Plasma Concentration of TNF- and Risk of Recurrent Coronary Events
2.5
2.0 1.5 1.0 0–2.47 (1st–50th) 2.48–3.05 (51st–75th)
distribution)
Relative Risk
3.06–4.17 4.18+ (76th–95th) (>95th)
(percentile of control
Slide Source: Lipids Online www.lipidsonline.org
TNF- Concentration, pg/mL
Predictive Value of CRP and Other Inflammatory Markers: LDL <130 mg/dL
4
Relative Risk of Future Coronary Events hs-CRP
3
SAA
2 1
1
IL-6
sICAM-1
2 3 4 Quartile of Inflammatory Marker
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
Parameter
hs-CRP
r
0.60
P
0.001
Total Cholesterol LDL-C
HDL-C
0.37 0.32
0.74
0.001 0.001
0.001
Triglycerides
0.49
0.001
Slide Source: Lipids Online www.lipidsonline.org
Population Distribution of hs-CRP in Apparently Healthy American Men and Women
Quintile
1
2 3
Range (mg/dL)
0.01–0.069
0.07–0.11 0.12–0.19
Risk Estimate
Low
Mild Moderate
4 5
0.20–0.38 0.39–1.50
High Highest
Slide Source: Lipids Online www.lipidsonline.org
Assessment of the Clinical Utility of Novel Markers of Cardiovascular Risk
Assay Conditions Standardized?
–
Marker Lp(a)
Prospective Studies Consistent?
+/–
Additive to TC and HDLC?
+/–
Homocysteine tPA and PAI-1
Fibrinogen
+ +/–
+/–
+/– +
+
+/– +/–
+
hs-CRP
+
+
+
Slide Source: Lipids Online www.lipidsonline.org
Is there clinical evidence that
inflammation can be modified by
preventive therapies?
Slide Source: Lipids Online www.lipidsonline.org
hs-CRP, Aspirin, and Risks of Future MI: Physicians' Health Study
5
Relative Risk of MI
Aspirin Placebo
4 3 2 1 0
1 2 3 4 Quartile of C-Reactive Protein
Slide Source: Lipids Online www.lipidsonline.org
Low-Dose Aspirin Reduces Thromboxane B2 but not CRP
140
Serum CRP (% of Baseline)
140 Serum Thromboxane (% of Baseline) 120 100 80 60 40 20 0
120 100 80 60 40 20 0
Placebo (n=11)
28 Days 31 Days
* p<0.001
* *
Placebo ASA 81 mg qd (n=11) (n=13)
Slide Source: Lipids Online www.lipidsonline.org
ASA 81 mg qd (n=13)
Reduction of Proinflammatory Cytokines and CRP with Higher-Dose Aspirin in Patients with Chronic Stable Angina
Placebo (n=40)
MCSF, pg/mL
IL-6, pg/mL CRP, mg/mL
ASA 300 mg (n=40)
843 (501-1357)
2.9 (2.5-3.4) 1 (0.5-3.1)
P
<0.05
<0.05 <0.05
991 (459-1476)
3.5 (3.2-4.6) 1.4 (0.54-4.05)
Slide Source: Lipids Online www.lipidsonline.org
Elevated CRP Levels in Obesity: NHANES 1988-1994
Percent with CRP 0.22 mg/dL
25 20 15 10 5 0
Normal
Overweight
Obese
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/m2) 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 www.lipidsonline.org
Effects of Weight Loss in Obese Women on IL-6, TNF-, and CRP
Before diet
3.00 2.50
pg/mL
After very low calorie diet (mean BMI reduction 2.1 kg/m2; mean reduction in body fat mass 4 kg)
p=0.14
p=0.05
7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
mg/L
2.00 1.50 1.00 0.50 0.00
IL-6
p=0.6
TNF-
CRP
Slide Source: Lipids Online www.lipidsonline.org
Effects of n-3 Fatty Acid Therapy on Lipids and sCAMs
0
TG
TC
sICAM-1
sE-selectin
Percent Change
-10 -20 -30 -40 -50
*
*
All Patients DM Patients
*
*
* p<0.05
Slide Source: Lipids Online www.lipidsonline.org
Effect of HRT on hs-CRP: the PEPI Study
3.0
hs-CRP (mg/dL)
CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE
2.0
Placebo
1.0 0 12 Months 36
Slide Source: Lipids Online www.lipidsonline.org
hs-CRP and Relative Risk of Recurrent Coronary Events: CARE
P Trend = 0.044
2.0
Relative Risk
P=0.02
1.5 1.0 0.5 0.0
1
<0.12
2
3
4
5
>0.66
Slide Source: Lipids Online www.lipidsonline.org
0.12-0.20 0.21-0.37 0.38-0.66
Quintile of hs-CRP (range, mg/dL)
Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: CARE
P Trend = 0.005
3
Relative Risk
2 1 0
Pravastatin Placebo Pravastatin Placebo
Inflammation Absent
Inflammation Present
Slide Source: Lipids Online www.lipidsonline.org
Baseline Lipid Levels in Patients with and without Inflammation: CARE
Mean Baseline (mg/dL)
250 200
150
Inflammation absent Inflammation present
100
50
0
TC
LDL-C
HDL-C
TG
Slide Source: Lipids Online www.lipidsonline.org
Long-Term Effect of Pravastatin on hs-CRP: CARE Placebo and Pravastatin Groups
Median hs-CRP Concentration (mg/dL)
0.25 0.24 0.23
0.22 0.21
Placebo
–21.6% (P=0.007)
0.20 0.19 0.18
Baseline 5 Years
Slide Source: Lipids Online www.lipidsonline.org
Pravastatin
Change in hs-CRP Concentration Over 5 Years: CARE Subgroup Analyses
Pravastatin
Age >60 years Age <60 years BMI >27 kg/m2 BMI <27 kg/m2 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 HDL-C <35 mg/dL Triglycerides >160 mg/dL Triglycerides <160 mg/dL
Placebo
All Subjects
-0.2 -0.1 0 0.1 0.2 0.3 Change in hs-CRP over 5 Years (mg/dL)
Click for larger picture
Slide Source: Lipids Online www.lipidsonline.org
Change in hs-CRP according to Observed Changes in LDL-C: CARE Placebo and Pravastatin Groups
0.15
Change in hs-CRP (mg/dL)
0.10
0.05 0 -0.05
Placebo Pravastatin
-0.10
-0.15
Increase 0–25
Decrease 0–25
Decrease 25–50
Decrease 50–75
Decrease >75
Slide Source: Lipids Online www.lipidsonline.org
Change in LDL-C (mg/dL)
CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS
Event Rate
Study Group Low LDL-C/low CRP Low LDL-C/high CRP Lovastatin 0.025 0.029 Placebo 0.022 0.051 NNT _ 48
High LDL-C/low CRP High LDL-C/high CRP
0.020 0.038
0.050 0.055
33 58
Median LDL-C = 149.1 mg/dL Median CRP = 0.16 mg/dL
Slide Source: Lipids Online www.lipidsonline.org
Statin Therapy, Lipid Levels, CRP, and Survival Among Patients with Severe Coronary Artery Disease
20
Mortality (%)
P Trend <0.0001
15 10 5 0
P Trend = 0.94
Low Medium High
Low Medium High
CRP Tertiles Statins
CRP Tertiles No Statins
Slide Source: Lipids Online www.lipidsonline.org
Effect of Statin Therapy on hs-CRP Levels at 6 Weeks
6 hs-CRP (mg/L) 5 *p<0.025 vs. Baseline
4 3
2
*
*
*
1 0
Baseline Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d)
Slide Source: Lipids Online www.lipidsonline.org
Effect of Pravastatin on CRP Levels in Primary and Secondary Prevention: PRINCE
Primary Prevention
0.0 -2.0 -4.0 -6.0 -8.0 -10.0 -12.0 -14.0 -16.0
Secondary Prevention
Change in CRP, %
*
*p<.001 vs. baseline **p<.005 vs. baseline
*
*
**
24 weeks vs. baseline
**
12 weeks vs. baseline
24 weeks ITT vs. placebo
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
Change at 24 weeks, %
15 10 5 0 -5 -10 -15 -20
Fibrinogen
PAI-1
CRP
n: 81 80 74
70 72 63 83 80 75
* *
*
Beza 400 mg/d
P<0.05 vs. baseline
Beza 400 mg/d + fluva 20 mg/d Beza 400 mg/d + fluva 40 mg/d
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
Event Rate
Study Group Low TC:HDL-C/low CRP Low TC:HDL-C/high CRP Lovastatin 0.024 0.025 Placebo 0.025 0.050 NNT 983 43
High TC:HDL-C/low CRP High TC:HDL-C/high CRP
0.021 0.041
0.050 0.057
35 62
Median TC:HDL-C = 5.96 Median CRP = 0.16 mg/dL
Slide Source: Lipids Online www.lipidsonline.org
Effect of Gemfibrozil and Ciprofibrate on Plasma Fibrinogen and CRP Levels in Patients with Primary Hypercholesterolemia
4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00
Pretreatment
*p<0.005 vs. pretreatment level
12 Weeks
1.40 1.20 1.00
Fibrinogen, g/L
* *
CRP, mg/L
0.80 0.60 0.40 0.20 0.00
Gemfibrozil 600 mg bid (n=51)
Ciprofibrate 100 mg/d (n=48)
Gemfibrozil 600 mg bid (n=51)
Ciprofibrate 100 mg/d (n=48)
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
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
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.
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.
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.
Slide Source: Lipids Online www.lipidsonline.org