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Atherosclerosis and CRP

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					Inflammation and CRP
Inflammatory Pathways in Atherogenesis

                              Pro-inflammatory Risk
                                      Factors


             Primary Pro-Inflammatory Cytokines (eg, IL-1, TNF-a)

                                                         IL-6
                                                 “Messenger” Cytokine
                       ICAM-1                  CRP
                Selectins, HSPs, etc.          SAA
                 Endothelium
                 and other cells
                                                              Liver
Adapted from Libby P et al.
Circulation. 1999;100:1148–1150.
                                           Circulation
   Inflammation, Plaque Stability, and the
   Risk of Cardiovascular Events

• Evidence suggests that in ACS elevated inflammatory
  markers—in particular, CRP—predict the future risk of
  cardiovascular events
• Factors such as laminar arterial shear stress, oxidized
  LDL, free radicals, and infectious organisms can trigger the
  release of pro-inflammatory cytokines (eg, IL-1, TNF-a, IL-
  6)
• Inflammatory cytokines influence the stability and
  degradation of the fibrous cap, leading to plaque rupture
  and subsequent thrombosis


ACS, acute coronary syndrome; CRP, C-reactive protein; LDL, low-density
lipoprotein; IL, interleukin; TNF, tumor necrosis factor.
Libby P, et al. Circulation. 2002;105:1135-1143.
   hs-CRP and Risk of Future MI in
   Apparently Healthy Men

                                        P Trend <.001
                            3                                             P<.001
                                                          P<.001
      Relative Risk of MI




                            2          P=.03



                            1



                            0
                                1        2               3                  4
                                         Quartile of hs-CRP
hs-CRP, high-sensitivity C-reactive protein; MI, myocardial infarction.
Adapted from Ridker PM, et al. N Engl J Med. 1997;336:973-979.
   Relative Risk of Cardiovascular Events
   According to Several Biochemical Markers
                       Relative Risk of Future CV Events

         Lipoprotein(a)
         Homocysteine
         TC
         LDLC
         Apolipoprotein B
         TC:HDLC
         hs-CRP
         hs-CRP + TC:HDLC

                                0            1.0          2.0           4.0          6.0
CV, cardiovascular; TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; HDL-C,
high-density lipo-protein cholesterol; CRP, C-reative protein; hs-CRP, high-sensitivity C-reactive protein;
TC, total cholesterol.
Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.
   Novel Risk Factors as Predictors of PAD
                         Relative Risk of Incident PAD*
              Lipoprotein(a)
              Homocysteine
              VCAM-1
              Fibrinogen
              LDLC
              ICAM-1
              hs-CRP
              TC:HDLC
              CRP + TC: HDLC

                           0           1.0         2.0          4.0           6.0
  VCAM, vascular cell adhesion molecule; LDLC, low-density lipoprotein cholesterol; ICAM, intercellular
  adhesion molecule; hs-CRP, high-sensitivity C-reactive molecule; TC, total cholesterol; HDL-C, high-
  density lipoprotein cholesterol.
* Adjusted for age, smoking, diabetes, hypertension, family history, exercise level, and body mass index.
  Ridker PM, et al. JAMA. 2001;285:2481-2485.
  CRP, the Metabolic Syndrome, and Future
  CV Events (N=14,719)
                           1.00



                           0.99                                ATP III Metabolic Syndrome – No
    Survival Probability




                                                               CRP <3.0
      CV-Event–free




                           0.98



                           0.97
                                                               CRP >3.0

                                                               ATP III Metabolic Syndrome – Yes
                           0.96
                                  00   2
                                       2     4      6      8
                                       Follow-up (years)
CRP, C-reactive protein; CV, cardiovascular.
Ridker PM, et al. Circulation. 2003;107:391-397. (with permission)
   Risk Factors for Future Cardiovascular
   Events: Women’s Health Study
          Relative Risk of Future Cardiovascular Events
      Lipoprotein(a)
      Homocysteine
      IL-6
      TC
      LDL-C
      sICAM-1
      SAA
      Apo B
      TC: HDL-C
      hs-CRP
      hs-CRP + TC: HDL-C
                     0                 1.0               2.0                4.0                6.0

IL, interleukin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; sICAM, serum intercellular
adhesion molecule; SAA, serum amyloid A; ApoB, Apolipoprotein B; HDL-C, high-density lipo-protein
cholesterol; hs-CRP, high-sensitivity C-reactive protein.
Ridker PM, et al. N Engl J Med. 2000;342:836-843.
                  Markers of Inflammation in the Prediction
                  of Cardiovascular Disease in Women
                  6.0                                                                    6.0
Relative Risk




                                                                         Relative Risk
                  5.0                                                                    5.0
                  4.0                                                                    4.0
                  3.0                                                                    3.0
                  2.0                                                                    2.0
                  1.0                                             High                   1.0                                                 High
                                                         Medium                                                                     Medium
                  0.0                                                                    0.0
                        High    Medium       Low   Low                                           High    Medium      Low      Low
                               Total Cholesterol                                                          Total Cholesterol
  Relative Risk




                  6.0                                                                      6.0




                                                                         Relative Risk
                  5.0                                                                      5.0
                  4.0                                                                      4.0
                  3.0                                                                      3.0
                  2.0                                                                      2.0
                  1.0                                             High                     1.0                                                High
                                                         Medium                                                                      Medium
                  0.0                                                                      0.0
                        High    Medium       Low   Low                                            High    Medium      Low      Low
                               Total Cholesterol                                                          Total Cholesterol


hs-CRP, high-sensitivity C-reactive protein; SAA, serum amyloid A; sICAM, serum intracellular adhesion
molecule; IL, interleukin.
Ridker PM, et al. N Engl J Med. 2000;342:836-843. (with permission)
   hs-CRP, Aspirin, and Risks of Future
   Myocardial Infarction
                                                                      4


                                                                      3

                                                                        Relative Risk
                                                                      2 Myocardial
                                                                         Infarction

                                                                      1



            Placebo                                                   0
                                                        3         4
                Aspirin                       2
                                   1
                                  Quartile of C-Reactive Protein

hs-CRP, high-sensitivity C-reactive protein.
Ridker PM, et al. N Engl J Med. 1997;336:973-979. (with permission)
   Inflammation, Statin Therapy, and Relative
   Risk of Recurrent Coronary Events
                                              P Trend=.005
                           3
           Relative Risk




                           2




                           1




                           0
                               Pravastatin   Placebo        Pravastatin   Placebo
                                Inflammation Absent          Inflammation Present

Ridker PM, et al. Circulation. 1998;98:839-844. (with permission)
  Long-term Effect of Pravastatin on hs-CRP:
  Placebo and Pravastatin Groups
              Median hs-CRP Concentration (mg/dL)   0.25                    Placebo

                                                    0.24

                                                    0.23
                                                                                 -21.6%
                                                    0.22                        (P=.007)

                                                    0.21

                                                    0.20

                                                    0.19                    Pravastatin

                                                    0.18
                                                           Baseline   5 Years
hs-CRP, high-sensitivity C-reactive protein.
Adapted from Ridker PM, et al. Circulation. 1999;100:230-235.
   CRP as a Method to Target Statin Therapy
   in Primary Prevention: AFCAPS/TexCAPS
   Study Group                             Statin (mg/dl) Placebo (mg/dl) 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 mg/dL
                                                             Median CRP = 0.16 mg/dL
CRP, C-reactive protein; AFCAPS/Tex Caps, AirForce Texas Coronary Athersclerosis Prevention Study; NNT,
number needed to treat; LDL-C, low-density lipoprotein cholesterol.
Adapted from Ridker PM, et al. N Engl J Med. 2001;344:1959-1965.
    CRP, Metabolic Syndrome, and Future CV
    Events (N=14,719)
                          1.00



                          0.99                               ATP III Metabolic Syndrome – No
   Survival Probability




                                                             CRP <3.0
     CV-Event–free




                          0.98



                          0.97
                                                             CRP >3.0

                                                             ATP III Metabolic Syndrome – Yes
                          0.96
                                 0   2       4       6      8
                                     Follow-up (years)

CRP, C-reactive protein; CV, cardiovascular.
Ridker PM, et al. Circulation. 2003;107:391-397. (with permission)
   Metabolic Syndrome and CRP Levels

                                      8
          C-reactive Protein (mg/L)




                                      6



                                      4



                                      2



                                      0
                                          0       1       2       3        4       5
                                          Number of Components of the Metabolic Syndrome
Ridker PM, et al. Circulation. 2003;107:391-397. (with permission)
                                 CRP Levels and Event-Free Survival
                                                                                                      1.00
                                 CRP (mg/L)             Risk
                                 <1                     Low                                                                              <1 mg/L
                                 1 to 3                 Moderate                                      0.99

                                 >3                     High
                                                                                                                                     1 to 3 mg/L
                                                                                                      0.98




                                                                                        Probability
Multivariate Relative Risk




                             3

                                                                                                      0.97
                             2

                                                                                                                                      <3 mg/L
                             1
                                                                                > 3.0
                                                                                                      0.96
                                                                      1.0-3.0
                             0
                                  >160     130 - 160   <130    <1.0


                                         LDL Cholesterol                                              0.95
                                                                                                             0   2    4      6       8
                    Ridker PM. Circulation. 2003;107:363-369.
                    (with permission)                                                                            Follow-up (years)
  Clinical Application of hs-CRP for
  Cardiovascular Risk Prediction



         1 mg/L        3 mg/L                 10 mg/L                        >100 mg/L




      Low      Moderate             High                    Acute Phase Response
      Risk      Risk                Risk                 Ignore Value, Repeat Test in 3
                                                                    weeks



Adapted from Ridker PM. Circulation. 2003;107:363-369.
    Clopidogrel Reduces ADP-Induced
    Expression of Platelet-Derived CD40L

                                0.5
      CD40L Expression (Mn X)




                                0.4                                                      Control
                                                                                         ADP 30 M
                                0.3
                                                              P<.05 vs ADP-
                                0.2                        stimulated controls


                                0.1

                                 0
                                                                     †
                                      Control   ASA*   Clopidogrel          ASA* +
                                                                                     †
                                                                         clopidogrel
* ASA 100 M in vitro.
† Clopidogrel 75 mg/d for 7 d.

  CD40L, CD40 ligand; ASA, acetylsalicylic acid.
  Hermann A, et al. Platelets. 2001;12:74-82. (with permission)
    Inflammation in Unstable Angina
                UA/LAD            UA/RCA          Stable Angina   Variant Angina   Controls
                 (n=24)            (n=9)              (n=13)           (n=13)       (n=6)
    15
                                                        P=.96        P=.93          P=.12
    10             P<.001             P=.003

      5
                P=.44
                                 P=.42
      0

     -5

   -10

   -15
                                              Femoral Vein        Aorta      Great Cardiac Vein

Buffon A, et al. N Engl J Med. 2002;347:5-12. (with permission)
   CRP and Outcome by Quartile in
   Stented Patients
    20 %
                   *2 for trend=0.001

                  **2 for trend=0.003                                                   *
                                                                                       15.3 %
    15 %
                     Death
                                                                      12.3 %
                     Death/MI

    10 %                                          9.6 %


                         6.0 %
      5%
                                                                                **
                                                                               2.3 %

                  0%                     0%                   0.4 %
      0%
                  <0.3mg/dL             0.3-0.5mg/dL          0.5-1.1mg/dL     >1.1mg/dL
                    (n=216)                 (n=218)               (n=227)        (n=216)
CRP, C-reactive protein.                         CRP Quartiles (mg/dl)
Chew DP, et al. Circulation. 2001;104:974-975.

				
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