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Slide Source:Lipids Onlinewww.lipidsonline.org
Plasma Concentration of TNF-Plasma Concentration of TNF- and Risk of and Risk of Recurrent Coronary EventsRecurrent Coronary Events
2.5
2.0
1.5
1.0
0–2.47(1st–50th)
Rela
tive R
isk
TNF- Concentration, pg/mL (percentile of control distribution)
2.48–3.05(51st–75th)
3.06–4.17(76th–95th)
4.18+(>95th)
Slide Source:Lipids Onlinewww.lipidsonline.org
Predictive Value of CRP and Other Predictive Value of CRP and Other Inflammatory Markers: LDL <130 mg/dLInflammatory Markers: LDL <130 mg/dL
4
3
2
1
1
Rela
tive R
isk
of
Futu
reC
oro
nary
Events
Quartile of Inflammatory Marker
hs-CRP
2 3 4
SAA
IL-6
sICAM-1
Slide Source:Lipids Onlinewww.lipidsonline.org
Age-Adjusted Correlation Coefficients for Age-Adjusted Correlation Coefficients for hs-CRP Levels and Lipid Parameters over hs-CRP Levels and Lipid Parameters over a 5-Year Follow-up Perioda 5-Year Follow-up Period
Parameter r P
hs-CRP 0.60 0.001
Total Cholesterol 0.37 0.001
LDL-C 0.32 0.001
HDL-C 0.74 0.001
Triglycerides 0.49 0.001
Slide Source:Lipids Onlinewww.lipidsonline.org
Population Distribution of hs-CRP in Population Distribution of hs-CRP in Apparently Healthy American Men and Apparently Healthy American Men and WomenWomen
Quintile Range (mg/dL) Risk Estimate
1 0.01–0.069 Low
2 0.07–0.11 Mild
3 0.12–0.19 Moderate
4 0.20–0.38 High
5 0.39–1.50 Highest
Slide Source:Lipids Onlinewww.lipidsonline.org
Assessment of the Clinical Utility of Assessment of the Clinical Utility of Novel Markers of Cardiovascular RiskNovel Markers of Cardiovascular Risk
MarkerMarker
Assay Assay Conditions Conditions
Standardized?Standardized?
Prospective Prospective Studies Studies
Consistent?Consistent?
Additive to Additive to TC and HDL-TC and HDL-
C?C?
Lp(a) – +/– +/–
Homocysteine + +/– +/–
tPA and PAI-1 +/– + +/–
Fibrinogen +/– + +
hs-CRP + + +
Slide Source:Lipids Onlinewww.lipidsonline.org
Is there clinical evidence that Is there clinical evidence that
inflammation can be modified by inflammation can be modified by
preventive therapies?preventive therapies?
Slide Source:Lipids Onlinewww.lipidsonline.org
0
1
2
3
4
5
hs-CRP, Aspirin, and Risks of Future MI: hs-CRP, Aspirin, and Risks of Future MI: Physicians' Health StudyPhysicians' Health Study
Quartile of C-Reactive Protein
1 2 3 4
Aspirin
Placebo
Rela
tive R
isk
of
MI
Slide Source:Lipids Onlinewww.lipidsonline.org
Low-Dose Aspirin Reduces Thromboxane Low-Dose Aspirin Reduces Thromboxane
BB22 but not CRP but not CRP
Seru
m C
RP
(% o
f B
ase
line)
140
120
100
80
60
40
20
0Placebo(n=11)
140
120
100
80
60
40
20
0Seru
m T
hro
mb
oxane
(% o
f B
ase
line)
ASA 81 mg qd(n=13)
Placebo(n=11)
ASA 81 mg qd(n=13)
28 Days31 Days
* p<0.001
* *
Slide Source:Lipids Onlinewww.lipidsonline.org
Reduction of Proinflammatory Cytokines Reduction of Proinflammatory Cytokines and CRP with Higher-Dose Aspirin in and CRP with Higher-Dose Aspirin in Patients with Chronic Stable AnginaPatients 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/mL 1.4(0.54-4.05)
1(0.5-3.1)
<0.05
Slide Source:Lipids Onlinewww.lipidsonline.org
0
5
10
15
20
25
Elevated CRP Levels in Obesity: Elevated CRP Levels in Obesity: NHANES 1988-1994NHANES 1988-1994
Normal
Perc
en
t w
ith C
RP
0.2
2
mg/d
L
Overweight Obese
Slide Source:Lipids Onlinewww.lipidsonline.org
Effects of Weight Loss on CRPEffects of Weight Loss on CRPConcentrations in Obese Healthy WomenConcentrations 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 Onlinewww.lipidsonline.org
0.00
0.50
1.00
1.50
2.00
2.50
3.00
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Effects of Weight Loss in Obese Women on Effects of Weight Loss in Obese Women on IL-6, TNF-IL-6, TNF-, and CRP, and CRP
pg/m
L mg
/L
IL-6 TNF- CRP
Before diet
After very low calorie diet (mean BMI reduction 2.1 kg/m2; mean reduction in body fat mass 4 kg)
p=0.05
p=0.6
p=0.14
Slide Source:Lipids Onlinewww.lipidsonline.org
-50
-40
-30
-20
-10
0
Effects of n-3 Fatty Acid Therapy on Lipids Effects of n-3 Fatty Acid Therapy on Lipids and sCAMsand sCAMs
Perc
en
t C
han
ge
TG TC sICAM-1 sE-selectin
All Patients
DM Patients
*
*
**
* p<0.05
Slide Source:Lipids Onlinewww.lipidsonline.org
Effect of HRT on hs-CRP: Effect of HRT on hs-CRP: the PEPI Studythe PEPI Study
3.0
2.0
1.0hs-
CR
P (
mg/d
L)
Months
0 12 36
CEE + MPA cyclicCEE + MPA continuousCEE + MPCEE
Placebo
Slide Source:Lipids Onlinewww.lipidsonline.org
0.0
0.5
1.0
1.5
2.0
hs-CRP and Relative Risk of Recurrent hs-CRP and Relative Risk of Recurrent Coronary Events: Coronary Events: CARECARE
1<0.12
Rela
tive R
isk
Quintile of hs-CRP (range, mg/dL)
P=0.02
20.12-0.20
30.21-0.37
40.38-0.66
5>0.66
PP Trend = 0.044 Trend = 0.044
Slide Source:Lipids Onlinewww.lipidsonline.org
0
1
2
3
Inflammation, Pravastatin, and Relative Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: Risk of Recurrent Coronary Events: CARECARE
Pravastatin
Rela
tive R
isk
Inflammation Absent
PP Trend = 0.005 Trend = 0.005
Placebo Pravastatin Placebo
Inflammation Present
Slide Source:Lipids Onlinewww.lipidsonline.org
Mean B
ase
line (
mg
/dL) Inflammation absent
Inflammation present
250
200
150
100
50
0TC LDL-C HDL-C TG
Baseline Lipid Levels in Patients with and Baseline Lipid Levels in Patients with and without Inflammation: without Inflammation: CARECARE
Slide Source:Lipids Onlinewww.lipidsonline.org
Long-Term Effect of Pravastatin on hs-CRP:Long-Term Effect of Pravastatin on hs-CRP:CARE Placebo and Pravastatin GroupsCARE Placebo and Pravastatin Groups
PravastatinPravastatin
PlaceboPlacebo
Med
ian
hs-
CR
PC
on
cen
trati
on
(m
g/d
L)
––21.6%21.6%((PP=0.007)=0.007)
0.25
0.24
0.23
0.22
0.21
0.20
0.19
0.18Baseline 5 Years
Slide Source:Lipids Onlinewww.lipidsonline.org
Change in hs-CRP Concentration Over 5 Change in hs-CRP Concentration Over 5 Years: Years: CARE Subgroup AnalysesCARE Subgroup Analyses
Change in hs-CRP over 5 Years (mg/dL)
HDL-C <35 mg/dL
All Subjects
Pravastatin
Age >60 yearsAge <60 yearsBMI >27 kg/m2
BMI <27 kg/m2
Placebo
SmokersNonsmokers
SBP >128 mm HgSBP <128 mm HgDBP >78 mm HgDBP <78 mm Hg
LDL-C >138 mg/dLLDL-C <138 mg/dLHDL-C >35 mg/dL
Triglycerides >160 mg/dLTriglycerides <160 mg/dL
-0.2 -0.1 0 0.1 0.2 0.3
Click for larger picture
Slide Source:Lipids Onlinewww.lipidsonline.org
Change in hs-CRP according to Observed Changes Change in hs-CRP according to Observed Changes in LDL-C: in LDL-C: CARE Placebo and Pravastatin GroupsCARE Placebo and Pravastatin Groups
Change in LDL-C (mg/dL)
Increase0–25
Decrease0–25
Decrease25–50
Decrease50–75
Decrease>75
Change in h
s-C
RP
(mg/d
L)
Placebo
Pravastatin
-0.15
-0.10
-0.05
0
0.05
0.10
0.15
Slide Source:Lipids Onlinewww.lipidsonline.org
CRP in Combination with LDL-C as a Method CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary to Target Statin Therapy in Primary Prevention: Prevention: AFCAPS/TexCAPSAFCAPS/TexCAPS
Study Group Lovastatin Placebo NNT
Low LDL-C/low CRP 0.025 0.022 _
Low LDL-C/high CRP 0.029 0.051 48
High LDL-C/low CRP 0.020 0.050 33
High LDL-C/high CRP 0.038 0.055 58
Median LDL-C = 149.1 mg/dLMedian CRP = 0.16 mg/dL
Event Rate
Slide Source:Lipids Onlinewww.lipidsonline.org
0
5
10
15
20
Statin Therapy, Lipid Levels, CRP, and Statin Therapy, Lipid Levels, CRP, and Survival Among Patients with Severe Survival Among Patients with Severe Coronary Artery DiseaseCoronary Artery Disease
CRP Tertiles StatinsStatins
Low
Mort
alit
y (
%)
CRP Tertiles No StatinsNo Statins
Medium High Low Medium High
PP Trend = Trend = 0.940.94
PP Trend Trend <0.0001<0.0001
Slide Source:Lipids Onlinewww.lipidsonline.org
hs-
CR
P (
mg/L
)Effect of Statin Therapy on hs-CRP Levels Effect of Statin Therapy on hs-CRP Levels at 6 Weeksat 6 Weeks
6
5
4
3
2
1
0Baseline
* * *
Prava(40 mg/d)
Simva(20 mg/d)
Atorva(10 mg/d)
*p<0.025 vs. Baseline
Slide Source:Lipids Onlinewww.lipidsonline.org
Effect of Pravastatin on CRP Levels in Effect of Pravastatin on CRP Levels in Primary and Secondary Prevention: Primary and Secondary Prevention: PRINCEPRINCE
-16.0-14.0-12.0-10.0-8.0-6.0-4.0-2.00.0
Primary Prevention
Chan
ge in
CR
P,
%
Secondary Prevention
* *
*
****
12 weeksvs. baseline
24 weeksvs. baseline
24 weeks ITTvs. placebo
*p<.001vs.
baseline
**p<.005vs.
baseline
Slide Source:Lipids Onlinewww.lipidsonline.org
Effect of Bezafibrate with and without Fluvastatin Effect of Bezafibrate with and without Fluvastatin on Plasma Fibrinogen, PAI-1, and CRP in Patients on Plasma Fibrinogen, PAI-1, and CRP in Patients with CAD and Mixed Hyperlipidemiawith CAD and Mixed Hyperlipidemia
Beza 400 mg/d
Beza 400 mg/d+ fluva 20 mg/d
Beza 400 mg/d+ fluva 40 mg/d
-20-15-10
-505
1015
Chan
ge a
t 24
weeks
, %
n: 81
Fibrinogen PAI-1 CRP
80 74
70 72 63 83 80 75
P<0.05 vs. baseline**
*
Slide Source:Lipids Onlinewww.lipidsonline.org
CRP in Combination with TC:HDL-C Ratio as CRP in Combination with TC:HDL-C Ratio as a Method to Target Statin Therapy in a Method to Target Statin Therapy in Primary Prevention: Primary Prevention: AFCAPS/TexCAPSAFCAPS/TexCAPS
Study Group Lovastatin Placebo NNT
Low TC:HDL-C/low CRP 0.024 0.025 983
Low TC:HDL-C/high CRP 0.025 0.050 43
High TC:HDL-C/low CRP 0.021 0.050 35
High TC:HDL-C/high CRP 0.041 0.057 62
Median TC:HDL-C = 5.96Median CRP = 0.16 mg/dL
Event Rate
Slide Source:Lipids Onlinewww.lipidsonline.org
Effect of Gemfibrozil and Ciprofibrate on Plasma Effect of Gemfibrozil and Ciprofibrate on Plasma Fibrinogen and CRP Levels in Patients with Fibrinogen and CRP Levels in Patients with Primary HypercholesterolemiaPrimary Hypercholesterolemia
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40Pretreatment 12 Weeks
*
*
Fib
rin
og
en
, g
/L CR
P, m
g/L
Gemfibrozil600 mg bid
(n=51)
Ciprofibrate100 mg/d
(n=48)
Gemfibrozil600 mg bid
(n=51)
Ciprofibrate100 mg/d
(n=48)
*p<0.005 vs. pretreatment level
Slide Source:Lipids Onlinewww.lipidsonline.org
hs-CRP: Potential Clinical Applicationshs-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 Onlinewww.lipidsonline.org
SummarySummary
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 Onlinewww.lipidsonline.org
Infection and CHD - is there a connection?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 Onlinewww.lipidsonline.org
Prospective Studies of CHD and Infectious Prospective Studies of CHD and Infectious PathogensPathogens 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 Onlinewww.lipidsonline.org
Infectious Agents and the FutureInfectious 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.
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