1. Slide Source: Lipids Online www.lipidsonline.org Plasma Concentration of TNF- and Risk of Recurrent Coronary Events 2.5 2.0 1.5 1.0 0–2.47 (1 st –50 th ) Relative Risk TNF- Concentration, pg/mL (percentile of control distribution) 2.48–3.05 (51 st –75 th ) 3.06–4.17 (76 th –95 th ) 4.18+ (>95 th )

2. Slide Source: Lipids Online www.lipidsonline.org Predictive Value of CRP and Other Inflammatory Markers: LDL <130 mg/dL 43214321 1 Relative Risk of Future Coronary Events Quartile of Inflammatory Marker hs-CRP 234 SAA IL-6 sICAM-1

3. Slide Source: Lipids Online www.lipidsonline.org Age-Adjusted Correlation Coefficients for hs-CRP Levels and Lipid Parameters over a 5-Year Follow-up Period ParameterrP hs-CRP0.600.001 Total Cholesterol0.370.001 LDL-C0.320.001 HDL-C0.740.001 Triglycerides0.490.001

4. Slide Source: Lipids Online www.lipidsonline.org Population Distribution of hs-CRP in Apparently Healthy American Men and Women QuintileRange (mg/dL)Risk Estimate 10.01–0.069Low 20.07–0.11Mild 30.12–0.19Moderate 40.20–0.38High 50.39–1.50Highest

5. Slide Source: Lipids Online www.lipidsonline.org Assessment of the Clinical Utility of Novel Markers of Cardiovascular Risk Marker Assay Conditions Standardized? Prospective Studies Consistent? Additive to TC and HDL- C? Lp(a)–+/– Homocysteine++/– tPA and PAI-1+/–+ Fibrinogen+/–++ hs-CRP+++

6. Slide Source: Lipids Online www.lipidsonline.org Is there clinical evidence that inflammation can be modified by preventive therapies?

7. Slide Source: Lipids Online www.lipidsonline.org hs-CRP, Aspirin, and Risks of Future MI: Physicians' Health Study Quartile of C-Reactive Protein 1234 Aspirin Placebo Relative Risk of MI

8. Slide Source: Lipids Online www.lipidsonline.org Low-Dose Aspirin Reduces Thromboxane B 2 but not CRP Serum CRP (% of Baseline) 140 120 100 80 60 40 20 0 Placebo (n=11) 140 120 100 80 60 40 20 0 Serum Thromboxane (% of Baseline) ASA 81 mg qd (n=13) Placebo (n=11) ASA 81 mg qd (n=13) 28 Days 31 Days * p<0.001 *

9. Slide Source: Lipids Online www.lipidsonline.org Reduction of Proinflammatory Cytokines and CRP with Higher-Dose Aspirin in Patients with Chronic Stable Angina Placebo (n=40) ASA 300 mg (n=40) P MCSF, pg/mL 991 (459-1476) 843 (501-1357) <0.05 IL-6, pg/mL 3.5 (3.2-4.6) 2.9 (2.5-3.4) <0.05 CRP, mg/mL1.4 (0.54-4.05) 1 (0.5-3.1) <0.05

10. Slide Source: Lipids Online www.lipidsonline.org Elevated CRP Levels in Obesity: NHANES 1988-1994 Normal Percent with CRP 0.22 mg/dL OverweightObese

11. Slide Source: Lipids Online www.lipidsonline.org Effects of Weight Loss on CRP Concentrations in Obese Healthy Women 83 women (mean BMI 33.8, range 28.2-43.8 kg/m 2 ) placed on very low fat, energy-restricted diet (6.0 MJ, 15% fat) for 12 weeks Baseline CRP positively associated with BMI (r=0.281, p=0.01) CRP reduced by 26% (p<0.001) Average weight loss 7.9 kg, associated with change in CRP Change in CRP correlated with change in TC (r=0.240, p=0.03) but not changes in LDL-C, HDL-C, or glucose At 12 weeks, CRP concentration highly correlated with TG (r=0.287, p=0.009), but not with other lipids or glucose

12. Slide Source: Lipids Online www.lipidsonline.org Effects of Weight Loss in Obese Women on IL-6, TNF-, and CRP pg/mL mg/L IL-6 TNF- CRP Before diet After very low calorie diet (mean BMI reduction 2.1 kg/m 2 ; mean reduction in body fat mass 4 kg) p=0.05 p=0.6 p=0.14

13. Slide Source: Lipids Online www.lipidsonline.org Effects of n-3 Fatty Acid Therapy on Lipids and sCAMs Percent Change TGTCsICAM-1sE-selectin All Patients DM Patients * * * * * p<0.05

14. Slide Source: Lipids Online www.lipidsonline.org Effect of HRT on hs-CRP: the PEPI Study 3.0 2.0 1.0 hs-CRP (mg/dL) Months 01236 CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE Placebo

15. Slide Source: Lipids Online www.lipidsonline.org hs-CRP and Relative Risk of Recurrent Coronary Events: CARE 1 <0.12 Relative Risk Quintile of hs-CRP (range, mg/dL) P=0.02 2 0.12-0.20 3 0.21-0.37 4 0.38-0.66 5 >0.66 P Trend = 0.044

16. Slide Source: Lipids Online www.lipidsonline.org Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: CARE Pravastatin Relative Risk Inflammation Absent P Trend = 0.005 PlaceboPravastatinPlacebo Inflammation Present

17. Slide Source: Lipids Online www.lipidsonline.org Mean Baseline (mg/dL) Inflammation absent Inflammation present 250 200 150 100 50 0 TCLDL-CHDL-CTG Baseline Lipid Levels in Patients with and without Inflammation: CARE

18. Slide Source: Lipids Online www.lipidsonline.org Long-Term Effect of Pravastatin on hs-CRP: CARE Placebo and Pravastatin Groups Pravastatin Placebo Median hs-CRP Concentration (mg/dL) –21.6% (P=0.007) 0.25 0.24 0.23 0.22 0.21 0.20 0.19 0.18 Baseline5 Years

19. Slide Source: Lipids Online www.lipidsonline.org Change in hs-CRP Concentration Over 5 Years: CARE Subgroup Analyses Change in hs-CRP over 5 Years (mg/dL) HDL-C <35 mg/dL All Subjects Pravastatin Age >60 years Age <60 years BMI >27 kg/m 2 BMI <27 kg/m 2 Placebo Smokers Nonsmokers SBP >128 mm Hg SBP <128 mm Hg DBP >78 mm Hg DBP <78 mm Hg LDL-C >138 mg/dL LDL-C <138 mg/dL HDL-C >35 mg/dL Triglycerides >160 mg/dL Triglycerides <160 mg/dL -0.2-0.100.10.20.3 Click for larger picture

20. Slide Source: Lipids Online www.lipidsonline.org Change in hs-CRP according to Observed Changes in LDL-C: CARE Placebo and Pravastatin Groups Change in LDL-C (mg/dL) Increase 0–25 Decrease 0–25 Decrease 25–50 Decrease 50–75 Decrease >75 Change in hs-CRP (mg/dL) Placebo Pravastatin -0.15 -0.10 -0.05 0 0.05 0.10 0.15

21. Slide Source: Lipids Online www.lipidsonline.org CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study GroupLovastatinPlaceboNNT Low LDL-C/low CRP0.0250.022_ Low LDL-C/high CRP0.0290.05148 High LDL-C/low CRP0.0200.05033 High LDL-C/high CRP0.0380.05558 Median LDL-C = 149.1 mg/dL Median CRP = 0.16 mg/dL Event Rate

22. Slide Source: Lipids Online www.lipidsonline.org Statin Therapy, Lipid Levels, CRP, and Survival Among Patients with Severe Coronary Artery Disease Statins CRP Tertiles Statins Low Mortality (%) No Statins CRP Tertiles No Statins MediumHighLowMediumHigh P Trend = 0.94 P Trend <0.0001

23. Slide Source: Lipids Online www.lipidsonline.org hs-CRP (mg/L) Effect of Statin Therapy on hs-CRP Levels at 6 Weeks 65432106543210 Baseline * ** Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) *p<0.025 vs. Baseline

24. Slide Source: Lipids Online www.lipidsonline.org Effect of Pravastatin on CRP Levels in Primary and Secondary Prevention: PRINCE Primary Prevention Change in CRP, % Secondary Prevention * * * ** 12 weeks vs. baseline 24 weeks vs. baseline 24 weeks ITT vs. placebo *p<.001 vs. baseline **p<.005 vs. baseline

25. Slide Source: Lipids Online www.lipidsonline.org Effect of Bezafibrate with and without Fluvastatin on Plasma Fibrinogen, PAI-1, and CRP in Patients with CAD and Mixed Hyperlipidemia Beza 400 mg/d Beza 400 mg/d + fluva 20 mg/d Beza 400 mg/d + fluva 40 mg/d Change at 24 weeks, % n: 81 FibrinogenPAI-1CRP 8074 707263838075 P<0.05 vs. baseline * * *

26. Slide Source: Lipids Online www.lipidsonline.org CRP in Combination with TC:HDL-C Ratio as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study GroupLovastatinPlaceboNNT Low TC:HDL-C/low CRP0.0240.025983 Low TC:HDL-C/high CRP0.0250.05043 High TC:HDL-C/low CRP0.0210.05035 High TC:HDL-C/high CRP0.0410.05762 Median TC:HDL-C = 5.96 Median CRP = 0.16 mg/dL Event Rate

27. Slide Source: Lipids Online www.lipidsonline.org Effect of Gemfibrozil and Ciprofibrate on Plasma Fibrinogen and CRP Levels in Patients with Primary Hypercholesterolemia Pretreatment12 Weeks * * Fibrinogen, g/L CRP, mg/L Gemfibrozil 600 mg bid (n=51) Ciprofibrate 100 mg/d (n=48) Gemfibrozil 600 mg bid (n=51) Ciprofibrate 100 mg/d (n=48) *p<0.005 vs. pretreatment level

28. Slide Source: Lipids Online www.lipidsonline.org hs-CRP: Potential Clinical Applications Adjunct to lipid screening in the detection of individuals at high risk for coronary artery disease Method to better target statin therapy in the setting of primary prevention Potential prognostic value in acute coronary syndromes Inflammation is likely to represent a new target for both the treatment and prevention of acute myocardial infarction

29. Slide Source: Lipids Online www.lipidsonline.org Summary Lifestyle modification and some pharmacotherapies (full-dose ASA, statins) lower hs-CRP Lipid-modifying therapies with oral estrogens and fibrates are not associated with reduction in hs-CRP Individuals with high levels of hs-CRP are at increased risk for CHD events and benefit from ASA and statins

30. Slide Source: Lipids Online www.lipidsonline.org Infection and CHD - is there a connection? Local or systemic infections resulting from gram negative bacteria such as Chlamydia pneumoniae and Helicobacter pylori, including cytomegalovirus (CMV) have been implicated in atheroscelosis While several case control studies have shown increased titers of C.pneumoniae and H. Pylori in those with vs. without CHD, convincing evidence from prospective studies is lacking.

31. Slide Source: Lipids Online www.lipidsonline.org Prospective Studies of CHD and Infectious Pathogens Physician’s Health Study (nested case- control) shows RR 1.1 (0.8-1.5) for C. Pneumoniae, 0.94 (0.7-1.2) for cytomegalovirus, and 0.72 (0.6-0.9) for Herpes simplex virus. H. pylori also shows mixed results. Whincup showed a nonsignificant 1.3 OR when adjusted for other risk factors, the large ARIC study showed no relation, and the Caerphilly Prospective study showed RR=1.05 in 1796 men followed 14 years.

32. Slide Source: Lipids Online www.lipidsonline.org Infectious Agents and the Future Individuals with greater infectious burdens may be at greater risk, because they are older, have poorer health habits, less access to care. Observed associations often may be due to selection biases or confounding from age and other factors Prospective clinical trials under way examining role of certain antibiotics such as azithromycin on reduction of recurrent events in CHD patients. Until these data are available, no role for measurement or treatment of infectious burden.