1、Vasilios Papademetriou,MDProfessor of Medicine(Cardiology)Georgetown UniversityDirector Hypertension and Cardiovascular ResearchVAMC Washington DCCumulativeIncidence(%)CumulativeIncidence(%)Time(y)Stage 12520151050246810121416Stage 2+Men aged 60-69 yNormotensive2468101214Men aged 70-79 yStage 2+Stag
2、e 1Normotensive403020100Levy D et al.JAMA.1996;275:1557-1562.2520151050246810121416Stage 2+Stage 1Women aged 60-69 yNormotensiveStage 1NormotensiveStage 2+4030201002468101214Women aged 70-79 yPopulation-attributable risk defined as:(100 x prevalence x hazard ratio 1)/(prevalence x hazard ratio 1+1)L
3、evy D et al.JAMA.1996;275:1557-1562AP5%DM6%LVH4%VHD7%MI34%HTN 39%MenWomenHTN 59%DM12%LVH5%VHD8%AP5%MI12%Redfield MM et al.JAMA.2003;289:194-202.%of Population01020304050EF50%EF75ALL60lLOW EFlHIGH LV MASSlMYOCYTE HYPERTOPHYlINTERSTITIAL FIBROSISlABNORM CALC HANDLINGlREDUCED CONTRACTILITYlSLOWED RELAX
4、ATIONlDEPLETED PREL0AD RESERVElLARGE VOLUMESlNORMAL EFlHIGH LV MASSlMYOCYTE HYPERTROPHYlINTERSTITIAL FIBROSISlABNORM CALC HANDLINGlREDUCED CONTRACTILITYlSLOWED RELAXATIONlDEPLETED PRELOAD RESERVElSMALL VOLUMESKONSTAM MA;J OF CARDIAC FAILURE,2003 VOL 9,No 1;1-3.*Other antihypertensives excluding ACEI
5、s,AII antagonists,beta-blockers.Dahlf B et al Am J Hypertens 1997;10:705713.LIFE:Design DosingDay 14Day 7Day1Mth1Mth2Mth 4Mth6Yr1Yr1.5Yr2Yr2.5Yr3Yr3.5Yr4Yr5Titration to target blood pressure:140/90 mmHgPlaceboLosartan 50 mg Atenolol 50 mgLosartan 50 mg+HCTZ 12.5 mgLosartan 100 mg+HCTZ 12.5 mgLosarta
6、n 100 mg+HCTZ 12.5-25 mg+others*Atenolol 50 mg+HCTZ 12.5 mgAtenolol 100 mg+HCTZ 12.5 mgAtenolol 100 mg+HCTZ 12.5-25 mg+others*LIFE:Blood Pressure Results Follow-up061218243036424854Study Month406080100120140160180SystolicDiastolicMean ArterialmmHgAtenololLosartanAtenolol 145.4 mmHgLosartan 144.1 mmH
7、gAtenolol 80.9 mmHgLosartan 81.3 mmHgB Dahlof et al.Lancet 2002;359:995-1003Intention-to-TreatLIFE:Fatal/Nonfatal StrokeLosartanAtenololAdjusted Risk Reduction 249%,p=0001Unadjusted Risk Reduction 258%,p=0.0006Proportion of patients with first event(%)0 1 2 3 4 5 6 7 8B Dahlof et al.Lancet 2002;359:
8、995-1003 0 6 12 18 24 30364248546066Study MonthLIFE:Fatal/Nonfatal Myocardial InfarctionIntention-to-Treat 0 1 2 3 4 5 6 7 8Proportion of patients with first event(%)AtenololLosartanAdjusted Risk Reduction-73%,p=049Unadjusted Risk Reduction-50%,p=063B Dahlof et al.Lancet 2002;359:995-1003 0 6 12 18
9、24 30364248546066Study MonthLIFE:Cardiovascular MortalityIntention-to-Treat 0 1 2 3 4 5 6 7 8LosartanAtenololAdjusted Risk Reduction 114%,p=021Unadjusted Risk Reduction 133%,p=014Proportion of patients(%)B Dahlof et al.Lancet 2002;359:995-1003 0 6 12 18 24 30364248546066Study Month00.511.52Total Mor
10、talityHosp for APHosp for HFRevascularization23LIFE:Other Classified EndpointsFavors LosartanFavors AtenololHazard Ratio(95%CI)LVH Prevalence at Baseline and Annual Follow-Up in LIFE06121824303642485460Month02468101214Endpoint Rate(%)Composite Endpoint Stratified by Time-Varying Presence of Echo-LVH
11、LVH AbsentLVH PresentHR=0.58,95%CI 0.38-0.86P-0.008Hazard ratios represent risk reduction associated with absence versus presence of LVH06121824303642485460Month01234567Endpoint Rate(%)CV Death Stratified by Time-Varying Presence of Echo-LVHLVH AbsentLVH PresentHR=0.34,95%CI 0.17-0.71P-0.004Hazard r
12、atios represent risk reduction associated with absence versus presence of LVH06121824303642485460Month01234567Endpoint Rate(%)MI Stratified by Time-Varying Presence of Echo-LVHLVH AbsentLVH PresentHR=0.48,95%CI 0.24-0.930.031Hazard ratios represent risk reduction associated with absence versus prese
13、nce of LVH06121824303642485460Month02468101214Endpoint Rate(%)Mortality Stratified by Time-Varying Presence of Echo-LVHLVH AbsentLVH PresentHR=0.36,95%CI 0.23-0.53P0.001Hazard ratios represent risk reduction associated with absence versus presence of LVHLIFE Echo Substudy:Change in LVMI-25-20-15-10-
14、50Year 1 Year 234Year 5LastEchoLosartanAtenololChange from Baseline to Year in LIFE*p=0.021,adjusted for baseline LVMI and baseline&in-treatment BPChange(g/m2)Devereux RB et al.Am J Hypertens 2002;15:15A Regression of Hypertensive LVH:Results of 2000 Meta-Analysis-12-10-8-6-4-20%DecreaseSchmieder et
15、 al:J Am Coll Cardiol 2001;37:261-262AP0.05P40%ACE inhibitor treated/not treatedPrimary outcome for Overall Programme:All-cause deathPrimary outcome for each trial:CV death or CHF hospitalisation33CHARM-Preserved Primary and secondary outcomesCV death,CHF hosp.333 366-CV death170170-CHF hosp.241276C
16、V death,CHF hosp,365399 MI CV death,CHF hosp,388429 MI,stroke CV death,CHF hosp,460497 MI,stroke,revasc candesartan betterHazard ratioplacebo better0.81.01.2p-value0.9180.0720.1180.1260.0780.123Covariateadjustedp-value0.6350.0470.0510.0510.0370.13Candesartan Placebo0.890.990.850.900.880.91Effects of
17、 Hypertension on The Heart Left Ventricular Hypertrophy Vascular Disease:-Atherosclerosis -Arteriosclerosis ATHERO-ARTERIO-SCLEROSIS SCLEROSIS (Increased vascular stiffness Decreased vascular compliance)Focal,Occlusive Inflammatory Endothelial dysfunction Related to LDL cholesterol oxidation“Inside-
18、out”Sensitive to A II and other substances Diffuse,Dilatory Fibrotic(elastin breakdown,collagen increase)Adventitial and medial hypertrophy Related to age and BP“Outside-in”Sensitive to A II and other substancesCVDiseaseRoss R,N Engl J Med 340(1999)&Davies,Circulation 94(1996)Hemorrhaged microvessel
19、sRuptured plaque(coronary artery)Plaque ruptureUnstable PlaqueThinning of fibrous capBP and Risk of CHD MortalityCHD,coronary heart disease.Multiple Risk Factor Intervention Trial(MRFIT);n=347,978 men without previous myocardial infarction.Neaton JD et al.In:Hypertension:Pathophysiology,Diagnosis,an
20、d Management.1995:127-144.SBP(mm Hg)120120-129130-139140-159 160-179180-209 210DBP(mm Hg)8080-8485-8990-99100-109110-119 120SBPDBP1.481.211.001.842.563.455.171.661.281.002.453.425.266.40Relative risk of CHD mortality43210765)AGING AND ARTERIAL STIFFNESS PATHOPHYSIOLOGY Young elastic vessels Old inel
21、astic vesselsAdapted from Izzo JL.J Am Geriatr Soc.1981;29:520-524.SYSTOLEDIASTOLEDIASTOLESYSTOLESTROKEVOLUMERESISTANCEARTERIOLESAORTAPRESSURE(FLOW)STROKEVOLUMERESISTANCEARTERIOLESAORTAPRESSURE(FLOW)(Increased systolicDecreased diastolic18-29 30-39 40-49 50-59 60-69 70-79 80+0708011013015018-29 30-3
22、9 40-49 50-59 60-69 70-79 80+070801101301500708011013015007080110130150DBP(mm Hg)SBP(mm Hg)DBP(mm Hg)SBP(mm Hg)DBP(mm Hg)SBP(mm Hg)DBP(mm Hg)SBP(mm Hg)Men,Age(y)Women,Age(y)SBP&DBP by Age&Race/Ethnicity&Gender (US Population Age 18 Years,NHANES III)Burt VI,et al.Hypertension.1995;25:305-313.4040-495
23、0-5960-6970-7980+Age(y)17%16%16%20%20%11%ISH(SBP 140 mm Hg and DBP 90 mm Hg)SDH(SBP 140 mm Hg and DBP 90 mm Hg)IDH(SBP 140 mm Hg and DBP 90 mm Hg)020406080100Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age.Franklin et al.Hypertension 2001;37:869-
24、874.Frequency of hypertensionsubtypes in all untreated hypertensives(%)Franklin SS,et al.Circ.1999;100:354.60708090100110DBP(mm Hg)0.511.522.53SBP 170 mm Hg(P=0.01)SBP 150 mm Hg(P=0.02)SBP 130 mm Hg(P=0.06)SBP 110 mm Hg(P=0.03)CHD hazard ratioRelationship of SBP and DBP to risk for CHD:The Framingha
25、m Heart Study Mean age=61 years (range:50-79),n=1924 Adjusted for age,sex,and other risk factors P=probability for coefficients10090-9980-8975-7970-7470120120-139140-159160483735443881312625252525241714131312211012999Time,decadesVasan RS,Levy D.Arch Intern Med.1996;156:1789-1796.DeathObesityDiabetes
26、SmokingDyslipidemiaSystolic DysfunctionDiastolic DysfunctionSubclinicalLeft VentricularDysfunctionCHFOvert HeartFailureTime,monthsHypertensionLVHMILeft VentricularRemodeling00.511.522.533.5ActivePlacebo1.63.5p.001Development of CHFActive 112 of 6,914Placebo 240 of 6,92355%risk reductionMoser,Herbert
27、 JACC 1996;27:1214-28-60-50-40-30-20-100Coops&WarrenderEWPHESHEPSTOPHypertension-35-53-54-51Risk Reduction of Heart Failurein Elderly HypertensivesRiskreduction(%)HEART FAILUREFROM HYPERTENSION TO HEART FAILURE IN SHEPKostis et al,JAMA 1997about 85%about 15%Kostis et al.JAMA.1997.%Follow-Up(y)Age 60
28、-69 yAge 70-79 yAge 80+y17 randomized,placebo-controlled trials(48,000 subjects)14 diuretic and 3 beta blocker based trials.All differences are statistically significant.CVD,cardiovascular disease;CHD,coronary heart disease.Herbert PR et al.Arch Intern Med.1993;153:578-581.Moser M,Herbert PR.J Am Co
29、ll Cardiol.1996;27:1214-1218.-16-21-38-52-60-50-40-30-20-100HeartfailureFatal/nonfatalstrokesCVD deathsFatal/nonfatalCHD eventsRiskreduction(%)Does it Matter How We Do it?ACE/CCB Trials vs Beta-Blockers/DiureticsSTOP2UKPDS-HDSCAPPPOverallINSIGHTNICS-EHSTOP-2NORDILVHASOverallACE vs B/DiureticsCCB vs
30、B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/DiureticsCCB vs B/Diuretics6614758109851835763214296614108811414256590.941.211.081.001.070.691.001.041.071.02nRRnRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR
31、RRR0.512Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard
32、Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Hazard Ratio(95%CI)Los925 ACM Gomes 1 Mar.14,2002Favors CCB Favors B/DiureticsFavors ACEi Favors B/DiureticsMajor cardiovascular events
33、included stroke,myocardial infarction,heart failure,or death from any cardiovascular cause Adapted from Blood Pressure Lowering Treatment Trialists Collaboration.Lancet 2000;356:1956-1964.Hazard Ratios for Subgroups SOC Diuretic 181165SOC -Blocker 183200USA 204212Canada 93 86Western Europe 39 35Othe
34、r 28 32COER-v SOCNo.of Events0.40.60.81.01.21.41.61.8Hazard Ratio(COER-verapamil/SOC)COER-vSOC-BlockerJAMA.2003.(No.of events)JAMA.2003.Randomized Designof ALLHATHigh-risk hypertensive patientsConsent/Randomize(42,418)AmlodipineChlorthalidoneDoxazosinLisinoprilEligible for lipid-loweringNot eligible
35、 for lipid-loweringConsent/Randomize(10,355)Pravastatin Usual careFollow for CHD and other outcomes until death or end of study(up to 8 yr).ALLHATYears to CHD Event01234567Cumulative CHD Event Rate0.04.08.12.16.2Number at Risk:Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodip
36、ine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195 Cumulative Event Rates for the Primary Outcome(Fatal CHD or Nonfatal MI)by ALLHAT Treatment Group RR(95%CI)p valueA/C0.98(0.90-1.07)0.65L/C0.99(0.91-1.08)0.81ALLHATChlorthalidoneAmlodipineLisin
37、oprilCumulativeEventRateYears of follow-updoxazosinchlorthalidoneHeart FailureC:15,268D:9,06713,644 7,8455,5313,0892,4271,351 9,541 5,457 Rel risk 2.04z=10.95,p=651.33 (1.18,1.49)Age=651.20 (1.06,1.35)Age 651.23 (1.01,1.50)Total1.20 (1.09,1.34)Compared to chlorthalidone:SBP significantly higher in t
38、he amlodipine group(1 mm Hg)and the lisinopril group(2 mm Hg).ALLHAT1301351401451500123456YearsBP(mmHg)ChlorthalidoneAmlodipineLisinoprilCompared to chlorthalidone:DBP significantly lower in the amlodipine group(1 mm Hg).70758085900123456YearsBP(mmHg)0.51.02.0Relative Risk0.51.02.0Relative RiskTime,decadesVasan RS,Levy D.Arch Intern Med.1996;156:1789-1796.DeathObesityDiabetesSmokingDyslipidemiaSystolic DysfunctionDiastolic DysfunctionSubclinicalLeft VentricularDysfunctionCHFOvert HeartFailureTime,monthsHypertensionLVHMILeft VentricularRemodeling
