This document summarizes research on C-reactive protein (CRP) and its relationship to atherosclerosis and coronary death. It finds that CRP levels are elevated in patients with unstable angina and predict future cardiovascular risk. A study of sudden coronary deaths found higher CRP levels in those who died from plaque rupture compared to controls or those who died from stable plaques or erosion. The study also observed a positive correlation between CRP staining in atherosclerotic plaques and serum CRP levels, independent of the death mechanism. However, questions remain about how well postmortem CRP correlates with pre-death levels and the extent to which elevated CRP results from cardiac injury rather than reflecting the plaque vulnerability.

1. Editorial Slides
VP Watch - May 1, 2002 - Volume 2, Issue 17
Plaque CRP or Myocardial CRP; Chicken or Egg?!

2. • Plasma CRP is the classical acute-phase protein,
increasing 1,000-fold in response to infection,
ischemia, trauma, burns, and inflammatory conditions.1
• Key inflammatory molecules are synthesized within
atherosclerotic plaques including complement proteins
and CRP. 2
• CRP levels have been considered to reflect the extent
of inflammatory reactions in the atherosclerotic
vessels. 4,5
CRP, an Old Marker of Inflammation

3. • High-sensitivity CRP (hsCRP) is a strong independent
predictor of endothelial dysfunction, future myocardial
dysfunction, stroke, peripheral artery disease, and
vascular death among individuals without known
cardiovascular disease. 6,7
• Berk, Alexander and colleagues found that CRP was
significantly elevated in 90% of unstable angina patients
admitted to the coronary care unit. 3
CRP A Predictor of Event and Prognosis

4.  Ridker et al. in cohort of women measured levels of
homocysteine, lipoprotein-A, several inflammatory
parameters including hsCRP, and a full lipid panel as
markers of subsequent vascular risk. 8
 In multivariate analysis, only hsCRP level and total /
HDL ratio proved to have independent predictive value once
age, smoking status, obesity, hypertension, family history,
and diabetes also were accounted for.
CRP An Independent Predictor

5.  Yeh and colleagues found that CRP can induce
adhesion molecule expression by human endothelial
cells. 9
 They showed that CRP, at concentrations 5 µg/mL,
has significant pro-inflammatory effects in both umbilical
vein and coronary artery endothelial cells, inducing high
levels of expression of ICAM-1, VCAM-1, and
E-selectin.
CRP A Risk Factor Not A Marker

6. • In Bogalusa Heart Study, Gerald Berenson and his
colleagues showed the relation of atherosclerotic plaques
to antemortem and postmortem lipid levels. 12
• They found that relation of plaques to antemortem and
postmortem lipid levels differed only slightly for total
cholesterol, LDL and HDL. In contrast, coronary plaques
showed the strongest association with antemortem VLDL,
but were not associated with postmortem VLDL.
Antemortem vs. Postmortem

7.  As reported in this week of VP Watch,
Burke, Virmani, and colleagues showed a
modest elevation of serum hsCRP in autopsy
samples of all sudden coronary death versus
control, regardless of underlying coronary
pathology. 13
 They found significant elevations of serum
hsCRP compared with controls in patients dying
with acute coronary thrombi associated with
plaque rupture

8. CRP Values: Sudden Unexpected Deaths
Controls
StablePlaques
Rupture
Erosion
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Controls Stable
Plaques
Rupture Erosion
CRP Values in cases without known predisposing cause for elevations of
CRP other than atherosclerosis with sudden unexpected deaths.
Allen P. Burke, Russell P. Tracy, Frank Kolodgie, Gray T. Malcom, Arthur Zieske, Robert Kutys, Joseph Pestaner, John Smialek, and Renu
Virmani; Elevated C-Reactive Protein Values and Atherosclerosis in Sudden Coronary Death: Association With Different Pathologies
Circulation 2002 105: 2019 - 2023
% of CRP
> 3 µ g/ml

9. • Burke et al. showed a positive correlation between the
intensity of CRP staining within atherosclerotic plaques
and serum levels of CRP independent of mechanism of
death (rupture, erosion, and stable plaque).
• They found less thin cap atheromas in low hs-CRP
group vs. high hs-CRP group of coronary death.
• Association of CRP with plaque burden and acute
coronary thrombosis is lessened when covariates of
glycohemoglobin and HDL are included in analysis.

10. Conclusion
 For the first time, in postmortem autopsy
series increased hsCRP is
retrospectively associated with plaque
rupture.
 The study also showed higher CRP level
in subjects with more rupture prone
vulnerable plaque.

11. Questions:
• Knowing imperfect correlation between
pre- and postmortem cholesterol in
Bogalusa Study, how well postmortem
CRP correlates with antemortem CRP?
• Knowing CRP rise after MI and ischemic
injury, and since all of the victims died
with heart attack, the question is what part
of the increased CRP in this study
subjects is resulted from cardiac injury
after plaque rupture?

12. Questions:
• Does CRP staining in culprit plaques
significantly differ across the study group
(ruptured, erosion, and stable)?
• Since the extent of myocardial ischemia
and injury is closely correlated with CRP
level, the question is whether in
comparison across the study groups
(ruptured, erosion, and stable) this factor
has been adjusted and taken into account.

13. 1) Westhuyzen J, Healy H. Biology and relevance of C-reactive protein in cardiovascular and renal disease. Ann
Clin Lab Sci. 2000; 30: 133–143.
2) Yasojima K, Schwab C, McGeer EG, et al. Generation of C-reactive protein and complement components in
atherosclerotic plaques. Am J Pathol. 2001; 158: 1039–1051
3) Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease.
Am J Cardiol. 1990; 65: 168–172.
4) Heinrich J, Schulte H, Schönfeld R, Köhler E, Assmann G. Association of variables of coagulation, fibrinolysis
and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the
brain. Thromb Haemost. 1995;73:374–378
5) Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentrations of C-reactive
protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428
6) Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med. 2000; 45: 391–418
7) Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin
Chem. 1999; 45: 2136–2141
8) Ridker PM, Hennekens CH, Buring JE, et al. C reactive protein and other markers of inflammation in the
prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843
9) Pasceri, V., Willerson, J. T., Yeh, E. T. H. (2000). Direct Proinflammatory Effect of C-Reactive Protein on
Human Endothelial Cells. Circulation 102: 2165-2168
10) Lemieux I, Pascot A, Prud'homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP.
Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal
obesity.Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):961-7
11) Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with
obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose
tissue? Arterioscler Thromb Vasc Biol. 1999;19:972–978
12) Freedman DS, Wattigney WA, Srinivasan S, Newman WP 3rd, Tracy RE, Byers T, Berenson GS.
The relation of atherosclerotic lesions to antemortem and postmortem lipid levels: the Bogalusa Heart Study.
Atherosclerosis. 1993 Dec;104(1-2):37-46.
13) Allen P. Burke, Russell P. Tracy, Frank Kolodgie, Gray T. Malcom, Arthur Zieske, Robert Kutys, Joseph
Pestaner, John Smialek, and Renu Virmani; Elevated C-Reactive Protein Values and Atherosclerosis in
Sudden Coronary Death: Association With Different Pathologies Circulation 2002 105: 2019 - 2023
References