1、,Epidemiology of Inflammatory Markers and CHD: Evidence for High-Sensitivity C-Reactive Protein Paul M. Ridker, MD, MPH,Beyond Cholesterol: Predicting Cardiovascular Risk In the 21st Century,Cardiovascular Risk,Total Cholesterol Distribution: CHD vs Non-CHD Population,Castelli WP. Atherosclerosis. 1
2、996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science.,35% of CHD Occurs in People with TC200 mg/dL,150,200,Total Cholesterol (mg/dL),250,300,No CHD,CHD,Framingham Heart Study26-Year Follow-up,Inflammation and Atherosclerosis,Inflammation may determine plaque stability- Unstable
3、 plaques have increased leukocytic infiltrates- T cells, macrophages predominate rupture sites- Cytokines and metalloproteinases influence both stability and degradation of the fibrous cap Lipid lowering may reduce plaque inflammation- Decreased macrophage number- Decreased expression of collagenoly
4、tic enzymes (MMP-1)- Increased interstitial collagen- Decreased expression of E-selectin- Reduced calcium deposition,Libby P. Circulation 1995;91:2844-2850. Ross R. N Engl J Med 1999;340:115-126.,Is there clinical evidence that inflammatory markers predict future coronary events and provide addition
5、al predictive information beyond traditional risk factors?,hs-CRP and Risk of Future MI in Apparently Healthy Men,Ridker PM et al. N Engl J Med 1997;336:973-979.,1 0.055,Relative Risk of MI,P = 0.03,Quartile of hs-CRP (range, mg/dL),2 0.0560.114,3 0.1150.210,4 0.211,P 0.001,P 0.001,P Trend 0.001,hs-
6、CRP and Risk of Future MI: Analysis Stratified by Smoking Status,Ridker PM et al. N Engl J Med 1997;336:973-979.,1,Relative Risk of Future MI,Quartile of CRP,2,3,4,All Patients,Nonsmokers,hs-CRP and Risk of Future MI: Analysis Stratified by Year of Follow-up,Ridker PM et al. N Engl J Med 1997;336:97
7、3-979. 1997 Massachusetts Medical Society. All rights reserved.,0 2,Relative Risk (per Quartile),Years of Study Follow-up,2 4,4 6,6+,hs-CRP and Risk of Future Stroke in Apparently Healthy Men,Ridker PM et al. N Engl J Med 1997;336:973-979.,1 0.055,Relative Risk of Ischemic Stroke,Quartile of hs-CRP
8、(range, mg/dL),2 0.0560.114,3 0.1150.210,4 0.211,P =0.02,P =0.02,P Trend 0.03,hs-CRP and Risk of Developing PVD in Apparently Healthy Men,Ridker PM et al. Circulation 1998;97:425-428. 1998 Lippincott Williams & Wilkins.,None,hs-CRP (mg/dL),Intermittent Claudication,Peripheral Artery Surgery,hs-CRP a
9、nd Risk of Future Cardiovascular Events in Apparently Healthy Women,Ridker PM et al. Circulation 1998;98:731-733.,1 0.15,Relative Risk,Quartile of hs-CRP (range, mg/dL),2 0.150.37,3 0.370.73,4 0.73,P Trend 0.002,Any Event,MI or Stroke,hs-CRP and Risk of Future Cardiovascular Events in Apparently Hea
10、lthy Women: Low-Risk Subgroups,Ridker PM et al. Circulation 1998;98:731-733.,1 0.15,Relative Risk,Quartile of hs-CRP (range, mg/dL),2 0.150.37,3 0.370.73,4 0.73,No hypertension No hyperlipidemia No current smoking No diabetes No family history,hs-CRP and Coronary Heart Disease in Initially Healthy M
11、en: MONICAAugsburg Cohort,Koenig W et al. Circulation 1999;99:237-242.,1 0.6,Rate Ratio (Age Adjusted),Quartile of CRP (mg/dL),2 0.61.1,3 1.12.2,4 2.24.5,5 4.5,hs-CRP as a Risk Factor for Future CVD,1.0 2.0 3.0 4.0 5.0 6.0,Relative Risk (upper vs lower quartile),CHD Death MI Stroke CHD PVD CVD CHD C
12、HD CHD CHD,0,MRFIT (Kuller 1996) PHS (Ridker 1997) PHS (Ridker 1997) CHS/RHPP (Tracy 1997) PHS (Ridker 1998) WHS (Ridker 1998, 2000) MONICA (Koenig 1999) Helsinki (Roivainen 2000) Caerphilly(Mendall 2000) Britain (Danesh 2000),hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining R
13、isk of First MI,Ridker PM et al. Circulation 1998;97:2007-2011. 1998 Lippincott Williams & Wilkins.,Adjusted Relative Risk,CRP 75th percentile,TC 75th percentile,+,+,+,+,P = 0.02,P = 0.001,P = 0.002,hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI,Ridker PM et al. Circ
14、ulation 1998;97:2007-2011. 1998 Lippincott Williams & Wilkins.,Total Cholesterol:HDL Ratio,hs-CRP,Quartile of TC: HDL-C,Quartile of hs-CRP,hs-CRP, Lipids, and Risk of Future Coronary Events: Womens Health Study (WHS),Ridker PM et al. N Engl J Med 2000;342:836-843.,Relative Risks for First MI for Bas
15、eline sICAM-1 260 ng/dL,Ridker PM et al. Lancet 1998;351:88-92. 1998 Reprinted with permission from Elsevier Science.,Years of Study Follow-up,01,3 2 1 0,12,24,48,Relative Risk,Predictivity of Interleukin-6 on CV Risk in Women,Ridker PM et al. N Engl J Med 2000;342:836-843. 2000 Massachusetts Medica
16、l Society. All rights reserved.,4 3 2 1 0,High,Medium,Low,High,Medium,Low,Interleukin-6,Total cholesterol,Plasma Concentration of TNF- and Risk of Recurrent Coronary Events,Ridker PM et al. Circulation 2000;101:2149-2153. 2000 Lippincott Williams & Wilkins.,2.5 2.0 1.5 1.0,02.47 (1st50th),Relative R
17、isk,TNF- Concentration, pg/mL (percentile of control distribution),2.483.05 (51st75th),3.064.17 (76th95th),4.18+ (95th),Risk Factors for Future Cardiovascular Events: WHS,Relative Risk of Future Cardiovascular Events,0,Ridker PM et al. N Engl J Med 2000;342:836-843.,Lipoprotein(a)HomocysteineIL-6TCL
18、DL-CsICAM-1SAAApo BTC:HDL-Chs-CRPhs-CRP + TC:HDL-C,1.0,2.0,4.0,6.0,Predictive Value of CRP and Other Inflammatory Markers: LDL 130 mg/dL,Ridker PM et al. N Engl J Med 2000;342:836-843.,4 3 2 1,1,Relative Risk of Future Coronary Events,Quartile of Inflammatory Marker,hs-CRP,2,3,4,SAA,IL-6,sICAM-1,Pot
19、ential Mechanisms Linking CRP to Atherothrombosis,Confounding by cigarette consumption Innocent bystander - Acute phase response Cytokine surrogate - IL-6, TNF-, IL-1 Direct effects of CRP - Innate immunity - Complement activation - CAM induction Prior infection - Chlamydia, H pylori, CMV,Marker for
20、 subclinical atherosclerosis - EBCT / IMT / ABI Marker for insulin resistance/ obesity Marker for endothelial dysfunction Marker for dysmetabolic syndrome Marker for plaque vulnerability,Evaluating Novel Risk Factors for CAD,Consistency of prospective data Strength of association Independence of ass
21、ociation Improve predictive value Standardized measure,Low variability High reproducibility Biologic plausibility Low cost Modifiable,CRP vs hs-CRP,CRP is an acute-phase protein produced by the liver in response to cytokine production (IL-6, IL-1, tumor necrosis factor) during tissue injury, inflamm
22、ation, or infection. Standard CRP tests determine levels which are increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range High-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels pr
23、oven to predict future cardiovascular events.,hs-CRP: Automated Commercial Latex-Enhanced Assay (Dade) vs Validated in-House ELISA,5 4 3 2 1 0 -1 -2 -3,Dade hs-CRP (Latex, Inmg/L),hs-CRP (ELISA, Inmg/L) (In-house),Rifai N et al. Clin Chem 1999;45:2136-2141.,r = 0.93 P 0.001,Age-Adjusted Correlation
24、Coefficients for hs-CRP Levels and Lipid Parameters over a 5-Year Follow-up Period,Ridker PM et al. Circulation 1999;100:230-235.,Population Distribution of hs-CRP in Apparently Healthy American Men and Women,Ridker PM et al. Circulation. In press.,Biomarkers for Venous and Arterial Thrombosis,Biomarkers for Venous and Arterial Thrombosis (contd),Assessment of the Clinical Utility of Novel Markers of Cardiovascular Risk,Ridker PM et al. Ann Intern Med 1999;130:933-937.,
