Levels and Values of Serum High-Sensitivity C-Reactive Protein Within 6 Hours After the Onset of Acute Myocardial Infarction*

November 28, 2004

Background: C-reactive protein (CRP), which has been suggested to directly enhance inflammation in plaques, is rapidly synthesized and secreted in the liver 6 h after an acute inflammatory stimulus. Therefore, serum levels of CRP within 6 h after the onset of acute myocardial infarction (AMI) merely reflect a chronic and persistent inflammatory process and are not due to acute myocardial damage. We hypothesized that the serum CRP level, which would abnormally elevate thereafter, is followed by a plaque rupture in the clinical setting of AMI.

Methods and results: CRP was prospectively measured by high- sensitivity CRP assay (hs-CRP) in 157 consecutive patients (106 patients within 6 h, and 51 patients ≥ 6 h but 3 h but

Conclusions: Serum levels of hs-CRP were significantly higher in patients with an onset of AMI

Key words: acute myocurdial infarction; high-sensitivity C- reactive protein

Abbreviations: AMI = acute myocardial infarction; BMI = body mass index; CRP = C-reactive protein; hs-CKP = high-sensitivity C- reactive protein assay; PCI = percutaneous coronary intervention; TIMI = thrombolysis in myocardial infarction

A growing number of studies1-6 report that inflammation plays a crucial role in the cell biology of atherosclerosis. Pathologic and immunohistochemical staining studies7-9 have clearly shown a preponderance of inflammatory cells in the ruptured plaques of patients who have died of acute coronary syndromes. Inflammation, manifested by elevated serum levels of C-reactive protein (CRP) measured by high-sensitivity CRP assay (hs-CRP) is associated with an increased risk of cardiovascular events.10-12 Little is known, however, whether elevated serum CRP levels reflect an increased tendency for plaque rupture or only a high atherosclerotic burden.

It is well recognized that myocardial damage promotes the synthesis of CRP,13,14 and the level of this CRP has been reported to be associated with poor prognosis after acute myocardial infarction (AMI).15,16 However, CRP is primarily synthesized and secreted rapidly in liver 6 h after an acute inflammatory stimulus.17,18 Thus, serum levels of CRP within 6 h alter the onset of AMI are suggested to offer valuable information with respect to cell biology activity on ruptured plaque without being affected by the effects of myocardial necrosis after AMI.19 Therefore, in the present study, we enrolled patients with AMI undergoing primary percutaneous coronary intervention (PCI) within 6 h of the onset of symptoms in order to evaluate whether serum hs-CRP levels are elevated prior to cardiomyocyte damage following AMI.


Study Population

In our hospital, all patient with AMI are considered eligible for primary PCI. For the purpose of this study, the hs-CRP of all patients who underwent primary PCI was prospectively measured. A blood sample was drawn alter vascular puncture before coronary augiography was performed in the cardiac catheterization room.

To avoid other variables that could influence the serum levels of hs-CRP, we excluded patients with a history of recent surgery or trauma within the preceding 2 mouths, renal insufficiency (creatinine > 1.5 mg/dL), malignancy, febrile disorders, and acute or chronic inflammatory disease at study entry, as well as those with a history of recent infection. Patients were also excluded it fever (body temperature > 37.5C) was observed in the emergency department Between November 2002 and September 2003 we prospectively investigated and recruited 171 consecutive patients of any age who presented with AMI of

Another 51 patients (32.5%) who experienced AMI with symptom onset of ≥ 6 h before blood sampling; were utilized for further study differences in serum levels of hs-CRP between AMI onset of

Blood Sampling and Laboratory Investigations

Blood samples were obtained once in both healthy volunteers (in the outpatient department) and coronary artery disease control subjects (in the catheterization room prior to coronary angiographic study). Measurement of whole blood counts, biochemistries, and electrolytes was done using standard laboratory methods.

The hs-CRP was measured by immunonephelometry using the BN system (Dade Behring; Newark. DE). The lower detection limit of this test is

Definitions and Data Collection

AMI was defined as typical chest pain lasting for > 30 min with ST-segment elevation > 1 mm in two consecutive precordial or interior leads. Detailed ill-hospital and follow-up data including age, sex, coronary risk factors, Killip score on admission, preinfarction angina, body mass index (BMI), body temperature on admission. WBC counts, creatinine level, serum level of hs-CRP, angiographic findings, and number of diseased vessels were obtained. These data were collected prospectively and entered into a computerized database.

Statistical Analysis

Data were expressed as mean SD. Categorical variables were compared using χ^sup 2^ test or Fisher Exact Test. Univariate analyses were performed using Student t test. Continuous variables were compared using Wilcoxon rank-sum test. Continuous variables among the three groups were compared using one-way analysis of variance for parametric data and Kruskal-Wallis test for nonparametric data. Repeated measures of analysis of variance were used for comparison of age among the three groups. Statistical analysis was performed using SAS statistical software for windows version 8.2 (SAS Institute; Cary, NC). A probability value


Baseline Characteristics of All Subjects

There were no significant differences among the three groups with regard to age, gender, body temperature, BMI, or creatinine level (Table 1). There were also no significant differences between study patients and angina subjects in terms of coronary artery disease risk factors, previous myocardial infarction, and previous stroke. Laboratory investigation demonstrated WBC counts were significantly higher in study patients than in the angina subjects and healthy control subjects. Furthermore, serum levels of hs-CRP that were measured within 6 h after AMI were significantly higher in study patients than in the angina subjects and control subjects. There was no significant difference in serum hs-CRP levels between angina patients and control subjects. However, WBC counts were found to be significantly higher in angina patients than in the control subjects. Angiographic results demonstrated that there was no significant difference in multiple-vessel disease between study patients and angina subjects.

Table 1-Baseline Characteristics of Study Patients, Angina, and Normal Control Groups*

Table 2-Comparison of Baseline Characteristics, Clinical Variables, Laboratory Findings, and Angiographic Results Between the Patients With Onset of AMI ≤ 3 h and Patients With Onset of AMI > 3 h to

Comparison of Baseline Characteristics, Clinical Variables, Laboratory Findings, and Angiographic Results Between the Patients With Onset of AMI ≤ 3 h and Patients With Onset of AMI > 3 \h but

There were no significant differences in terms of age, gender, coronary artery disease risk factors, previous myocardial infarction, previous stroke, body temperature, BMI, preinfarction angina, anterior wall infarction, or cardiogenic shock on admission between patients with an onset of AMI ≤ 3 h and patients with an onset of AMI > 3 h but

Comparison of the Effect of Baseline Characteristics, Clinical Variables, and Angiographic Findings on Serum hs-CRP Levels in 106 Study Patients

The effects of baseline characteristics, clinical variables, and angiographic findings on serum hs-CRP are shown in Table 3. Statistically, weakly significant higher serum hs-CRP levels (p = 0.04) were found to be in women, in patients with hypertension, and in patients without previous myocardial infarction. The effects of other baseline characteristics, clinical variables, and angiographic results on serum levels of hs-CRP did not appear to show any differences among the study patients.

Comparison of Baseline Characteristics, Clinical Variables, Laboratory Finding, and Angiographic Results Between Patients With Onset of AMI

There were no significant differences in terms of male sex, coronary artery disease risk factors, previous stroke or mvocardial infarction. BMI, body temperature, preinfarction angina, anterior wall infarction, or cardiogenic shock on hospital admission between patients with onset of AMI

Table 3-Comparison of the Effect of the Baseline Characteristics, Clinical Variables, and Angiographic Finding on Serum Levels of hs- CRP in 106 Study Patients*

Table 4-Comparison of Baseline, Clinical Characteristics, Laboratory Findings, and Angiographic Results Between Patients With Onset AMI of


In the present study, one of the important findings was that the serum hs-CRP level was significantly higher in patients with an onset of AMI ≥ 6 h than in patients with an onset of AMI 3 h but

CRP has been believed to directly participate in initiation and propagation of atherosclerosis.6,20,21 The direct proatherogenic effects of CRP extend beyond the endothelium to the vascular smooth muscle.21 Accumulating evidence from clinical observation suggests that CRP levels are one of the most powerful predictors of atherosclerosis and vascular death,11,12 offering prognostic value exceeding that of low-density lipoprotein cholesterol.22 Therefore, CRP has recently emerged as one of the most important novel inflammatory markers.10-12,16,22-24 This clinical observation10,12,16,22 is further corroborated by growing evidence from in vitro studies17,18,20,21 that have demonstrated that the mechanistic basis of the predictive value of CRP is its ability to incite endothelial dysfunction, stimulate endothelial-1 and interleukin-6 release, up-regulate adhesion molecules, and stimulate inonocyte chemoattractant protein-1 while facilitating macrophage low-density lipoprotein uptake.

Surprisingly, while these basic studies have aroused enthusiasm about CRP in vascular atherosclerosis, the potential impact of the increasing serum CRP triggering vulnerable plaque rupture has rarely been investigated.9 Until recently, only one study from Tomoda and Aoki19 tried to find a correlation between the serum levels of CRP and the vulnerability of culprit coronary lesions within 6 h of onset of AMI. They demonstrated that patients with elevated CRP levels on hospital admission had more vulnerable coronary artery lesions and worse clinical outcomes than patients with normal serum CRP levels. However, this study was retrospective and had no comparison between risk control and healthy control subjects. Therefore, it could not answer whether are different levels of serum CRP among patients with AMI of onset

The main finding of the present study is that the serum level of hs-CRP was more markedly elevated in patients with AMI of onset

Our study hits limitations. First, the exact time of symptom onset was usually difficult to determine in our patients. Therefore, a potentially inaccurate duration from onset of AMI to blood sample could be present. Hence, the effect of myocardial damage on serum hs- CRP would not be completely eliminated in the present study. Second, although the striking impact of serum CRP on long-term outcomes has been investigated,12 our study was not designed to investigate the correlation between serum hs-CRP and short- or long-term clinical outcomes. Theretore, we could not provide evidence other than serum levels of hs-CRP in the clinical setting of AMI. Third, although serum hs-CRP markedly elevated within 6 h alter the onset of AMI in the present study, we did not know whether this elevation was chronic and persistent or only reflected a surge episode. However, it would he impossible to measure serial changes in hs-CKP level in patients before an AMI.

In conclusion, hs-CRP might not only mirror an inflammatory stimulus, hut also have direct effect promoting atherosclerotic propagation and destabilizing plague. Elevated serum hs-CRP levels in patients with AMI

* From the Division of Cardiology, Chang Gung Memorial Hospital, Kaohsiung, Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, ROC.


1 Ross R. The pathogenesis of atherosclerosis: a perspective for 1990s. Nature 1993: 362:801-809

2 Faruqi RM, DiCorleto PE. Mechanisms of monocyte recruitment and accumulation. Br Heart J 1993; 69:S19-S29

3 van der Wal AC, Becker AE. van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is cliaracterized by an inflammatory process irrespective of the dominant plaque morpholog. Circulation 1994; 89:36-44

4 Libby P, Geng VJ, Sukhova GK, et al. Molecular determinants of atherosclerotic plaque vulnerability. Ann N Y Acad Sci 1997; 811:134- 145

5 Ross R. Atherosclerosis: an inflammatory discase. N Fngl J Med 1999; 340:115-126

6 Pasceri V, Cluing J. Willerson JT, et al. Modulation of C’- reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cell by anti-atherosclerosis drugs. Circulation 2001; 103:2531-2534

7 Falk E, Shah Pk. Fuster Y. Coronary plaque disruption. Circulation 1995; 92:657-761

S Burke AP, Farb A. Malcom GT. et al. Coronary risk factors and plaque morphologx in men with coronary disease who died suddenly. N Engl J Med 1997; 336:1276-1282

9 Burke AP, Tracy RP, Kologie F, et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation 2002; 105:2019- 2023

10 Koe\nig W, Sund M Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA Augsburg Cohort Study, 1984 to 1992. Circulation 1999; 99:237- 242

11 Shak PK. Circulating markers of inflammation for vascular risk prediction: are they ready for prime time? Circulation 2000; 101:1758-1759

12 Mueller C. Buettner HJ, Hodgson JM, et al. Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients. Circulation 2002; 105:1412-1415

13 Kushner I, Broder ML, Karp D. Control of the acute phase response: serum C-reactive protein kinetics alter acute myocardial infarction. J Clin Invest 1978; 61:235-242

14 deBeer FC, Hind CBK, Fox KM, et al. Measurement of serum C- reactive protein concentration in mvocardial ischemia and infarction. Br Heart J 1982; 47:239-243

15 Pietila KO, Harmoinen AP, Jokiniitty J, et al. Serum C- reactive protein concentration in acute mvocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolvtic treatment. Eur Heart J 1996; 17:1345- 1349

16 Ueda S, Ikeda U, Yamamoto K, et al. C-reactive protein as a predictor of cardiac rupture after acute mvocardial infarction. Am Heart J 1996; 131:857-860

17 Morrone C, Ciliberto C. Oliviero S. et al. Recombinant interleukin 6 retaliates the tianscriptional activation of a set of human acute phase genes. J Biol Chem 1988; 263:12554-12558

18 Le J, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 1989; 61:588-602

19 Tomoda H, Aoki N. Prognostic value of C-reactive protein levels within six hours after the onset of acute myocardial infarction. Am Heart J 2000; 140:324-328

20 Pasceri Y, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102:2165-2168

21 Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C- reactive protein. Circulation 2002; 105:1890-1896

22 Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557-1565

23 Rider PM. Novel risk factors and makers for coronarv disease. Adv Intern Med 2000; 45:391-418

24 Szmitko PE, Wang CH, Weisel RD, et al. New makers of inflammation and endothelial cell activation: part I. Circulation 2003; 108:1917-1923

Hon-Kan Yip, MD; Chiung-Jen Wu, MD; Hsueh-Wen Chang, PhD; Cheng- Hsu Yang, MD; Kuo-Ho Yeh, MD; Sarah Chua, MD, FCCP; and Morgan Fu, MD

Manuscript received March 10, 2004; revision accepted June 8, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Morgan Fu, MD, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, 123, Ta Pei Rd, Niao Sung Hsiang, Kaohsiung Hsien, 83301, Taiwan, ROC; e-mail: tang@adm.cgmh.or.tw

Copyright American College of Chest Physicians Nov 2004

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