多重心血管风险患者管理课件.ppt

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1、,New Frontiers in CVD Risk Management:Optimizing Outcomes in Patients with Multiple Cardiovascular Risks,多重心血管风险患者管理课件,US population at high risk,AHA. 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. .,*To

2、tal-C 200 mg/dL BP 140/90 mm Hg FBG 126 mg/dL,Diabetes,14.6 million diagnosed 6.2 million undiagnosed,Hypercholesterolemia*,106.9 million 94 million not treated,Patients with CHD/stroke: 18.4 million/yDirect: $105.7 billion/y Indirect: $93.2 billion/y Total cost: $198.9 billion/y,Hypertension,65 mil

3、lion 27 million not treated,US population at high riskAHA.,Adapted from Pepine CJ. Am J Cardiol. 2001;88(suppl):5K-9K.,Development and progression of CVD,Risk factors, Oxidative stress,Functional alterations,Structural alterations,Clinical sequelae,Age, gender, smoking, inactivity, obesity,cholester

4、ol, BP, glucose,Genetic factors, Endothelial function EPCs,EPCs = endothelial progenitor cells,Adapted from Pepine CJ. Am J,Obesity,Hypertension,Diabetes,STROKE / MI,GENES,GENES,ENVIRONMENT,InadequateMedical Care,GENES,Inactivity Diet Psychosocial Stress Culture,Genetics augment effects of environme

5、ntal risk factors,ObesityHypertensionDiabetesSTR,Cardiovascular risk factors, adults 5564 years,Prevalence (%),Hypertension,Obesity,High cholesterol,One or more risk factors,Hypertension,Obesity,High cholesterol,One or more risk factors,Men,0,20,40,60,80,100,Women,19881994,19992002,CDC. .,Cardiovasc

6、ular risk factors, a,Jackson R et al. Lancet. 2005;365:434-41.,Synergistic interaction of traditional multiple risk factors on CVD risk,0,Reference,5-year CVD risk per 100 people,TC = 270 mg/dL,Smoker,HDL = 39 mg/dL,Male,Diabetes,60 yearsof age,10,20,30,40,50,44%,33%,24%,18%,12%,6%,3%,110,SBP (mm Hg

7、),120,130,140,150,160,170,180,1%,TC = total cholesterol,Additive risk factors,Jackson R et al. Lancet. 2005;,Obesity decreases life expectancy regardless of smoking,Framingham Heart Study,Peeters A et al. Ann Intern Med 2003;138:24-32.,Obesity and smoking risks are equivalent,Female nonsmokers,Femal

8、e smokers,0,10,20,30,40,1.0,0.8,0.6,0.4,0.2,0.0,Proportionalive,Follow-up (years),BMI 18.524.9 kg/m2,BMI 2529.9 kg/m2,BMI 30 kg/m2,0,10,20,30,40,1.0,0.8,0.6,0.4,0.2,0.0,Follow-up (years),Obesity decreases life expec,Decline in smoking vs rise in obesity: A trade-off?,Gruber J and Frakes M. J Health

9、Econ. Published online ahead of print. .,Proportionof population,1970,Year,1974,1978,1982,1986,1990,1994,1998,2002,Obesity rate,Smoking rate,0.35,0.3,0.25,0.2,0.15,0.1,0.05,0,0.4,Decline in smoking vs rise in,Development and progression of CVD,Adapted from Pepine CJ. Am J Cardiol. 2001;88(suppl):5K-

10、9K.,Risk factors,Functional alterations,Structural alterations,Clinical sequelae,Emerging biomarkers, Oxidative stress, Endothelial function EPCs,EPCs = endothelial progenitor cells,Development and progression of,Traditional CVD risk factors,Family history Older age Male gender Smoking Physical inac

11、tivity Overweight/obesity Total-C/LDL-C/HDL-C/TG BP Glucose,Adapted from Stampfer MJ et al. Circulation. 2004;109(suppl):IV3-IV5.,Traditional CVD risk factors,Selected emerging biomarkers,Adapted from Stampfer MJ et al. Circulation. 2004;109(suppl):IV3-IV5.,Lipids Lp(a)apoA/apoB Particle size/densit

12、y,Inflammation CRPSAA IL-6IL-18 TNFAdhesion mols Lp-PLA2 CD40L CSF,Hemostasis/Thrombosis HomocysteinetPA/PAI-1 TAFIFibrinogen D-dimer,CSF = colony-stimulating factor,MPO = myeloperoxidase,TAFI = thrombin activatable fibrinolysis inhibitor,Selected emerging biomarkers,LDL infiltration triggers inflam

13、matory response,Hansson GK. N Engl J Med. 2005;352:1685-95.,Coronaryartery,Activation,Uptake,Modification,Retention,LDL,Endothelium,Accumulation of cholesterol,Macrophage,LDL infiltration triggers inf,Role of ox-LDL in macrophage recruitment,Hansson GK. N Engl J Med. 2005;352:1685-95.,Migration,Coro

14、naryartery,Adhesion,Differentiation,Inflammation. tissue damage,Toll-likereceptor,Endothelium,Monocyte,Endotoxins,heat-shock proteins, oxidized LDL, others,Inflammatory cytokines, chemokines, proteases,radicals,Macrophage,Role of ox-LDL in macrophage r,Hypertension increases atherogenic lipoprotein

15、content of arterial vessel walls,Sposito AC. Eur Heart J Suppl. 2004;6(suppl G):G8-G12.,BP,AtherogenicVLDL, VLDL-R,IDL, LDL,Intima- Enhanced LP penetrationmedia LP retention, Pressure-induced distension Stretching,Intima-media,Pressure-drivenconvection,LP = lipoprotein,Hypertension increases atherog

16、,AT1 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 dyslipidemia,Growth Factors,LOX-1,Fibroblasts,Angiotensin II,Ox-LDL,LDL,AT1R,Smooth Muscle Cells,Monocyte adhesion,EC,NO,Oxyge

17、n,*,*,*,*,*,*,*,*,*,*,*,*,*,Angiotensin II LDL Oxidation Cytokines Platelet Aggregation Monocyte Adhesion,EC = endothelial cell,SRs = scavenger receptors,AT1 and LOX-1 receptor cross-t,Lipoprotein-associated phospholipase A2 (Lp-PLA2),Macphee CH et al. Curr Opin Lipidol. 2005;16:442-6.,Produced by i

18、nflammatory cells,Hydrolyzes oxidized phospholipids to generate proinflammatory molecules Lysophosphatidylcholine Oxidized fatty acids,Upregulated in atherosclerotic lesions where it co-localizes with macrophages,Lipoprotein-associated phospho,Studies demonstrating association of Lp-PLA2 with incide

19、nt CHD,HR 1.23 (1.02-1.47) per 1 SD ,General population97 cases, 837 controls,Koenig et al,HR 1.97 (1.28-3.02)4th vs 1st quartile,General population418 cases, 1820 controls,Oei et al,HR 1.78 (1.33-2.38)tertile 3 vs tertile 1,General population608 cases, 740 controls,Ballantyne et al,RR 1.18 (1.05-1.

20、33) per 1 SD ,WOSCOPS subgroupLDL-C 174232 mg/dL 580 cases, 1160 controls,Packard et al,Findings*,Subjects,Study,*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:

21、1903-8.Oei H-HS et al. Circulation. 2005;111:570-5.,Studies demonstrating associat,Hill JM et al. N Engl J Med. 2003;348:593-600.,Flow-mediated dilation,L,o,w,M,i,d,H,i,g,h,EPCs(colony-formingunits),0,1,0,2,0,3,0,N = 45 healthy males, mean age 50.3 y, no CVD,EPC number/function correlates with endot

22、helial function,EPCs = endothelial progenitor cells,Hill JM et al. N Engl J Med. 2,Werner N et al. N Engl J Med. 2005;353:999-1007.,N = 507 males with CAD, mean age 66 y,EPC number has prognostic importance,1.00,0.98,0.96,0.94,0.92,0.90,0,100,200,300,365,Group 3 (high EPC level),Group 2 (medium EPC

23、level),Group 1 (low EPC level),0,Follow-up (days),Event-freesurvival(CV mortality),EPC = endothelial progenitor cell,P = 0.01,Werner N et al. N Engl J Med.,Arterial stiffness: Cause and consequence of atherosclerosis,Adapted from Dart AM and Kingwell BA. J Am Coll Cardiol. 2001;37:975-84.,Pulsepress

24、ure,Central wavereflection,Large arterystiffness,Atherosclerosis,Endothelial damage & mechanical fatigue,Sympatheticmodulation,Arterial stiffness: Cause and,Correlation between number of risk factors and arterial distensibility,Urbina EM et al. Am J Hypertens. 2005;18:767-71.,N = 803, mean age 30 y,

25、 Brachial artery distensibility occurs long before clinical manifestations of CVD appear,5.5,6,7,7.5,0,3,1,4,2,6.5,5,Number of CV risk factors,Brachialarterydistensibility(% / mm Hg),Linear trendP 0.0001,Bogalusa Heart Study,Correlation between number of,Herrington DM et al. Circulation. 2004;110:43

26、2-7.,MRI resultsQuartile of abdominal aorta wall thickening,N = 256,Thigh arterial compliance*,Peripheral arterial stiffness is associated with subclinical atherosclerosis,Q1,50,Q2,Q4,40,30,20,10,0,Q3,Brachial pulse pressure,P 0.0001 for trend,*Maximum volume change,X 50,Herrington DM et al. Circula

27、ti,Liao JK. Am 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 o

28、xygen species, NO bioactivity,Pleiotropic effects of statins,Statins,Liao JK. Am J Cardiol. 2005;96,High-dose statin treatment reduces Ox-LDL markers,Tsimikas S et al. Circulation. 2004;110:1406-12.,OxPL = oxidized phospholipidsIC-IgG, -IgM = immune complexes with IgG and IgM, respectivelyMyocardial

29、 Ischemia Reduction with Aggressive Cholesterol Lowering,MIRACL study subgroup analysis, N = 2341 with ACS, atorvastatin 80 mg for 16 weeks,ApoB-100,Atorvastatin,Placebo,Total apoB-OxPL,Atorvastatin,Placebo,Total apoB-IC IgG,Atorvastatin,Placebo,Total apoB-IC IgM,Atorvastatin,Placebo,% change,40,20,

30、0,20,40,Mean,95% CI,33.034.2, 31.8,5.84.6, 7.0,29.731.5, 28.0,0.22.3, 1.9,29.531.9, 27.0,2.11.1, 5.4,25.728.1, 23.3,13.29.3, 17.3,High-dose statin treatment red,Statin 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

31、 min-1),*P 0.001 vs baseline,Atorvastatin 20 mg, 4 mos,Baseline,Type IIA dyslipidemia(n = 55),Type IIB dyslipidemia(n = 21),87.1,62.2*,73.5,42.3*,20,40,60,80,100,0,Statin treatment reduces Lp-PL,Statins increase circulating EPCs,Vasa M et al. Circulation. 2001;103:2885-90.Liao JK. Am J Cardiol. 2005

32、;96(suppl):24F-33F.,N = 15 with CAD treated with atorvastatin 40 mg for 4 weeks,Postulated mechanism:Activation ofPI3-K/Akt pathwayEndothelial NO synthase,700,600,500,400,300,200,100,0,0,7,14,21,28,n = 13,n = 12,n = 14,n = 12,Treatment (days),EPCs(cells/mm2),*P 0.05 vs baseline,*,*,*,*,n = 15,Statin

33、s increase circulating E,Intensive lipid lowering improves arterial compliance,N = 22 with ISH treated with atorvastatin 80 mg for 3 months,Ferrier KE et al. J Am Coll Cardiol. 2002;39:1020-5.,P = 0.03,Placebo,0.5,Atorvastatin,0.4,0.3,0.0,Systemicarterialcompliance(mL/mm Hg),Intensive lipid lowering

34、 impro,Comparative effects of statin and ezetimibe on EPCs and endogenous antioxidant system,N = 20 with HF treated with simvastatin 10 mg or ezetimibe 10 mg for 4 weeks,Landmesser U et al. Circulation. 2005;111:2356-63.,Number per high power field,450,300,150,0,P 0.05,Statin,NS,Ezetimibe,160,0,P 0.

35、05,Statin,NS,Ezetimibe,Extracellular superoxide dismutase,EPCs,(U x mL-1 x min-1),Endothelium-bound ecSOD activity,120,80,40,Pre,Group:,Pre = baselinePost = 4 weeks,Post,Pre,Post,Pre,Post,Pre,Post,Comparative effects of statin,Pre-treated with statin before occlusion,Simvastatin,Post-treated with st

36、atin after occlusion,Sironi L et al. Arterioscler Thromb Vasc Biol. 2003;23:322-7.,Occlusion of middle cerebral artery in rats,Vehicle,24 hrs,48 hrs,24 hrs,48 hrs,Neuroprotection with statins in stroke model,Statin effect accompanied by eNOS upregulation in cerebral blood vessels,Ischemic areas indi

37、cated by arrows,Pre-treated with statin before,Pleiotropic effects of BP-lowering agents,Lonn E et al. Eur Heart J Suppl. 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/ARBs,CCBs, Fibrino

38、lysis, Platelet aggregation, Mononuclear cell migration, Collagen matrix formation, Endothelial function, Oxidative stress, Inflammation, Plaque stability, Arterial compliance, NO, MMP activity, VSMC proliferation, Cholesterol depositionin membrane,MMP = matrix metalloproteinase,AHTNagents,Both,BP-l

39、oweringagents,Pleiotropic effects of BP-lowe,Mason RP et al. Am J Cardiol. 2005;96(suppl):11F-23F.,Human LDL incubated with O-hydroxy metabolite of atorvastatin (100 nmol/L), lovastatin (100 nmol/L), and amlodipine (2.5 mol/L),TBARS = thiobarbituric acid-reactive substances*P 0.0001 vs vehicle treat

40、ment,Statin metabolite and CCB show additive antioxidant effect,Atorvastatin metabolite,*,50,Amlodipine+Lovastatin,Amlodipine+Atorvastatinmetabolite,*,40,30,20,10,0,Inhibition ofTBARSformation(%),Mason RP et al. Am J Cardiol.,Fogari R et al. Am J Hypertens. 2004;17:823-7.,*P 0.05 vs placebo P 0.01 v

41、s placebo,N = 45 with hypertension, placebo-controlled, crossover trial,Additive effects of statin + CCB on fibrinolytic balance,Change from baseline, PAI-1(U/mL), t-PA(U/mL),9.9,0.5,10.2,0.08,0.17,0.26,P 0.05,*,*,*,t-PA / PAI-1 ratio0.045 0.030.06,Fogari R et al. Am J Hypertens,Beneficial effect of

42、 statin + ACEI on endothelial function,0,1,2,3,4,5,6,7,Koh KK et al. Hypertension. 2004;44:180-5.,Flow-mediateddilation(%),PL = placebo Ram = ramipril 10 mg Sim = simvastatin 20 mg,N = 50 with dyslipidemia, placebo-controlled, crossover trial,Baseline 1,Sim + PL,Baseline 2,Sim + Ram,4.81,6.02,6.58,P

43、 0.001,4.56,Beneficial effect of statin +,Approaches to CVD prevention,Approaches to CVD preventionLi,Lifestyle changes reduce need for drug therapy,Lifestyle change goalsWeight reduction of 7% initial body weight via low-fat, low-calorie dietModerate-intensity physical activity 150 min/week,Lifesty

44、leMetforminPlacebo,16%,16%,12%,Lipid-lowering agents required,31%,32%,23%,BP-lowering agents required,Diabetes 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, metformin 850 mg 2x/d, or placebo,At 3

45、 years,*,*,Lifestyle changes reduce need,2000 Report 2005 Report,HHS/USDA. www.healthierus.gov/dietaryguidelines.,Exercise,Fruits and vegetables,New lifestyle guidelines: More exercise, fruits and vegetables,2000 Report,Exercise reduces CV and all-cause mortality,Fang J et al. Am J Hypertens. 2005;1

46、8:751-8.,N = 9791, moderate exercise vs little or no exercise NHANES I Epidemiological Follow-up Survey (1971-1992),0.75,0.76,0.79,All-cause death,CV death,All-cause death,Prehypertension,CV death,Hypertension,Hazard ratio,1.5,1.0,0.5,Normal BP,0,2.0,All-cause death,CV death,0.79,0.88,0.84,HR,Favors

47、 exercise,Favors no exercise,Exercise reduces CV and all-ca,Parikh 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 Prospective Investigation into Cancer and Nutritionelderly cohort (N = 74,607),*Blood levels

48、of n-3 fatty acids inversely related to deathGreater adherence associated with lower mortality,2002Nurses Health Study(N = 84,688),2004The Healthy Aging: A Longitudinal Study in Europe (N = 2339),2002Physicians Health Study(N = 20,551)*,2003Cardiovascular Health Study(N = 5,201)*,2003European Prospe

49、ctive Investigation into Cancer and NutritionGreek cohort (N = 22,043),Diet reduces mortality in primary prevention trials,Parikh P et al. J Am Coll Card,Potential cardioprotective mechanisms of dietary components,Kris-Etherton PM et al. Circulation. 2002;106:2747-57. Verhaar MC et al. Arterioscler

50、Thromb Vasc Biol. 2002;22:6-13.,Omega-3 fatty acidsAntiarrhythmicAntithrombogenicAntiinflammatory AntihypertensiveImproved endothelial function,Folic acidAntioxidantNO bioavailabilityImproved endothelial function,Potential cardioprotective mec,Non-pharmacologic interventions and BP reduction,Adapted