HypertensionandTheHeartVasiliosPapademetriou,MDProfessorofMedicine(Cardiology)GeorgetownUniversityDirectorHypertensionandCardiovascularResearchVAMCWashingtonDCHypertensionandTheHeartVaFDR’sFinalPicture(April11,1945)

FDR’sFinalPicture(April11,2FDR’sBPasrecordedApril1944atBethesdaNavalHospital

FDR’sBPasrecordedApril1943【高血壓英文課件】-Hypertension-and-The-Heart4【高血壓英文課件】-Hypertension-and-The-Heart5CumulativeIncidence

(%)CumulativeIncidence

(%)CumulativeIncidenceofHeartFailurebyBaselineHypertensionStatusTime(y)Stage12520151050246810121416Stage2+Menaged60-69yNormotensive2468101214Menaged70-79yStage2+Stage1Normotensive403020100LevyDetal.JAMA.1996;275:1557-1562.2520151050246810121416Stage2+Stage1Womenaged60-69yNormotensiveStage1NormotensiveStage2+4030201002468101214Womenaged70-79yCumulativeCumulativeCumulative6Population-attributableriskdefinedas:

(100xprevalencex[hazardratio–1])/(prevalencex[hazardratio–1]+1)Population-AttributableRisks

forDevelopmentofCHFCHF,chronicheartfailure;AP,anginapectoris;DM,diabetesmellitus;LVH,leftventricularhypertrophy;

VHD,valvularheartdisease;HTN,hypertension;MI,myocardialinfarction.LevyDetal.JAMA.1996;275:1557-1562.AP

5%DM

6%LVH

4%VHD

7%MI

34%HTN39%MenWomenHTN59%DM

12%LVH

5%VHD

8%AP

5%MI

12%Population-attributableriskd7EffectsofHypertensiononTheHeartLeftVentricularHypertrophyVascularDisease:-Atherosclerosis-ArteriosclerosisEffectsofHypertensiononThe8【高血壓英文課件】-Hypertension-and-The-Heart【高血壓英文課件】-Hypertension-and-The-Heart10【高血壓英文課件】-Hypertension-and-The-Heart11【高血壓英文課件】-Hypertension-and-The-HeartPrevalenceofSystolicandDiastolicDysfunctionbyAgeRedfieldMMetal.JAMA.2003;289:194-202.%ofPopulation01020304050EF<50%EF<40%DiastolicDysfunctionSystolicDysfunctionMildModerateSevere45-5455-6465-74>75ALL60PrevalenceofSystolicandDiaSYSTOLICANDDIASTOLICHEARTFAILURELOWEFHIGHLVMASSMYOCYTEHYPERTOPHYINTERSTITIALFIBROSISABNORMCALCHANDLINGREDUCEDCONTRACTILITYSLOWEDRELAXATIONDEPLETEDPREL0ADRESERVELARGEVOLUMESNORMAL

EFHIGHLVMASSMYOCYTEHYPERTROPHYINTERSTITIALFIBROSISABNORMCALCHANDLINGREDUCEDCONTRACTILITYSLOWEDRELAXATIONDEPLETEDPRELOADRESERVESMALLVOLUMESKONSTAMMA;JOFCARDIACFAILURE,2003VOL9,No1;1-3.SYSTOLICANDDIASTOLICHEARTFLeftVentricularHypertrophyIndependentPredictorof:

MyocardialinfarctionStrokeHeartFailureTotalMortalitySuddenDeathLeftVentricularHypertrophyIn15【高血壓英文課件】-Hypertension-and-The-Heart16【高血壓英文課件】-Hypertension-and-The-Heart17*OtherantihypertensivesexcludingACEIs,AIIantagonists,beta-blockers.Dahl?fBetalAmJHypertens1997;10:705

713.LIFE:DesignDosingDay

14Day

7Day1Mth1Mth2Mth4Mth6Yr1Yr1.5Yr2Yr2.5Yr3Yr3.5Yr4Yr5Titrationtotargetbloodpressure:<140/<90mmHgPlaceboLosartan50mgAtenolol50mgLosartan50mg+HCTZ12.5mgLosartan100mg+HCTZ12.5mgLosartan100mg+HCTZ12.5-25mg+others*Atenolol50mg+HCTZ12.5mgAtenolol100mg+HCTZ12.5mgAtenolol100mg+HCTZ12.5-25mg+others**OtherantihypertensivesexcluLIFE:BloodPressureResults–Follow-up061218243036424854StudyMonth406080100120140160180SystolicDiastolicMeanArterialmmHgAtenololLosartanAtenolol145.4mmHgLosartan144.1mmHgAtenolol80.9mmHgLosartan81.3mmHgBDahlofetal.Lancet2002;359:995-1003LIFE:BloodPressureResults–Intention-to-TreatLIFE:Fatal/NonfatalStrokeLosartanAtenololAdjustedRiskReduction24·9%,p=0·001UnadjustedRiskReduction25·8%,p=0.0006Proportionofpatientswithfirstevent(%)

0

1

2

3

4

5

6

7

8BDahlofetal.Lancet2002;359:995-10030612182430364248546066StudyMonthIntention-to-TreatLIFE:Fatal/LIFE:Fatal/NonfatalMyocardialInfarctionIntention-to-Treat

0

1

2

3

45

6

7

8Proportionofpatientswithfirstevent(%)AtenololLosartanAdjustedRiskReduction-7·3%,p=0·49UnadjustedRiskReduction-5·0%,p=0·63BDahlofetal.Lancet2002;359:995-10030612182430364248546066StudyMonthLIFE:Fatal/NonfatalMyocardiaLIFE:CardiovascularMortalityIntention-to-Treat0

1

2

3

45

6

7

8LosartanAtenololAdjustedRiskReduction11·4%,p=0·21UnadjustedRiskReduction13·3%,p=0·14Proportionofpatients(%)BDahlofetal.Lancet2002;359:995-10030612182430364248546066StudyMonthLIFE:CardiovascularMortality00.511.52TotalMortalityHospforAPHospforHFRevascularization23LIFE:OtherClassifiedEndpointsFavorsLosartanFavorsAtenololHazardRatio(95%CI)00.511.52TotalMortalityHospfLVHPrevalenceatBaselineandAnnualFollow-UpinLIFELVHPrevalenceatBaselineand24HR=0.58,95%CI0.38-0.86P-0.008HazardratiosrepresentriskreductionassociatedwithabsenceversuspresenceofLVHHR=0.58,95%CI0.38-0.86Haz25HR=0.34,95%CI0.17-0.71P-0.004HazardratiosrepresentriskreductionassociatedwithabsenceversuspresenceofLVHHR=0.34,95%CI0.17-0.71Hazar26HR=0.48,95%CI0.24-0.930.031HazardratiosrepresentriskreductionassociatedwithabsenceversuspresenceofLVHHR=0.48,95%CI0.24-0.93Hazar27HR=0.36,95%CI0.23-0.53P<0.001HazardratiosrepresentriskreductionassociatedwithabsenceversuspresenceofLVHHR=0.36,95%CI0.23-0.53Hazar28LIFEEchoSubstudy:ChangeinLVMIChangefromBaselinetoYearinLIFE**p=0.021,adjustedforbaselineLVMIandbaseline&in-treatmentBPChange(g/m2)DevereuxRBetal.AmJHypertens2002;15:15A

LIFEEchoSubstudy:Changein【高血壓英文課件】-Hypertension-and-The-Heart30RegressionofHypertensiveLVH:Resultsof2000Meta-AnalysisSchmiederetal:JAmCollCardiol2001;37:261-262AP<0.05P<0.09vs?-blockersLVMRegression(%)DiureticsBeta-BlockersACE-InhibitorsCa++BlockersAIIreceptorBlockersRegressionofHypertensiveLVHCHARM

AddedCHARM

PreservedCHARMProgramme3componenttrialscomparingcandesartantoplaceboinpatientswithsymptomaticheartfailureCHARM

Alternativen=2028

LVEF￡40%

ACEinhibitor

intolerantn=2548LVEF￡40%

ACEinhibitor

treatedn=3025LVEF>40%

ACEinhibitor

treated/nottreatedPrimaryoutcomeforOverallProgramme:All-causedeathPrimaryoutcomeforeachtrial:CVdeathorCHFhospitalisationCHARM

AddedCHARM

PreservedCHACHARM-Preserved

PrimaryandsecondaryoutcomesCVdeath,CHFhosp. 333 366-CVdeath 170 170-CHFhosp. 241 276CVdeath,CHFhosp, 365 399

MI CVdeath,CHFhosp, 388 429

MI,stroke CVdeath,CHFhosp, 460 497

MI,stroke,revasc candesartan

betterHazardratioplacebo

better0.81.01.2p-value0.9180.0720.1180.1260.0780.123Covariateadjusted

p-value0.6350.0470.0510.0510.0370.13CandesartanPlacebo0.890.990.850.900.880.91CHARM-Preserved

PrimaryandsEffectsofHypertensiononTheHeartLeftVentricularHypertrophyVascularDisease:-Atherosclerosis-ArteriosclerosisEffectsofHypertensiononThe

ATHERO-

ARTERIO-

SCLEROSIS SCLEROSIS

(Increasedvascularstiffness

Decreasedvascularcompliance)Focal,OcclusiveInflammatoryEndothelialdysfunctionRelatedtoLDLcholesteroloxidation“Inside-out”SensitivetoAIIandothersubstancesDiffuse,DilatoryFibrotic(elastinbreakdown,collagenincrease)AdventitialandmedialhypertrophyRelatedtoageandBP“Outside-in”SensitivetoAIIandothersubstancesATHERO- ARTERIO-

S35IntegratedPerspectiveonCVRiskFactorsandVascularDiseaseSmokingDiabetesHypertensionDyslipidemiaOxidativeStressInflammationEndothelialDysfunctionCVDiseaseRoss.NEnglJMed.1999;340:115-126.OxidativeStress&InflammationEndothelialDysfunctionRoss.NEnglJMed.1999;340:115-126.IntegratedPerspectiveonCVRRossR,NEnglJMed340(1999)&Davies,Circulation94(1996)HemorrhagedmicrovesselsRupturedplaque(coronaryartery)PlaqueruptureUnstablePlaqueThinningoffibrouscapRossR,NEnglJMed340(199937BPandRiskofCHDMortalityCHD,coronaryheartdisease.MultipleRiskFactorInterventionTrial(MRFIT);n=347,978menwithoutpreviousmyocardialinfarction.NeatonJDetal.In:Hypertension:Pathophysiology,Diagnosis,andManagement.1995:127-144.SBP(mmHg) <120 120-129 130-139 140-159 160-179 180-209 ≥210DBP(mmHg) <80 80-84 85-89 90-99 100-109 110-119 ≥120SBPDBP1.481.211.001.842.563.455.171.661.281.002.453.425.266.40RelativeriskofCHDmortality43210765BPandRiskofCHDMortalityCH38StrokeandIHDMortalityvsUsualSystolicBPbyAgeIHD=ischemicheartdisease

ProspectiveStudiesCollaboration.Lancet.2002;360:1903-1913.Mortality

(FloatingAbsoluteRiskand95%CI)UsualSystolicBP(mmHg)50-59years60-69years70-79years80-89yearsStrokeAgeatrisk:25612864321684210120140160180IHDUsualSystolicBP(mmHg)50-59years60-69years70-79years80-89yearsAgeatrisk:40-49years25612864321684210120140160180StrokeandIHDMortalityvsUs)AGINGANDARTERIALSTIFFNESS

PATHOPHYSIOLOGY

YoungelasticvesselsOldinelasticvessels

AdaptedfromIzzoJL.JAmGeriatrSoc.1981;29:520-524.SYSTOLEDIASTOLEDIASTOLESYSTOLESTROKEVOLUMERESISTANCEARTERIOLESAORTAPRESSURE(FLOW)STROKEVOLUMERESISTANCEARTERIOLESAORTAPRESSURE(FLOW)(IncreasedsystolicDecreaseddiastolic)AGINGANDARTERIALSTIFFNES4018-2930-3940-4950-5960-6970-7980+0708011013015018-2930-3940-4950-5960-6970-7980+070801101301500708011013015007080110130150DBP(mmHg)SBP(mmHg)DBP(mmHg)SBP(mmHg)DBP(mmHg)SBP(mmHg)DBP(mmHg)SBP(mmHg)Men,Age(y)Women,Age(y)Non-HispanicBlackNon-HispanicWhiteMexicanAmericanPulsepressurePulsepressureSBP&DBPbyAge&Race/Ethnicity&Gender

(USPopulationAge18Years,NHANESIII)BurtVI,etal.Hypertension.1995;25:305-313.18-2930-3940-4950-5960-6970-7941<4040-4950-5960-6970-7980+Age(y)17%16%16%20%20%11%DistributionofHypertensionSubtypeintheuntreatedHypertensivePopulationinNHANESIIIbyAgeISH(SBP3140mmHgandDBP<90mmHg)SDH(SBP3140mmHgandDBP390mmHg)IDH(SBP<140mmHgandDBP390mmHg)020406080100Numbersattopofbarsrepresenttheoverallpercentagedistributionofuntreatedhypertensionbyage.Franklinetal.Hypertension2001;37:869-874.Frequencyofhypertensionsubtypesinalluntreatedhypertensives(%)<4040-4950-5960-6970-7980+Age42FranklinSS,etal.Circ.1999;100:354.60708090100110DBP(mmHg)0.511.522.53SBP170mmHg(P=0.01)SBP150mmHg(P=0.02)SBP130mmHg(P=0.06)SBP110mmHg(P=0.03)CHDhazardratioRelationshipofSBPandDBPtorisk

forCHD:TheFraminghamHeartStudy

Meanage=61years(range:50-79),n=1924

Adjustedforage,sex,andotherriskfactorsP=probabilityforcoefficientsFranklinSS,etal.Circ.199943EffectofSystolicBPandDiastolicBP

onCHDMortality:MRFITScreenees(N=316,099)**Menaged35to57yearsfollowedupforameanof12years.Adaptedfrom:Neatonetal.ArchInternMed.1992;152:56-64.Deathrate

per10,000

person-yearsDiastolicBP(mmHg)SystolicBP(mmHg)EffectofSystolicBPandDiasHypertension:AMajorRiskFactorforCHFTime,decadesVasanRS,LevyD.ArchInternMed.1996;156:1789-1796.DeathObesityDiabetesSmokingDyslipidemiaSystolicDysfunctionDiastolicDysfunctionSubclinicalLeftVentricularDysfunctionCHFOvertHeartFailureTime,monthsHypertensionLVHMILeftVentricularRemodelingHypertension:AMajorRiskFac4500.511.522.533.5ActivePlacebo1.63.5p<.001DevelopmentofCHFActive112of6,914Placebo240of6,92355%riskreductionMoser,HerbertJACC1996;27:1214-2800.511.522.533.5ActivePlacebo1-60-50-40-30-20-100Coops&WarrenderEWPHESHEPSTOPHypertension-35-53-54-51RiskReductionofHeartFailureinElderlyHypertensivesRiskreduction(%)-60-50-40-30-20-100Coops&EWPH47HEARTFAILUREFROMHYPERTENSIONTOHEARTFAILUREINSHEPKostisetal,JAMA1997about85%about15%HEARTFAILUREFROMHYPERTENSIONFatalandNonfatalHospitalized

HeartFailure

SHEPStudybyAgeGroupKostisetal.JAMA.1997.%Follow-Up(y)Age60-69yAge70-79yAge80+yFatalandNonfatalHospitalize49TreatmentofHypertensionandCVDOutcomes

PlaceboControlledTrials17randomized,placebo-controlledtrials(48,000subjects)—14diureticand3betablockerbasedtrials.Alldifferencesarestatisticallysignificant.CVD,cardiovasculardisease;CHD,coronaryheartdisease.HerbertPRetal.ArchInternMed.1993;153:578-581.MoserM,HerbertPR.JAmCollCardiol.1996;27:1214-1218.-16-21-38-52-60-50-40-30-20-100HeartfailureFatal/nonfatalstrokesCVDdeathsFatal/nonfatalCHDeventsRiskreduction(%)TreatmentofHypertensionand50ThereisnoquestionthattreatmentofHypertensionwillpreventCVComplicationsDoesitMatterHowWeDoit?ThereisnoquestionthattreaACE/CCBTrialsvsBeta-Blockers/DiureticsMajorcardiovasculareventsincludedstroke,myocardialinfarction,heartfailure,ordeathfromanycardiovascularcauseAdaptedfromBloodPressureLoweringTreatmentTrialists’Collaboration.Lancet2000;356:1956-1964.ACE/CCBTrialsvsBeta-BlockerCONVINCE

HazardRatiosforSubgroups

SOCDiuretic181165SOC

-Blocker183200USA

204212Canada9386WesternEurope3935Other

2832COER-vSOCNo.ofEvents0.40.60.81.01.21.41.61.8HazardRatio(COER-verapamil/SOC)FavorsCOER-vFavorsSOC ←→-BlockerJAMA.2003.CONVINCE

HazardRatiosforSub53CONVINCE

CVD-Related2°EndpointsEventCOER-vSOCHRPvalue1°orCVDHosp7937751.050.31CVDHospitalizationAngina2021901.090.39Revascularization1631661.010.91CHF1261001.300.05TIA891050.870.33RenalInsufficiency27340.810.43AccHTN22181.260.37(No.ofevents)JAMA.2003.CONVINCE

CVD-Related2°Endpoi54RandomizedDesign

ofALLHATHigh-riskhypertensivepatientsConsent/Randomize(42,418)AmlodipineChlorthalidoneDoxazosinLisinoprilEligibleforlipid-loweringNoteligibleforlipid-loweringConsent/Randomize(10,355)PravastatinUsualcareFollowforCHDandotheroutcomesuntildeathorendofstudy(upto8yr).ALLHATRandomizedDesign

ofALLHATHig55YearstoCHDEvent01234567CumulativeCHDEventRate0.04.08.12.16.2CumulativeEventRatesforthePrimaryOutcome(FatalCHDorNonfatalMI)byALLHATTreatmentGroup

RR(95%CI)pvalueA/C0.98(0.90-1.07)0.65L/C0.99(0.91-1.08)0.81ALLHATChlorthalidoneAmlodipineLisinoprilYearstoCHDEvent01234567Cumu56CumulativeEventRateYearsoffollow-updoxazosinchlorthalidoneHeartFailureC:15,268D:9,06713,6447,8455,5313,0892,4271,3519,5415,457Relrisk2.04z=10.95,p<0.000195%CI1.79-2.32ALLHATJAMA.2000;283:1967-1975.CumulativeYearsoffollow-updo57SBPResultsbyTreatmentGroupALLHAT1301351401451500612182430364248MonthsBP(mmHg)ChlorthalidoneDoxazosinSBPResultsbyTreatmentGroup58HeartFailure–SubgroupComparisons–RR(95%CI)ALLHATAmlodipineBetterChlorthalidoneBetter0.5012Non-Diabetic1.33(1.16,1.52)Diabetic1.42(1.23,1.64)Non-Black1.33(1.18,1.51)Black1.47(1.24,1.74)Women1.33(1.14,1.55)Men1.41(1.24,1.61)Age>=651.33(1.18,1.49)Age<651.51(1.25,1.82)Total1.38(1.25,1.52)LisinoprilBetterChlorthalidoneBetter0.5012Non-Diabetic1.20(1.04,1.38)Diabetic1.22(1.05,1.42)Non-Black1.15(1.01,1.30)Black1.32(1.11,1.58)Women1.23(1.05,1.43)Men1.19(1.03,1.36)Age>=651.20(1.06,1.35)Age<651.23(1.01,1.50)Total1.20(1.09,1.34)HeartFailure–SubgroupCompa59BPResultsbyTreatmentGroupComparedtochlorthalidone:SBPsignificantlyhigherintheamlodipinegroup(~1mmHg)andthelisinoprilgroup(~2mmHg).ALLHAT1301351401451500123456YearsBP(mmHg)ChlorthalidoneAmlodipineLisinoprilComparedtochlorthalidone:DBPsignificantlylowerintheamlodipinegroup(~1mmHg).70758085900123456YearsBP(mmHg)BPResultsbyTreatmentGroupC60Favors

FirstListedFavors

SecondListed0.51.02.0BP-LoweringTreatmentTrialists

ComparisonsofdifferentactivetreatmentsLancet.Inpress.RelativeRisk

RR(95%CI)BPDifference

(mmHg)CAvsD/BB1.33(1.21,1.47)1/00.93(0.86,1.01)CAvsD/BB1/01.01(0.94,1.08)CAvsD/BB1/0ACEvsCA0.82(0.73,0.92)1/11.12(1.01,1.25)ACEvsCA1/10.96(0.88,1.05)ACEvsCA1/1StrokeCoronaryHeartDiseaseHeartFailure1.09(1.00,1.18)ACEvsD/BB2/00.98(0.91,1.05)ACEvsD/BB2/01.07(0.96,1.19)ACEvsD/BB2/0Favors

FirstListedFavors

Seco0.51.02.0BP-LoweringTreatmentTrialists

ComparisonsofdifferentactivetreatmentsLancet.Inpress.RelativeRisk

RR(95%CI)BPDifference

(mmHg)Favors

FirstList