Slide Source: Lipids Online Plasma Concentration of TNF- and Risk of Recurrent Coronary Events –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 ) (>95 th )

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

Slide Source: Lipids Online Age-Adjusted Correlation Coefficients for hs-CRP Levels and Lipid Parameters over a 5-Year Follow-up Period ParameterrP hs-CRP Total Cholesterol LDL-C HDL-C Triglycerides

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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+++

Slide Source: Lipids Online Is there clinical evidence that inflammation can be modified by preventive therapies?

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

Slide Source: Lipids Online Low-Dose Aspirin Reduces Thromboxane B 2 but not CRP Serum CRP (% of Baseline) Placebo (n=11) 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 *

Slide Source: Lipids Online 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 ( ) 843 ( ) <0.05 IL-6, pg/mL 3.5 ( ) 2.9 ( ) <0.05 CRP, mg/mL1.4 ( ) 1 ( ) <0.05

Slide Source: Lipids Online Elevated CRP Levels in Obesity: NHANES Normal Percent with CRP 0.22 mg/dL OverweightObese

Slide Source: Lipids Online Effects of Weight Loss on CRP Concentrations in Obese Healthy Women 83 women (mean BMI 33.8, range 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

Slide Source: Lipids Online 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

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

Slide Source: Lipids Online Effect of HRT on hs-CRP: the PEPI Study hs-CRP (mg/dL) Months CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE Placebo

Slide Source: Lipids Online hs-CRP and Relative Risk of Recurrent Coronary Events: CARE 1 <0.12 Relative Risk Quintile of hs-CRP (range, mg/dL) P= >0.66 P Trend = 0.044

Slide Source: Lipids Online Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: CARE Pravastatin Relative Risk Inflammation Absent P Trend = PlaceboPravastatinPlacebo Inflammation Present

Slide Source: Lipids Online Mean Baseline (mg/dL) Inflammation absent Inflammation present TCLDL-CHDL-CTG Baseline Lipid Levels in Patients with and without Inflammation: CARE

Slide Source: Lipids Online 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) Baseline5 Years

Slide Source: Lipids Online 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 Click for larger picture

Slide Source: Lipids Online 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

Slide Source: Lipids Online CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Study GroupLovastatinPlaceboNNT Low LDL-C/low CRP _ Low LDL-C/high CRP High LDL-C/low CRP High LDL-C/high CRP Median LDL-C = mg/dL Median CRP = 0.16 mg/dL Event Rate

Slide Source: Lipids Online 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

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

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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 P<0.05 vs. baseline * * *

Slide Source: Lipids Online 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 CRP Low TC:HDL-C/high CRP High TC:HDL-C/low CRP High TC:HDL-C/high CRP Median TC:HDL-C = 5.96 Median CRP = 0.16 mg/dL Event Rate

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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

Slide Source: Lipids Online 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.

Slide Source: Lipids Online Prospective Studies of CHD and Infectious Pathogens Physician’s Health Study (nested case- control) shows RR 1.1 ( ) for C. Pneumoniae, 0.94 ( ) for cytomegalovirus, and 0.72 ( ) 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.

Slide Source: Lipids Online 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.