slide source: lipids online plasma concentration of tnf- and risk of recurrent coronary events 2.5...

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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)


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


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


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


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 + + +


Is there clinical evidence that Is there clinical evidence that

inflammation can be modified by inflammation can be modified by

preventive therapies?preventive therapies?


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


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

* *


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


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


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


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


-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


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


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


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


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


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


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


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


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


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


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


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


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**

*


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


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


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


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


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.


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.


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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