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Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Cardiology

The 2 nd Vulnerable Patient Satellite Symposium Towards a National Screening Program New Orleans, LA, March 6 th , 2004. CRP, Lp-PLA 2 , and Other Serum Markers of Disease and Vulnerability. Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Cardiology

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Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Cardiology

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  1. The 2nd Vulnerable Patient Satellite Symposium Towards a National Screening ProgramNew Orleans, LA, March 6th, 2004 CRP, Lp-PLA2 , and Other Serum Markers of Disease and Vulnerability Wolfgang Koenig, MD, FESC, FACC Dept. of Internal Medicine II - Cardiology University of Ulm Medical Center Ulm, Germany

  2. Low-Risk Intermediate-Risk High-Risk (~35 % of Pts.) (~40% of Pts.) (~25% of Pts.) <6 (10) % 6 (10) -19 % ≥ 20 % over 10 years Identity Test Positive Test Negative 0.5 0.4 0.3 0.2 0.1 0.0 0.05 0.1 0.15 0.2 CHD Risk Assessment in Asymptomatic Patients: Selective Use of Noninvasive Testing Modification of Probability Estimates of CHD by Non-invasive Testing • Assessment by multivariable statistical models: e.g. Framingham Risk Score or PROCAM Score • Clear guidelines for high or low risk subjects, but not so for those at intermediate risk Post-test Probability of CHD Event in 10 Yrs Pre-test Probability of CHD Event in 10 Yrs modified after Greenland et al. Circulation 2001;104:1863-1867

  3. Acute Phase Reactants Investigated Prospectively in Epidemiological Studies * ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor; CIC, circulating immune complexes; Lp-PLA2 lipoprotein-associated phospholipase A2 mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24

  4. CRP as a Risk Factor for Future CVD –Results from Population-Based Studies Kuller MRFIT1996 CHD death Ridker PHS1997 MI Ridker PHS1997 Stroke Tracy CHS/RHPP1997 CHD Ridker PHS1998,2001 PAD Ridker WHS 1998,2000,2002 CVD Koenig MONICA1999 CHD Roivainen HELSINKI 2000 CHD Mendall CAERPHILLY 2000 CHD Danesh BRITAIN 2000 CHD Gussekloo LEIDEN2001 Fatal Stroke Lowe SPEEDWELL2001 CHD Packard WOSCOPS2001 CV Events Ridker AFCAPS2001 CV Events Rost FHS2001 Stroke Pradhan WHI2002 MI, CVD death Albert PHS 2002 Sudden Death Sakkinen HHS 2002 MI 0 1.0 2.0 3.0 4.0 5.0 6.0 Relative Risk (upper versus lower quartile) Ridker PM. Circulation 2003;107:363-369

  5. Variable 2 (>0.49- 1.08) 3 (>1.08- 2.09) 4 (>2.09- 4.19) 5 (>4.19) P-Value Area under ROC Curve Quintile of CRP (mg/L) 1 (0.49) Crude RR 1.0 1.8 2.3 3.2 4.5 <0.001 0.64 Age-adjusted RR 1.0 1.5 1.8 2.5 3.6 <0.001 0.74 Risk-factor–adj. RR 1.0 1.4 1.6 2.0 2.3 <0.001 0.81 Quintile of LDL Cholesterol (mg/dL) 1 (97.6) 2 (>97.6 -115.4) 3 (>115.4- 132.2) 4 (>132.2- 153.9) 5 (>153.9) Crude RR 1.0 1.0 1.3 1.8 2.2 <0.001 0.60 Age-adjusted RR 1.0 0.9 1.1 1.5 1.7 <0.001 0.73 Risk-factor–adj. RR 1.0 0.9 1.1 1.3 1.5 <0.001 0.81 Relative Risk (RR) of a First Cardiovascular Event, According to CRP and LDL- C at Baseline (WHS) Ridker et al. N Engl J Med 2002;347:1557-1565

  6. 3 CRP mg/L CRP mg/L <1.0 <1.0 1.0-3.0 1.0-3.0 2 >3.0 >3.0 1 0 <130 130-160 <160 RR of Cardiovascular Disease According to Levels of CRP and the Estimated10-Year Risk and According to Levels of CRP and Categories of LDL-C (WHS) 25 20 15 Multivariable Relative Risk Multivariable Relative Risk 10 5 0 0-1 2-4 5-9 10 LDL Cholesterol (mg/dL) Framingham Estimate of 10-Year Risk (%) Ridker et al. N Engl J Med 2002;347:1557-1565

  7. AHA/CDC Recommendations for Clinical and Public Health Practice Class I: Should be performed Class II: Conflicting evidence/opinion a: Weight in favor of usefulness/efficacy b: Usefulness/efficacy less well established Class III: Should not be performed Laboratory Tests • Of current inflammatory markers identified, hs-CRP has the analyte & assay characteristics most conducive to use in practice(Class IIa, Level of Evidence B) • Other inflammatory markers should not be measured for determination of CV risk in addition to hs-CRP(Class III, Level of Evidence C) AHA/CDC Statement. Circulation 2003;107:499–511

  8. The Value of CRP in Cardiovascular Risk Prediction: The Rotterdam Study • Nested case-control study (157/500) within a population based cohort study of 7983 men and women >55 years • Multivariable RR (Q4-Q1) for CRP 1.2 (95% CI, 0.6-2.2) • Assessment of Framingham Risk Score w/o and with CRP • Assessment of AUC by ROC analysis * Indicated by age, age squared, sex; † Indicated by age, age squared, sex, current smoking, BMI, BP, DM, family hystory of early MI, TC, HDL; ‡ based on the Framingham risk function + LVH Van der Meer et al. Arch Intern Med 2003;163:1323-1328

  9. CRP mg/L <1.0 1.0 – 3.0 > 3.0 RR of CHD According to the Estimated 10-Yr Risk Alone and in Combination With CRP: MONICA Augsburg Cohort (N=3,435 Men, 45-74 Yrs; 191 Events, FU 6.6 Yrs) P=0.14 Population at risk 809 914 650 526 536 8 8 P=0.02 7 7 6 6 AIC 2776 AIC 2789 5 5 Multivariable Relative Risk 4 4 P=0.03 3 3 P=0.28 2 2 P=0.19 1 1 18 32 35 50 56 0 0 < 6 6-10 11-14 15-19 20 < 6 6-10 11-14 15-19 20 Framingham Estimate of 10-Year Risk (%) Koenig et al. Circulation (in press)

  10. Risk of a First Coronary Event by Cox Model Without and With CRP for the FRS With 3 and 5 Categories AIC, Akaike’s Information Criterion; ΔAIC, AIC (model without CRP) – AIC (model with CRP); AUC, Area under the curve Koenig et al. Circulation (in press)

  11. Elevated CRP concentrations and an elevated TC/HDL-C ratio were both independently related to incident CHD. The addition of CRP to a prediction model of TC/HDL-C or the FRS resulted in a better fit of the model containing CRP and significantly improved prediction of incident CHD for TC/HDL-C and the calculated FRS. The latter was particularly true for those at intermediate risk (10-20% over 10 years). Thus, CRP measurement modulates coronary risk and may therefore modify the physician`s interpretation of the patient`s risk status. However, these findings have to be replicated in other populations. MONICA Augsburg Cohort Study: Summary Koenig et al. Circulation (in press)

  12. Acute Phase Reactants Investigated Prospectively in Epidemiological Studies * ESR, erythrocyte sedimentation rate; PAI-1, plasminogen activator inhibitor-1; vWF, von Willebrand factor; CIC, circulating immune complexes; Lp-PLA2 lipoprotein-associated phospholipase A2 mod. after Koenig & Rosenson. Sem Vasc Med 2002;2:417-24

  13. IL-18 and Risk of CHD*: PRIME Combined Endpoint Coronary Death and MI 3 2 1 0 3 2 1 0 B B Relative Risk (95% CI) Relative Risk (95% CI) B B F F F F [pg/mL] [pg/mL] <160 160-235 >235 <160 160-235 >235 * In tertiles of IL-18 Blankenberg et al. Circulation 2003;108:2453-2459

  14. Phospholipases A2 and Atherosclerosis • Lipoprotein-associated phospholipase A2 (Lp-PLA2) Platelet-activating factor acetylhydrolase 50kDa, Ca-insensitive lipase Produced predominantly by macrophages/ monocytes, T-cells, and mast cells Not responsive to IL-1, IL-6, TNF- • Secretory phospholipase A2 (sPLA2) 14 kDa, Ca-dependent lipase Produced by arterial wall SMC and macrophages Increased by cytokines IL-1, IL-6, TNF-

  15. Generates lyso-PC during oxidation of LDL Lp-PLA2-dependent oxFFA are also bioactive human monocyte chemoattractants Anti-atherosclerotic effect of inhibitor demonstrated in WHHL rabbit Plasma levels correlate with CHD in patients? Theory: Lp-PLA2 Promotes Atherogenesis

  16. Lumen Intima Media Monocyte LDL Plaque Formation Cytokines Adhesion Molecules Lp-PLA2 Foam Cell Lyso-PC + OxFA Oxidized LDL Macrophage Role of Lp-PLA2 in Coronary Heart Disease

  17. WOSCOPS StudyDesign randomized, double blind, placebo controlled trial 6,595 men, aged 45 to 65 elevated LDL levels (range 174-232 mg/dL or 4.5-6.0 mM) no previous myocardial infarction (MI) mean follow-up of 5 years Study Results treatment with Pravastatin reduced risk of first time heart attack (by 31%) and death (by 22%) West of Scotland Coronary Prevention Study (WOSCOPS) Packard et al. N Engl J Med 2000;343:1148-1155

  18. Lp-PLA2 as a Novel Risk Factor in CHD:WOSCOPS Baseline samples (stored @ -70oC) Samples drawn from freezer plasma Cases 580 coronary events 4.9 years n=6,595 1,160 event free (randomly selected, but age, smoking matched) Controls Packard et al. N Engl J Med 2000;343:1148-1155

  19. CRP, Lp-PLA2 and CHD Risk: WOSCOPS Relative Risk (confidence interval) Model 1 2 3 1.27 (1.14 - 1.42) 1.21 (1.06 - 1.39) 1.13 (0.98 - 1.29) CRP 1.22 (1.09 - 1.37) 1.15 (1.02 - 1.31) 1.10 (0.97 - 1.25) WCC 1.19 (1.07 - 1.31) 1.04 (0.92 - 1.17) 1.02 (0.90 - 1.15) Fibrinogen 1.20 (1.08 - 1.34) 1.19 (1.07 - 1.33) 1.18 (1.05 - 1.33) Lp - PLA2 All risk factors univariate Inflam. markers Packard et al. N Engl J Med 2000;343:1148-1155

  20. 12,819 apparently healthy men and women free of CHD at ARIC visit 2 608 individuals with incident CHD between visit 2 and visit 4 (6- to 8-year follow-up), with 740 controls from a cohort random sample Lp-PLA2 : diaDexus PLAC™ test (Dada et al. Expert Re Mol Diagn 2002), dual monoclonal Ab immunoassay standardized to recombinant Lp-PLA2 hs-CRP: Denka Seiken asssay, which has been validated to Dade Behring method (Roberts et al. Clin Chem 2001) Lp-PLA2 and Risk of CHD: ARIC Methods: Patient Population and Assays Ballantyne et al. Circulation 2004;109:837-842

  21. Lp-PLA2 and Risk of CHD: ARIC Weighted-Adjusted* Means of Risk Factors * Adjusted for age, sex, and race Ballantyne et al. Circulation 2004;109:837-842

  22. Lp-PLA2 and Risk of CHD: ARIC CHD HRs (95% CI) by Lp-PLA2 Tertiles Lp-PLA2 Tertiles * *Lowest tertile (<310µg/L) is reference; †Adjusted for age, sex, and race; ‡ Also adjusted for smoking status, SBP, LDL-C, HDL-C, and diabetes; § Additionally adjusted for CRP Ballantyne et al. Circulation 2004;109:837-842

  23. Weighted-Correlation Between Lp-PLA2 and Other Risk Factors: ARIC Ballantyne et al. Circulation 2004;109:837-842

  24. 3 2 1 0 Lp-PLA2 and Risk of CHD: ARIC Association of Lp-PLA2 and hs-CRP with Incident CHD in Patients with Low LDL-C (<130mg/dL) 95% CI 1.47 - 5.94, P=0.002 2.95 0.99 Lp-PLA2 µg/L CHD Hazard Ratio High (≥ 422) Low-Med (< 422) 1.14 1.00 High (>3) Low-Med (≤3) hs-CRP, mg/L Ballantyne et al. Circulation 2004;109:837-842

  25. 934 men aged 45-64 years, participating in the first MONICA survey 1984/85 Exclusion of prevalent CHD Standardized assessment of cardiovascular risk factors Lp-PLA2 by diaDexus PLAC ™ test (enzyme immunoassay); CRP by a high-sensitivity immunoradiometric assay (Hutchinson et al. Clin Chem 2000) Endpoint determination according to the MONICA protocol (fatal and non-fatal MI and SCD) Lp-PLA2 and Risk of CHD:MONICA-Augsburg Cohort 1984-98 Koenig et al. (AHA 2003)

  26. Age-adjusted Baseline Characteristics of 934 Men, Aged 45-64 Years Participating in the MONICA Augsburg Survey 1984/85 With Follow-up 1998 § geometric means calculated from the log-transformed distribution Koenig et al. (AHA 2003)

  27. Correlation Between Lp-PLA2, CRP and Other Cardiovascular Risk Factors: MONICA Koenig et al. (AHA 2003)

  28. MONICA: RR of CHD by a 1 SD Increase in CRP or Lp-PLA2 (separate models) *Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, education Koenig et al. (AHA 2003)

  29. MONICA: RR of CHD by a 1 SD Increase in Lp-PLA2 or CRP (same model) *Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, education Koenig et al. (AHA 2003)

  30. 6.0 N=447 N=176 N=203 N=108 4.0 CRP ≤ 3 mg/L Lp-PLA2 < 290.8 ng/mL CRP > 3 mg/L Lp-PLA2 < 290.8 ng/mL CRP ≤ 3 mg/L Lp-PLA2 ≥ 290.8 ng/mL CRP > 3 mg/L Lp-PLA2 ≥290.8 ng/mL 3.5 3.0 2.5 2.0 Ref. Ref. Ref. 1.5 1.0 0.5 0 Additive Effect of CRP and Lp-PLA2in Coronary Risk Prediction: MONICA Hazard Ratio (95% CI) Unadjusted Adjusted for age Multivariable DM, smoking adjustment* *Age, systolic BP, TC/HDL-ratio, physical activity, BMI, smoking, DM, alcohol intake, education Koenig et al. (AHA 2003)

  31. Lp-PLA2 was the strongest predictor/biomarker of coronary events, and was independent of traditional and emerging risk factors, including CRP in hyperlipidemic individuals (WOSCOPS) In particular, in individuals with low LDL-C (<130 mg/dL), levels of Lp-PLA2 were independentlyassociated with incident CHD in multivariable analysis including CRP (ARIC) Lp-PLA2 was predictive of coronary events in a population-based sample of initially healthy middle-aged men with moderately elevated total cholesterol levels during long-term FU of 14 years (MONICA cohort) In addition to CRP, Lp-PLA2 appears to be a promising marker of atherosclerotic complications and deserves further study Summary and Conclusions

  32. Diagnosing Risk: CRP and Lp-PLA2 Break

  33. Age- and gender- matched voluntary blood donors (n=479) Patients with clinically stable CAD aged 40-68 years (n=312) Case-Control Study: Population and Laboratory Methods Lp-PLA2 plasma levels - ELISA, diaDexus Inc. Complete lipid profile Inflammatory markers Hemostatic markers Khuseyinova et al. (unpublished data)

  34. Demographic Characteristics of Patients with Coronary Artery Disease (CAD) and Controls *mean  SD; †median and their interquartile ranges BMI = body mass index Khuseyinova et al. (submitted)

  35. Distribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (I) *mean  SD †median and their interquartile ranges Khuseyinova et al. (submitted)

  36. Distribution of Lipid Variables, Markers of Coagulation, Fibrinolysis and Inflammation (II) *mean  SD †median and their interquartile ranges Khuseyinova et al. (submitted)

  37. Spearman Rank Correlation Coefficients Between Traditional Risk Factors, Lipid Variables, Systemic Inflammatory and Hemostatic Markers, and Lp-PLA2 No significant effect for BMI, smoking, leukocytes, fibrinogen, IL-6, TNF-, PAI-1 activity, sCD14, Apo A1, Apo A2, Apo C2, Apo C3, Apo E Khuseyinova et al. (submitted)

  38. Odds Ratios (OR) of CAD Associated With Lp-PLA2 Levels After Various Adjustments * Adjustment for age and gender (matching variables) † Adjustment for matching variables and for BMI, smoking status, alcohol intake, school education years, hypertension, diabetes ‡ Model 2 and additional adjustment for TC and HDL cholesterol § Model 3 and additional adjustment for statin intake ¶ Additionally adjusted for CRP, fibrinogen, vWF, sICAM-1, plasma viscosity, plasminogen, D-Dimer Q = quartile Khuseyinova et al. (submitted)

  39. Endothelial cells Promotes endothelial dysfunction, upregulates adhesion molecules Monocytes Chemoattractant, stimulates cytokine production Macrophages Stimulates proliferation, inhibits migration, cytotoxic T-lymphocytes Chemoattractant, upregulates cytokine & CD40 ligand expression Smooth muscle cells Cytotoxic, upregulates growth factor expression Atherogenic Activities of Lyso-PC

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