Editorial Slides VP Watch - May 1, 2002 - Volume 2, Issue 17

Plaque CRP or Myocardial CRP; Chicken or Egg?!

• 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

• 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

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

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

• 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

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

CRP Values: Sudden Unexpected Deaths

Con

trol

s Stab

le P

laqu

es

Rup

ture

Eros

ion

0.0

10.0

20.0

30.0

40.0

50.0

60.0

Controls StablePlaques

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

• 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.

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.

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?

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.

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: 391–4187) Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin

Chem. 1999; 45: 2136–21418) 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;342:836–8439) Pasceri, V., Willerson, J. T., Yeh, E. T. H. (2000). Direct Proinflammatory Effect of C-Reactive Protein on

Human Endothelial Cells. Circulation 102: 2165-216810) 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