontrast, medicaltherapyisthetreatmentofchoiceforhypertensioninpatientswith atheroscleroticRAS,particularlyifBPandrenalfunctioncanbecontrolledorif comorbidconditionsincreasetheriskofintervention. Managementshouldincludeaggressivestatinandaspirintreatmentandsmoking cessationmeasures,asthesemayslowtheprogressionofintrarenal atherosclerosis.Closemonitoringofrenalfunctionandkidneysizeismandatory becausetheprogressionofatherosclerosismayleadtorenalfunctional impairment.Ifthereisdeteriorationinrenalfunctionorsize,orBPcannotbe controlledwithmedicines,revascularizationisindicated.Renalarteryangioplasty, usuallywithstenting,isthetreatmentofchoiceinthesepatients.Surgical revascularizationisindicatedforcomplexlesionsandwhenmedicaland percutaneousapproachesareunsuccessful. Itisnotclearwhetherrenalrevascularization,bywhatevermeans,changesthe naturalhistoryormortalityofpatientswithatheroscleroticRAS.Smallprospective, randomizedtrialscomparingmedicaltherapywitheithersurgicalorendovascular treatmenthavenotfoundconsistentdifferencesinrenalfunctionorevenBPcontrol. TheseverityofRASiscloselyrelatedtototalatheroscleroticburden,andadvanced atherosclerosishasanoverridingmortalityriskthatmaybeonlyminimallyaffected byrenalarteryrevascularization. ObstructiveSleepApnea Obstructivesleepapnea(OSA)ischaracterizedbyrepetitiveinterruptionofventilation for10secondsormoreduringsleepcausedbycollapseofthepharyngealairway, andwithassociatedrespiratoryeffort.7 Itshouldbedistinguishedfromcentralsleep apnea,inwhichthecauseoftheapneaislossofventilatorydrive,andcharacterized bya10secondpauseinventilationwithnoassociatedrespiratoryeffort.The syndromeofOSAischaracterizedbysnoring,sleepfragmentation,daytime hypersomnolence,andcognitiveimpairment.Clinicalfeaturesandpredisposing factorsarelistedinFigure15.Personswithhypertensionandtheclinical features/predisposingfactorsforOSA,particularlyloudsnoring,daytimesleepiness, orwitnessedapneas,shouldundergoformalovernightsleeptesting ("polysomnography")tomakethediagnosis. Approximately50%ofpatientswithOSAarehypertensive,andasmanyas30%of hypertensivepatientsareestimatedtohaveOSA.Ifthereisacausalrelation betweenthetwodisorders,itmaybethatrecurrenthypoxiainducedbysleepapnea triggerssustainedincreasesinperipheralresistanceandcardiacoutput,inpart secondarytochronicsympatheticactivation.Sleepdeprivationinuntreatedor inadequatelytreatedhypertensivepatientsmayincreasesympatheticnervous

activityduringthenightandthefollowingmorning,leadingtoincreasedBPandheart rate,andincreasedriskforbothtargetorgandamageandcardiovasculardisease events.Alternatively,hypertensionandsleepapneamaysimplyshareindependent riskfactors,suchasageandobesity. Themainstayoftreatmentisweightloss,whichmaybecurative,butisverydifficult toachieve.Behavioraltherapyincludes:1)cessationofalcoholandsedativeuse,2) avoidanceofsleepdeprivation,and3)sleeppositioningtoavoidthesupine position,inwhichupperairwayobstructionoccursmostcommonly.Asimpleand ofteneffectiveapproachisamandibularadvancementsplint,amouthguard designedtoholdthemandibleslightlydownandforwardrelativetothenatural, relaxedposition.Thispositionholdsthetonguefartherawayfromthebackofthe airway,andmaybeenoughtorelieveapneaorimprovebreathingforsomepatients. Othermedicaltherapiesinclude:1)treatmentofpredisposingcomorbidconditions, and2)nocturnalcontinuouspositiveairwaypressure(CPAP).Surgicalapproaches includeuvulopalatopharyngoplastyandgenioglossal/mandibularadvancementin adultsandtonsillectomy/adenoidectomyinchildren.Uvulopalatoplastyisoften ineffective(>50%recurrencerateofOSAin2years),andshouldbeusedonlyasa lastresort,exceptinpatientswithseverespecificcraniofacialabnormalities. AlthoughCPAPlowersnighttimeBP,daytimeBPdecreasesaremodestand inconsistent,andpatientswithOSAshouldbetreatedaccordingtostandard guidelinesformanagementofessentialhypertension.Thereisnoevidencethatone classofantihypertensiveagentsismoreorlessadvantageousthananyotherclass inpatientswithsleepapnea.Specialattentionshouldbepaidtocomorbid conditions,anddrugsthatcausesedationordaytimesomnolenceshouldbe avoided. CentralsleepapneaisdescribedinLVdysfunctionandheartfailure,stroke,andin theelderly,withaprevalenceinmen>65yearsofageof5%.Themechanisms underlyingcentralsleepapneaarecomplexandincludechemoreflexes,pulmonary congestion,increasedcardiacfillingpressures,andprolongedcirculationtime. Becausenorandomizedtrialsoftherapyforcentralsleepapneainheartfailurehave establishedadefinitebenefitwithrespecttohospitalizationormortality,thereisno consensusastowhethercentralsleepapneashouldbetreated,andifso,whatthe therapeuticstrategyshouldbe.Treatmentsthathavebeenassessedincludedrugs thatblocktheRAS,diuretics,theophylline,betablockers,supplementaloxygen,and CPAP,withinconsistentresults.

NoninvasiveScreeningTestsforRenalArteryStenosis Figure12 AspiralcomputedtomographyscanmaybesubstitutedforanMRAifthereisnorenalinsufficiencyorifanMRAiscontraindicated,orboth.Ifa patientsrenalfunctionsignificantlydeterioratesorbloodpressurecannotbecontrolledmedically,proceedtoangiography. MRA=magneticresonanceangiography. ReproducedwithpermissionfromSpitalewitzS,ReiserIW.OparilS,WeberM,eds.Hypertension,CompaniontoBrennerandRectors,The Kidney.Philadelphia:W.B.SaundersCo.,200066274.

ComprehensiveApproachtotheTreatmentofRenovascularHypertension(1of2) Figure13 ReproducedwithpermissionfromReiserIW,etal.Secondaryhypertension:Renalvascularcauses.In:AntmanE,ed.Cardiovascular Therapeutics:ACompaniontoBraunwaldsHeartDisease,2nded.Philadelphia:W.B.SaundersCo.,2002.

ComprehensiveApproachtotheTreatmentofRenovascularHypertension(2of2) Figure14 BP=bloodpressurePTRA=percutaneousrenalangioplastyRAS=renalarterystenosis. ReproducedwithpermissionfromReiserIW,etal.Secondaryhypertension:Renalvascularcauses.In:AntmanE,ed.Cardiovascular Therapeutics:ACompaniontoBraunwaldsHeartDisease,2nded.Philadelphia:W.B.SaundersCo.,2002.

ClinicalFeaturesandPredisposingFactorsAssociatedWithObstructive Figure15 ReproducedwithpermissionfromKahnDMetal.Obstructivesleepapnea.In:OparilS,WeberM,eds.Hypertension,CompaniontoBrennerand Rectors,TheKidney.Philadelphia,PA:W.B.SaundersCompany,200065762.

KeyPoints
"Hypertensiveurgency"isthesituationinwhichapatient'sDBPis>120mmHg.Ifthereisacuteorrapidly worseningtargetorgandamage,thenthetermusedis"hypertensiveemergency."Hypertensiveurgencycanbe managedasanoutpatient,buthypertensiveemergencyrequiresadmissiontoaunitwithcardiovascular monitoringfacilities,forparenteralantihypertensivetherapy. Therearemanycausesofsecondaryhypertension,includingprimaryaldosteronismandRAS.Primary aldosteronismmaybecausedbyanaldosteroneproducingadenomaoftheadrenalgland,orbybilateraladrenal hyperplasia.ThereissuppressedPRA,increasedurinarypotassiumloss,oftenbutnotalwayswithhypokalemia, andhypertension.Screeningforprimaryaldosteronismisappropriateinpatientswithhypertensionand spontaneoushypokalemia,orinanypatientwithtreatmentresistanthypertension.Thescreeningtestofchoiceis themorningPACtoPRAratio,whichif>20(withaPACof12ng/dl)issuggestiveofprimaryhyperaldosteronism, andif>70withaPACof15ng/dlandaPRAof1ng/ml/hisvirtuallydiagnostic.HighresolutionCTofthe adrenalglandscompletestheworkup. RASmayresultinhypertensionand/orischemicnephropathy.Mostcasesareduetoatherosclerosis,butabout 10%areduetofibromusculardysplasia,whichaffectsyoungerpersons,particularlywomen.Themostpowerful predictorsofthepresenceofRASare:age,atheroscleroticcardiovasculardiseaseelsewhere,thepresenceofan abdominalbruit,recentonsetofhypertensionorrecentlossofBPcontrol,unilateralsmallkidney,alarge increaseinserumcreatinineafteranACEinhibitororARB,hypercholesterolemia,cigarettesmoking,and absenceofafamilyhistoryofhypertension. AworkupforatheroscleroticRASshouldbedoneonlyifthereisresistanthypertensionorifthereisworsening renalfunction,andifthereisnocontraindicationtoaninvasiveprocedure(renalangioplastyorrevascularization surgery),andifthepatientiswillingtoacceptrevascularization.Otherwise,onlymedicalmanagementisadvised. MeasurementofperipheralvenousPRAatrestorfollowingstimulationwithACEinhibitorslacksthesensitivity andspecificitytobeusefulinscreeningforRAS.UsefultestsforRASincluderadioisotopescanningwithACE inhibition(captoprilscintigraphy),Dopplerultrasound,MRA,CTA,andrenalarteriography. Inatheroscleroticrenovascularhypertension,BPcontrolmaybeachievedin>90%ofcaseswithmedicaltherapy alone,usuallywithacombinationofantihypertensivedrugs,butmoreinvasivemanagementisindicatedifthe hypertensionisrefractorytomedicaltherapywithmultipleantihypertensiveagentsatmaximumdose,orifthereis progressivedeteriorationofrenalfunction.Bycontrast,infibromuscularhyperplasia,renalarteryangioplastyis thetreatmentofchoice. OSAischaracterizedbyrepetitiveinterruptionofventilationfor10secondsormoreduringsleepcausedby collapseofthepharyngealairway,andwithassociatedrespiratoryeffort.Personswithhypertensionandthe clinicalfeatures/predisposingfactorsforOSA,particularlyloudsnoring,daytimesleepiness,orwitnessed apneas,shouldundergoformalovernightsleeptesting("polysomnography")tomakethediagnosis.Therapyis behavioral,medical,andsurgical.

References
1. ChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeofPrevention,Detection, Evaluation,andTreatmentofHighBloodPressure.Hypertension200342:120652. 2. VidtDG.Treatmentofhypertensiveurgenciesandemergencies.In:IzzoJL,SicaD,BlackHR,eds.Hypertension Primer:TheEssentialsofHighBloodPressure.4thEd.IzzoJL,SicaDA,BlackHR,eds.Philadelphia:Lippincott Williams&Wilkins2007:48993. 3. OparilS,WeberMA,eds.Hypertension:ACompaniontoBrennerandRector'sTheKidney.2nded.Philadelphia: W.B.SaundersCo.2005. 4. BlackHR,ElliottWJ,eds.Hypertension:ACompaniontoBraunwald'sHeartDisease.Philadelphia:Saunders Elsevier2006. 5. KaplanNM,VictorRG.Kaplan'sClinicalHypertension.8thed.Philadelphia:LippincottWilliams&Wilkins2006. 6. ElliottWJ.Secondaryhypertension:renovascularhypertension.In:BlackHR,ElliottWJ,eds.Hypertension:A CompaniontoBraunwald'sHeartDisease.Philadelphia:SaundersElsevier2006:93105. 7. SomersVK,WhiteDP,AminR,etal.Sleepapneaandcardiovasculardisease:anAmericanHeart Association/AmericanCollegeofCardiologyFoundationScientificStatementfromtheAmericanHeartAssociation CouncilforHighBloodPressureResearchProfessionalEducationCommittee,CouncilonClinicalCardiology, StrokeCouncil,andCouncilonCardiovascularNursing.JAmCollCardiol200852:686717.

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Chapter5Exam
Visittheonlineversionoftheproducttoseethecorrectanswerandcommentary. 1. WhichofthefollowingstatementsisTRUE? A. Thetermprehypertensionisusedtoidentifythosewhowilldevelop hypertension,butdoesnotimplyincreasedCVrisk. B. Hypertensiveemergenciesrequireadmissiontoanintensivecareunit, whereashypertensiveurgenciescanusuallybemanagedintheoutpatient setting. C. Refractory(resistant)hypertensionisdefinedasadiastolicBPof>120mm Hgdespitethreedrugsofdifferentclassesatmaximumapproveddoses. D. BothsystolicanddiastolicBPincreaseprogressivelywithage,andthis increaseisacceleratedafterage50. E. Aboveage55,hypertensionismorecommoninmenthaninwomen.

2. Oftheidentifiablegeneticcausesofhumanhypertension,mostencodegenesthat dowhichofthefollowing? A. Setthelevelofsympatheticnervoussystemactivity. B. Governinsulinresistance. C. Regulaterenalhandlingofsodiumandchloride. D. Regulateplasmareninactivity. E. Encodethegeneforendothelin.

3. AngiotensinIIreceptorsoftheAT1subtypedowhichofthefollowing? A. Inducehypertrophyandhyperplasiaofvascularsmoothmusclecells. B. Inhibitmitogenactivatedproteinkinase(MAPkinase). C. Areupregulatedbychymase. D. Inhibitaldosteronesecretion. E. Causeprostacyclin(PGI2)releaseinthekidney.

4. Whichofthefollowingisatargetorganconsequenceofchronicallyelevatedblood pressure?

A. Slowedpulsewavevelocity. B. Increasedejectionfraction. C. Impairedsodiumreabsorptionbytheproximalrenaltubules. D. Atrophyofmesangialcellsofthekidney. E. Transientischemicattack(TIA).

5.A57yearoldman,previouslyuntreated,hasaBPof136/78mmHgonhisinitial visit.HeisaskedtoreturnthefollowingweekandhisBPis134/78mmHg.Theonly significantfindingontheworkupisananklebrachialindexof0.7.Heis asymptomatic,andtheperipheralpulsesarenormaltopalpation. Whichofthefollowingisappropriatemanagement? A. HeshouldbetoldthathisBPisnormalbutthathemayhaveperipheral arterialdisease,andbefullyworkedupforthat,includingMRangiography. B. Heshouldbetreatedforhypertension,includingaggressivemultiplerisk factorinterventionandantihypertensivedrug/s. C. IftherestingECGisnormal,nofurtherinterventionsarenecessary. D. HeshouldhaveanexerciseECGtest,becauseperipheralarterialdisease isamarkerforCAD. E. Heshouldbetoldthatheisnormalforhisage,butthatheshouldhave anothercheckupin6months.

6.A67yearoldwomanisreferredtoyouwithaBPof158/72mmHg.Thehistory andphysicalexaminationwereunremarkable.Sheiscurrentlyonathiazidediuretic, anACEinhibitor,andacalciumchannelblocker.Laboratorytestsincludea completebloodcount,chestXray,serumelectrolytes,andurinalysis,allofwhich werenormal. Yourtreatmentplanistodowhichofthefollowing? A. Orderaserumcreatinine,BUN,eGFR,fastingserumglucoseandlipid profile,aspoturinemicroalbumin:creatinineratio,anda12leadECG. B. ReassessherBPandlabsin3months. C. Addabetablockertotheregimen. D. OrderanechocardiogramtoassessLVsize. E. Orderanexerciseorpharmacologicstresstest

7.A52yearoldmanisadmittedtothecoronarycareunitwith8hoursofchestpain. HisECGshowsa3mmSTsegmentdepressionandTwaveinversioninleadsV4

6,andthetroponinIvalueisclearlyelevated.Heishemodynamicallystable,butthe BPis182/104mmHg.ThereisnoclinicalevidenceofLVdysfunction. TheelevatedBPshouldbetreatedinitiallywithwhichofthefollowing? A. Intravenoussodiumnitroprusside. B. OralACEIandthiazidediuretic. C. Oralbetablocker. D. Restinaquietroom. E. OralnondihydropyridineCCB(diltiazemorverapamil).

8.A77yearoldmanhasbeentreatedforamonthwithhydrochlorothiazide25mg andlosartan100mgdailywithnoimprovementinhisBP(172/78mmHg).Heis foundtohaveanelevatedplasmareninactivity,andmagneticresonance(MR)renal angiographyreveals90%ostialstenosisoftherightrenalartery.Thepatient undergoesstentingofthelesionwithhemodynamicsuccess. Inadditiontoafollowupvisitin2weeks,whichofthefollowinginstructionsismost appropriateatthetimeofhisdischargefromthehospital? A. Discontinehisantihypertensivemedications. B. Discontinuethediuretic. C. Reducethelisinoprilandhydrochlorothiazidebyonehalf. D. RepeatMRangiographyin1month. E. Addclopidogreltohisregimen.

9. Randomizedcontrolledtrialshaveshownthatthebenefitofantihypertensive treatmentinpreventingCVDoutcomessuchasheartattack,stroke,andCVmortality dependsprincipallyonwhichofthefollowing? A. ReductioninDBP. B. ReductioninSBP. C. Effectsonplasmareninactivity. D. Effectsonsympatheticneuralfunctionandcirculatingcatecholamines. E. Alloftheabove.

10. Whichofthefollowingisthedrugoffirstchoiceforhypertensivetype2diabetic patientswithmicroalbuminuria?

A. Adiuretic. B. AnangiotensinIIreceptorblocker. C. Analphablocker. D. Abetablocker. E. ACCB.

11. Whichofthefollowingisthedrugoffirstchoiceforhypertensivetype2diabetic patientswithoutmicroormacroalbuminuriaandwithnormalrenalfunction? A. Adiuretic. B. AnangiotensinIIreceptorblocker. C. Abetablocker. D. ACCB. E. Alloftheabove.

12.A64yearoldman,withahistoryofhypertensionandtype2diabetes,butno nephropathy,comesfora3monthfollowupvisit.HisBPatthepreviousvisit3 monthsagowas162/92mmHg,andthetherapywasincreasedtolisinopril40 mg/d(from20mg/d)andhydrochlorothiazide25mg/d.Hishomefastingfingerstick glucosehasrangedfrom102136mg/dl,andinyourofficeis124mg/dl.Hehasno symptomsandthephysicalexaminationincludingfundoscopicexamrevealsno newfindingshowever,hisBPafter15minutesofrestinaquietroomis212/116 mmHg.Heinsiststhatheistakingallofhisprescribedmedications.Theurine dipstickisnormal. Whichofthefollowingisthenextmostappropriatestepinhiscare? A. Havehimreturnin1weekforarepeatBPcheck. B. Addamlodipine5mg/dandhavethepatientreturnin12days. C. Admitthepatienttotheintensivecareunit/criticalcareunitforparenteral antihypertensivetherapy. D. Referhimforanisotope(captopril)renogramtoexcluderenovascular hypertension. E. Givesublingualnifedipine30mgandmeasuretheBP15minuteslater.

13.A56yearoldfemalepatientreferredforanewevaluationisfoundtohaveaBP of162/88mmHg.Sheistakinglosartan50mg/d.Sheis58andweighs174lbs. Labdatainclude:whitebloodcellcount7300/cmm,hemoglobin14.1g/dl, hematocrit43%,serumfastingglucose122mg/dl,glycatedhemoglobin6.2%, sodium141mEq/L,potassium3.4mEq/L,creatinine1.4mg/dl,bloodureanitrogen

33mg/dl,PRA0.5ng/ml/h,andplasmaaldosterone18ng/dl.Aspoturinehada concentrationofcreatinineof250mg/dl,andaproteinconcentrationof4.3mg/dl. Whichofthefollowingisthemostlikelydiagnosisinthispatient? A. Hypertensionduetodiabeticnephropathy. B. Renovascularhypertension. C. Primaryhypertensionwithnoevidenceoftargetorgandamage. D. Primaryhypertensionwithhypertensivenephropathy. E. Hypertensionduetoprimaryaldosteronism.

14.A45yearoldmancomestoseeyoubecauseofhypertensiondiagnosed recentlyathisworksite.Onphysicalexamination,hisBPis172/104mmHg.Hehas evidenceofLVhypertrophyonECG.Hisserumcreatinineis1.5,estimatedGFRby thepredictionequationis55ml/minhisfastingbloodsugaris200mg/dl,andhis glycatedhemoglobinis8.0%,consistentwithadiagnosisoftype2diabeteswith nephropathy.Analysisofaspoturinesamplerevealsevidenceofmicroalbuminuria. Heisonnoantihypertensivemedications. Whichofthefollowingshouldbeyourtreatmentplan? A. BeginanACEinhibitorasmonotherapy. B. BeginaCCBdiureticcombination. C. BeginanARBdiureticcombination. D. Beginaloopdiuretic. E. Begintripletherapywithabetablocker,diuretic,andCCB.

15.Thepatientdescribedinquestion3,returnsafter1monthwithaBPof138/86 mmHgandaserumcreatinineof2.0.Heisonthemaximumapproveddosesofan ARBanddiuretic. Whichofthefollowingshouldbeyournextstepinmanagementofthispatient? A. StoptheARBandsubstituteaCCBplusbetablocker. B. AddaCCBtotheARBdiureticcombination. C. Continuecurrenttreatmentandaskhimtoreturnin1month. D. Switchthethiazidediuretictoaloopdiuretic. E. Referthepatienttoanephrologistinpreparationfordialysis.

PleasevisittheonlineversiontoengageinthisExam. 1.ThecorrectanswerisB.Individualswithprehypertension(BP120139/8089mmHg)have agreaterriskofCVeventsthanthosewithanormalBP(<12/80mmHg).Refractory(resistant)

hypertensionisaBPof>140/90mmHgdespitethreedrugsofdifferentclassesatmaximum approveddoses.WhileSBPcontinuestorise,DBPtendstodeclineafterage50.Aboveage55, hypertensionismorecommoninwomenthaninmen. 2.ThecorrectanswerisC.Althoughrare,thegenesthatcauseMendelianformsofhuman hypertensionaffectBPbyalteringrenalsalthandling. 3.ThecorrectanswerisA.MAPkinaseisatransductionfactoractivatedbyangiotensinII. ChymaseisanenzymethatcangenerateangiotensinIIfromangiotensinI.AngiotensinII stimulatesaldosteronesecretion.AngiotensinIIactivatesvasoconstrictormechanismsPGI2is avasodilatorprostaglandin. 4.ThecorrectanswerisE.TIAandstrokearewellrecognizedcomplicationsofchronic hypertension.Chronichypertensioncanleadtoacceleratedpulsewavevelocityduetoincreased stiffnessoflargearteriesejectionfractionisunchangedordiminishedbecauseoftheincreased afterloadontheLV,resultinginLVHandmyocardialdysfunctionrenalsodiumreabsorptionis enhanced,andthereisoftenmesangialcellhyperplasia. 5.ThecorrectanswerisB.Hehasperipheralvasculardisease,whichisaCADequivalent,so thethresholdforpharmacologictherapyforhypertensionis130/80mmHg.Theperipheral arterialdiseasealsomandatesaggressiveriskfactorintervention. 6.ThecorrectanswerisA.Theworkupdescribedinthescenarioisincomplete,andshouldbe completedbytheadditionoftheinvestigationslistedinoptionA. OptionBisincorrectbecauseherBPisuncontrolledonthepresentmedications.OptionCis inappropriatebecausetheBPmaybecontrolledbyuptitratinghercurrentmedications,iftheyare beingtakenatsubmaximaldoses,withouttheadditionofanotherclassofdrugs. Echocardiographyandstresstestingarenotpartoftheroutineworkupforuncomplicated hypertensionbecauseofthepoorbenefit:costratio. 7.ThecorrectanswerisC.Ifthepatientishemodynamicallystable,andiftherearenoother contraindicationstobetablockers,theinitialtreatmentiswithabetablocker.Nitrates, intravenousororal,areusedforsymptomcontrol,butaredifficulttotitrateifusedaloneforBP control.AnACEI(orARB)canbeaddedlateriftheBPisstillelevated,thepatienthasananterior MI,thereisLVdysfunction,orifthepatienthasdiabetes.Oraldiltiazemorverapamilare appropriatealternativestobetablockersinpatientsintoleranttobetablockers,butnotifthereis LVdysfunction. 8.ThecorrectanswerisE.Fortheolderpatientwithrenovasculardiseasesuperimposedona lengthyhistoryofessentialhypertension,renalrevascularizationusuallydoesnotresultin normalizationofBP,rapidimprovementinrenalfunction,oranimmediatedrasticreductioninthe needforantihypertensivetherapy.Revascularizationdoeshelpwithpreservationofrenalfunction andpreventionofprogressiontoendstagerenaldisease.Also,BPcontrolgenerallybecomes easier,overthelongtermfacilitatingareductioninantihypertensivemedicationrequirement. Thisgenerallyrequirestime,however,andinmostcases,theprerevascularizationmedication regimenshouldbemaintaineduntiltheBPresponsetotheprocedurecanbeassessed. 9.ThecorrectanswerisB.ForallCVDoutcomesexceptHF,metaanalysesofrandomized controlledtrialshaveshownthatthebenefitsofanytreatmentcomparedtoeitherplacebooran activecomparatorareproportionaltoachievedreductionsinSBP. 10.ThecorrectanswerisB.TheKidneyDiseaseOutcomesQualityInitiativeandADA guidelinesrecommenduseofanangiotensinIIreceptorblockeroranACEI(notincludedinthis listofchoices)fordiabeticpatientswithmicroormacroalbuminuriaorwithrenalinsufficiency. 11.ThecorrectanswerisB.SinceACEIsandARBsarerenoprotectiveinpatientswithdiabetic nephropathy,itmakessensetoregardthemasthepreferredantihypertensivedrugsinall diabeticpatients,eventhosewithnoevidenceofnephropathy.However,accordingtoJNC7 guidelines,diabeticswithoutevidenceofrenaldamagerespondwelltotreatmentwith antihypertensivedrugsinallfiveoftheseclasses,JNC7identifiesnopreferenceforoneoverthe others,sooptionEisnotincorrectonthatbasis.SomeauthoritieswouldsaythatoptionsAand

Careincorrectbecauseboththiazidediureticsandbetablockersimpairinsulinsensitivityand maymakeglycemiccontrolmoredifficult. 12.ThecorrectanswerisB.SeverelyelevatedBPwithoutanyevidenceofacutetargetorgan damageisahypertensiveurgency,notanemergency.Increasingtheexistingtherapy,oradding anotherdrugfromanotherclassarereasonableoptions,andrequirefrequentvisitstoassess efficacyandtouptitratetherapyifnecessary.Hypertensiveemergencies,withacutetargetorgan compromise,requireadmissionforparenteraltherapyhypertensiveurgencydoesnot. RASisapossibilityinthispatient,butiftheBPcanbecontrolledwithmedicaltherapy,andthere isnodeterioratingrenalfunction,thediagnosisofrenovascularhypertensiondoesnotcontribute substantiallytothemanagement,andtheworkupcanbedeferred.Sublingualnifedipinehas causedischemicstrokeinthissituation,andshouldneverbeused. 13.ThecorrectanswerisE.TheratioofplasmaaldosteroneconcentrationtoPRAis36:1.Any ratio>20withaplasmaaldosteroneconcentrationofatleast12ng/dlshouldprompt confirmatorytestingforprimaryaldosteronism.Thepatientdoesnothavediabetes,becausethe fastingserumglucoseis<126mg/dl,althoughherfastingserumglucoseof122mg/dlputsher inthehighprediabetesrange.Renovascularhypertensionisalwaysapossibilityinpatientswith hypertension,butthereisnothingintheclinicalscenariotosuggestthisdiagnosisinparticular. Thereisalsonoevidenceofrenaldiseasethespoturinaryalbumin(17.2mg/gcreatinine)isnot inthemicroalbuminuriarange(20200mg/gcreatinine). 14.ThecorrectanswerisC.TheKidneyDiseaseOutcomesQualityInitiative,American DiabetesAssociation,andJNC7guidelinesindicatethatdiabeticswithnephropathyor proteinuriashouldbetreatedwithanARBorACEinhibitortodelaytheprogressionofproteinuria andthedevelopmentofESRD.Inaddition,guidelinesindicatethatpatientswithstage2 hypertension(BP>160/100mmHgor>20mmHgovergoal,whichinthispatientscaseis 130/80mmHg)shouldbestartedontwodrugs.AlogicalcombinationwouldbeanARBoran ACEinhibitorwithadiuretic. UseofanACEinhibitorasmonotherapywouldnotbeindicatedbecauseoftheseverityofthis patientshypertension.TheothercombinationssuggestedlackablockeroftheRAASand,thus, wouldnotberecommended. References
1. ChobanianAV,BakrisGL,BlackHR,etal.SeventhreportoftheJointNationalCommitteeof Prevention,Detection,Evaluation,andTreatmentofHighBloodPressure.Hypertension 200342:120652.

15.ThecorrectanswerisB.Anincreaseinserumcreatinineofupto35%ofpretreatment levelsisanacceptableandexpectedresponsetoantihypertensivetreatment,particularly treatmentwithanACEinhibitororanARB.Thisisanexpectedresponse,anddoesnotmandate discontinuationofthedrug.Thepatientsserumcreatinineshouldbemonitoredtoensurethatit remainsstable.Ifitcontinuestorise,thepatientshouldbeevaluatedforrenovasculardisease. ThepatientisnotyetattheBPgoalof130/80mmHgthus,additionaltherapyisindicatedatthis point.Acalciumchannelblockerwouldbeareasonablechoice.