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1、VBWGVBWGUS population at high riskAHA.Heart Disease and Stroke Statistics2005 Update.Hajjar I and Kotchen TA.JAMA.2003;290:199-206.Ford ES et al.Circulation.2003;107:2185-9.CDC.*Total-C 200 mg/dL BP 140/90 mm Hg FBG 126 mg/dLVBWGAdapted from Pepine CJ.Am J Cardiol.2001;88(suppl):5K-9K.Development an

2、d progression of CVDRisk factors Oxidative stressFunctional alterationsStructural alterationsClinical sequelaeAge,gender,smoking,inactivity,obesity,cholesterol,BP,glucoseGenetic factors Endothelial function EPCsEPCs=endothelial progenitor cellsVBWGObesityHypertensionDiabetesSTROKE/MIGENESGENESENVIRO

3、NMENTInadequateMedical CareGENESInactivity Diet Psychosocial Stress CultureGenetics augment effects of environmental risk factorsVBWGCardiovascular risk factors,adults 5564 yearsPrevalence(%)HypertensionObesityHigh cholesterolOne or more risk factorsHypertensionObesityHigh cholesterolOne or more ris

4、k factorsMen020406080100Women1988199419992002CDC.VBWGJackson R et al.Lancet.2005;365:434-41.Synergistic interaction of traditional multiple risk factors on CVD risk0Reference5-year CVD risk per 100 peopleTC=270 mg/dLSmokerHDL=39 mg/dLMaleDiabetes60 yearsof age102030405044%33%24%18%12%6%3%110SBP(mm H

5、g)1201301401501601701801%TC=total cholesterolAdditive risk factorsVBWG Obesity decreases life expectancy regardless of smoking Peeters A et al.Ann Intern Med 2003;138:24-32.Obesity and smoking risks are equivalentFemale nonsmokersFemale smokers0102030401.00.80.60.40.20.0ProportionaliveFollow-up(year

6、s)BMI 18.524.9 kg/m2BMI 2529.9 kg/m2BMI 30 kg/m20102030401.00.80.60.40.20.0Follow-up(years)VBWGDecline in smoking vs rise in obesity:A trade-off?Gruber J and Frakes M.J Health Econ.Published online ahead of print.Proportionof population1970Year19741978198219861990199419982002Obesity rateSmoking rate

7、0.350.30.250.20.150.10.0500.4VBWGDevelopment and progression of CVDAdapted from Pepine CJ.Am J Cardiol.2001;88(suppl):5K-9K.Risk factorsFunctional alterationsStructural alterationsClinical sequelaeEmerging biomarkers Oxidative stress Endothelial function EPCsEPCs=endothelial progenitor cellsVBWGTrad

8、itional CVD risk factors Family history Older age Male gender Smoking Physical inactivity Overweight/obesity Total-C/LDL-C/HDL-C/TG BP GlucoseAdapted from Stampfer MJ et al.Circulation.2004;109(suppl):IV3-IV5.VBWGSelected emerging biomarkers Adapted from Stampfer MJ et al.Circulation.2004;109(suppl)

9、:IV3-IV5.Lipids Lp(a)apoA/apoB Particle size/densityInflammation CRPSAA IL-6IL-18 TNFAdhesion mols Lp-PLA2 CD40L CSFHemostasis/Thrombosis HomocysteinetPA/PAI-1 TAFIFibrinogen D-dimerCSF=colony-stimulating factorOxidation Ox-LDL MPOGlutathioneAsp299Gly polymorphism in TLR4 geneMCP-1 2578G alleleCX3CR

10、1 chemokine receptorpolymorphism V249I16Gly variant of 2-adrenergicreceptor260T/T CD14 allele117 Thr/Thr variant of CSFLIGHTGeneticMPO=myeloperoxidaseTAFI=thrombin activatable fibrinolysis inhibitorVBWGLDL infiltration triggers inflammatory responseHansson GK.N Engl J Med.2005;352:1685-95.Coronaryar

11、teryActivationUptakeModificationRetentionLDLEndotheliumAccumulation of cholesterolMacrophageVBWGRole of ox-LDL in macrophage recruitmentHansson GK.N Engl J Med.2005;352:1685-95.MigrationCoronaryarteryAdhesionDifferentiationInflammation.tissue damageToll-likereceptorEndotheliumMonocyteEndotoxins,heat

12、-shock proteins,oxidized LDL,othersInflammatory cytokines,chemokines,proteases,radicalsMacrophageVBWGHypertension increases atherogenic lipoprotein content of arterial vessel wallsSposito AC.Eur Heart J Suppl.2004;6(suppl G):G8-G12.BPAtherogenicVLDL,VLDL-R,IDL,LDLIntima-Enhanced LP penetrationmedia

13、LP retention Pressure-induced distension StretchingIntima-mediaPressure-drivenconvectionLP=lipoproteinVBWGAT1 and LOX-1 receptor cross-talk promotes adhesion molecule expression Adapted from Singh BM and Mehta JL.Arch Intern Med.2003;163:1296-304.Interaction between RAAS and dyslipidemiaGrowth Facto

14、rsLOX-1FibroblastsAngiotensin IIOx-LDLLDLAT1RSmooth Muscle CellsMonocyte adhesionECNOOxygen*SRs Angiotensin II LDL Oxidation Cytokines Platelet Aggregation Monocyte AdhesionEC=endothelial cellSRs=scavenger receptorsVBWGLipoprotein-associated phospholipase A2(Lp-PLA2)Macphee CH et al.Curr Opin Lipido

15、l.2005;16:442-6.Produced by inflammatory cellsHydrolyzes oxidized phospholipids to generate proinflammatory molecules Lysophosphatidylcholine Oxidized fatty acidsUpregulated in atherosclerotic lesions where it co-localizes with macrophagesVBWGStudies demonstrating association of Lp-PLA2 with inciden

16、t CHDHR 1.23 (1.02-1.47)per 1 SD General population97 cases,837 controlsKoenig et alHR 1.97 (1.28-3.02)4th vs 1st quartileGeneral population418 cases,1820 controlsOei et alHR 1.78(1.33-2.38)tertile 3 vs tertile 1General population608 cases,740 controlsBallantyne et alRR 1.18(1.05-1.33)per 1 SD WOSCO

17、PS subgroupLDL-C 174232 mg/dL 580 cases,1160 controlsPackard et alFindings*SubjectsStudy*Adjusted relative risk(RR)or hazard ratio(HR)Packard CJ et al.N Engl J Med.2000;343:1148-55.Ballantyne CM et al.Circulation.2004;109:837-42.Koenig W et al.Circulation.2004;110:1903-8.Oei H-HS et al.Circulation.2

18、005;111:570-5.VBWGHill JM et al.N Engl J Med.2003;348:593-600.Flow-mediated dilationLowMidHighEPCs(colony-formingunits)0102030P 0.001N=45 healthy males,mean age 50.3 y,no CVDEPC number/function correlates with endothelial functionEPCs=endothelial progenitor cells VBWGWerner N et al.N Engl J Med.2005

19、;353:999-1007.N=507 males with CAD,mean age 66 yEPC number has prognostic importance1.000.980.960.940.920.900100200300 365Group 3(high EPC level)Group 2(medium EPC level)Group 1(low EPC level)0Follow-up(days)Event-freesurvival(CV mortality)EPC=endothelial progenitor cell P=0.01VBWGArterial stiffness

20、:Cause and consequence of atherosclerosisAdapted from Dart AM and Kingwell BA.J Am Coll Cardiol.2001;37:975-84.Pulsepressure Central wavereflection Large arterystiffnessAtherosclerosisEndothelial damage&mechanical fatigue SympatheticmodulationVBWGCorrelation between number of risk factors and arteri

21、al distensibilityUrbina EM et al.Am J Hypertens.2005;18:767-71.N=803,mean age 30 y Brachial artery distensibility occurs long before clinical manifestations of CVD appear5.5677.5031426.55Number of CV risk factorsBrachialarterydistensibility(%/mm Hg)Linear trendP 0.0001Bogalusa Heart StudyVBWGHerring

22、ton DM et al.Circulation.2004;110:432-7.MRI resultsQuartile of abdominal aorta wall thickeningN=256Thigh arterial compliance*Peripheral arterial stiffness is associated with subclinical atherosclerosisQ150Q2Q4403020100Q3Brachial pulse pressureP 0.0001 for trend*Maximum volume changeX 50VBWGLiao JK.A

23、m J Cardiol.2005;96(suppl 1):24F-33F.MMPs=matrix metalloproteinases Platelet activation Coagulation Endothelial progenitor cells Effects on collagen MMPs AT1 receptor VSMC proliferation Endothelin Macrophages Inflammation Immunomodulation Endothelial function Reactive oxygen species NO bioactivityPl

24、eiotropic effects of statinsStatinsVBWGHigh-dose statin treatment reduces Ox-LDL markersTsimikas S et al.Circulation.2004;110:1406-12.OxPL=oxidized phospholipidsIC-IgG,-IgM=immune complexes with IgG and IgM,respectivelyMyocardial Ischemia Reduction with Aggressive Cholesterol Lowering MIRACL study s

25、ubgroup analysis,N=2341 with ACS,atorvastatin 80 mg for 16 weeksApoB-100AtorvastatinPlaceboTotal apoB-OxPLAtorvastatinPlaceboTotal apoB-IC IgGAtorvastatinPlaceboTotal apoB-IC IgMAtorvastatinPlacebo%change402002040Mean95%CI33.034.2,31.85.84.6,7.029.731.5,28.00.22.3,1.929.531.9,27.02.11.1,5.425.728.1,

26、23.313.29.3,17.3VBWGStatin treatment reduces Lp-PLA2 Tsimihodimos V et al.Arterioscler Thromb Vasc Biol.2002;22:306-11.Plasma Lp-PLA2 activity(nmol x mL-1 x min-1)*P 0.001 vs baselineAtorvastatin 20 mg,4 mosBaselineType IIA dyslipidemia(n=55)Type IIB dyslipidemia(n=21)87.162.2*73.542.3*204060801000V

27、BWGStatins increase circulating EPCsVasa M et al.Circulation.2001;103:2885-90.Liao JK.Am J Cardiol.2005;96(suppl):24F-33F.N=15 with CAD treated with atorvastatin 40 mg for 4 weeksPostulated mechanism:Activation of PI3-K/Akt pathway Endothelial NO synthase 700600500400300200100007142128n=13n=12n=14n=

28、12Treatment(days)EPCs(cells/mm2)*P 0.05 vs baseline*n=15VBWGIntensive lipid lowering improves arterial complianceN=22 with ISH treated with atorvastatin 80 mg for 3 monthsFerrier KE et al.J Am Coll Cardiol.2002;39:1020-5.P=0.03Placebo0.5Atorvastatin0.40.30.0Systemicarterialcompliance(mL/mm Hg)VBWGCo

29、mparative effects of statin and ezetimibe on EPCs and endogenous antioxidant systemN=20 with HF treated with simvastatin 10 mg or ezetimibe 10 mg for 4 weeksLandmesser U et al.Circulation.2005;111:2356-63.Number per high power field4503001500P 0.05Statin NSEzetimibe 1600P 0.05Statin NSEzetimibe Extr

30、acellular superoxide dismutaseEPCs(U x mL-1 x min-1)Endothelium-bound ecSOD activity1208040PreGroup:Pre=baselinePost=4 weeksPostPrePostPrePostPrePostVBWGPre-treated with statin before occlusionSimvastatinPost-treated with statin after occlusionSironi L et al.Arterioscler Thromb Vasc Biol.2003;23:322

31、-7.Occlusion of middle cerebral artery in ratsVehicle24 hrs48 hrs24 hrs48 hrsNeuroprotection with statins in stroke modelStatin effect accompanied by eNOS upregulation in cerebral blood vesselsIschemic areas indicated by arrowsVBWGPleiotropic effects of BP-lowering agentsLonn E et al.Eur Heart J Sup

32、pl.2003;5(suppl A):A43-A8.Wassman S and Nickenig G.Eur Heart J Suppl.2004;6(suppl H):H3-H9.Mason RP et al.Arterioscler Thromb Vasc Biol.2003;23:2155-63.ACEIs/ARBsCCBs Fibrinolysis Platelet aggregation Mononuclear cell migration Collagen matrix formation Endothelial function Oxidative stress Inflamma

33、tion Plaque stability Arterial compliance NO MMP activity VSMC proliferation Cholesterol depositionin membraneMMP=matrix metalloproteinaseAHTNagentsBothBP-loweringagentsVBWGMason RP et al.Am J Cardiol.2005;96(suppl):11F-23F.Human LDL incubated with O-hydroxy metabolite of atorvastatin(100 nmol/L),lo

34、vastatin(100 nmol/L),and amlodipine(2.5 mol/L)TBARS=thiobarbituric acid-reactive substances*P 0.0001 vs vehicle treatmentStatin metabolite and CCB show additive antioxidant effectAtorvastatin metabolite*50Amlodipine+LovastatinAmlodipine+Atorvastatinmetabolite*403020100Inhibition ofTBARSformation(%)V

35、BWGFogari R et al.Am J Hypertens.2004;17:823-7.*P 0.05 vs placebo P 0.01 vs placeboN=45 with hypertension,placebo-controlled,crossover trialAdditive effects of statin+CCB on fibrinolytic balanceAtorvastatin 20 mgAmlodipine5 mgAtorvastatin+20 mgAmlodipine5 mgChange from baseline PAI-1(U/mL)t-PA(U/mL)

36、9.90.510.20.080.170.26P 0.05*t-PA/PAI-1 ratio0.045 0.030.06VBWGBeneficial effect of statin+ACEI on endothelial function01234567Koh KK et al.Hypertension.2004;44:180-5.Flow-mediateddilation(%)PL=placebo Ram=ramipril 10 mg Sim=simvastatin 20 mgN=50 with dyslipidemia,placebo-controlled,crossover trialB

37、aseline 1Sim+PLBaseline 2Sim+Ram4.816.026.58P 0.0014.56VBWGApproaches to CVD preventionLipidmodificationLifestyle interventionBPloweringGlucose loweringVBWGLifestyle changes reduce need for drug therapyLifestyle change goalsWeight reduction of 7%initial body weight via low-fat,low-calorie dietModera

38、te-intensity physical activity 150 min/week LifestyleMetforminPlacebo16%16%12%Lipid-lowering agents required31%32%23%BP-lowering agents requiredDiabetes Prevention Program Research Group.Diabetes Care.2005;28:888-94.*P 0.001 vs other groups N=3234 with IGT randomized to intensive lifestyle change,me

39、tformin 850 mg 2x/d,or placeboAt 3 years*VBWG 30 minutes of moderate physical activity 5-7 days/week 30 minutes of moderately intense exercise every day 60 min to prevent weight gain5 servings/day 9 servings/day2000 Report 2005 ReportHHS/USDA.www.healthierus.gov/dietaryguidelines.ExerciseFruits and

40、vegetablesNew lifestyle guidelines:More exercise,fruits and vegetablesVBWGExercise reduces CV and all-cause mortalityFang J et al.Am J Hypertens.2005;18:751-8.N=9791,moderate exercise vs little or no exercise NHANES I Epidemiological Follow-up Survey(1971-1992)0.750.760.79All-cause deathCV deathAll-

41、cause deathPrehypertensionCV deathHypertensionHazard ratio1.51.00.5Normal BP02.0All-cause deathCV death0.790.880.84HRFavors exerciseFavors no exerciseVBWGParikh P et al.J Am Coll Cardiol.2005;45:1379-87.Trichopoulou A et al.BMJ.2005;330:991-7.Knoops KTB et al.JAMA.2004;292:1433-9.2005European Prospe

42、ctive Investigation into Cancer and Nutritionelderly cohort(N=74,607)*Blood levels of n-3 fatty acids inversely related to deathGreater adherence associated with lower mortality2002Nurses Health Study(N=84,688)2004The Healthy Aging:A Longitudinal Study in Europe(N=2339)2002Physicians Health Study(N=

43、20,551)*2003Cardiovascular Health Study(N=5,201)*2003European Prospective Investigation into Cancer and NutritionGreek cohort(N=22,043)Diet reduces mortality in primary prevention trials VBWGPotential cardioprotective mechanisms of dietary components Kris-Etherton PM et al.Circulation.2002;106:2747-

44、57.Verhaar MC et al.Arterioscler Thromb Vasc Biol.2002;22:6-13.Omega-3 fatty acids Antiarrhythmic Antithrombogenic Antiinflammatory Antihypertensive Improved endothelial functionFolic acid Antioxidant NO bioavailability Improved endothelial functionVBWGNon-pharmacologic interventions and BP reductio

45、nAdapted from Messerli FH et al.In:Griffin BP et al,eds.2004.Manual of Cardiovascular Medicine.2nd ed.Whelton SP et al.Ann Intern Med.2002;136:493-503.Cutler JA et al.Am J Clin Nutr.1997;65(suppl):643S-651S.Xin X et al.Hypertension.2001;38:1112-7.Whelton PK et al.JAMA.1997;277:1624-32.BP decrease(mm

46、 Hg)SBPDBP543210ExerciseLow salt dietAlcohol reductionPotassiumsupplementVBWGBenefit of multifactorial interventionsLipidmodificationLifestyle interventionBPloweringGlucose loweringVBWGKey findings from recent lipid-lowering trials Benefit in CVD and DM regardless of baseline LDL-CBenefit in high-ri

47、sk HTN regardless of baseline LDL-CBenefit in DM Benefit of intensive vsmoderate lipid loweringin stable CADNeutral effect in HTN with mild lipid lowering Early and late benefit of intensive vs moderate lipid lowering in ACSPrimary preventionSecondary prevention(ACS)Secondary prevention(stable CAD)N

48、eutral effect in ESRD Late benefit of intensive vs moderate lipid lowering in ACS Benefit of intensive vs moderate lipid lowering in stable CADVBWGPROVE IT-TIMI 22:Assessment of intensive lipid lowering in ACSCannon CP et al.N Engl J Med.2004;350:1495-504.Design:4162 patients with ACS randomized to

49、atorvastatin 80 mgor pravastatin 40 mgFollow-up:2 yearsPrimary outcome:All-cause death,MI,hospitalization for UA,revascularization,strokePRavastatin Or AtorVastatin Evaluation and Infection TherapyThrombolysis In Myocardial Infarction 22VBWGPROVE IT-TIMI 22:Early benefit with intensive lipid lowerin

50、gRay KK and Cannon CP Am J Cardiol.2005;96(suppl):54F-60F.Adapted from Cannon CP et al.N Engl J Med.2004;350:1495-504.30203691230100151821242740 mg Pravastatin80 mg AtorvastatinP=0.03 at 4 mosP=0.005Follow-up(months)Death or major CV event(%)0N=4162 with ACSPRavastatin Or AtorVastatin Evaluation and