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(Chest. 2004;126:1417-1422.)
© 2004 American College of Chest Physicians

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

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

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

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{at}adm.cgmh.org.tw


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 < 12 h after the onset of AMI) with ST-segment elevation AMI undergoing primary percutaneous coronary intervention (PCI). Serum levels of hs-CRP were also measured in 30 patients with stable angina undergoing elective PCI and in 30 healthy control subjects. The serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 ± 2.3 mg/L vs 1.4 ± 0.7 mg/L, p < 0.0001 [mean ± SD]) and in healthy subjects (2.7 ± 2.3 mg/L vs 1.0 ± 0.6 mg/L, p < 0.0001). There were no significant differences in serum levels of hs-CRP in patients with an onset of AMI ≤ 3 h than in those patients with an onset of AMI > 3 h but < 6 h (2.7 ± 2.5 mg/L vs 2.7 ± 2.2 mg/L, p = 0.87). However, the serum level of hs-CRP was significantly higher in patients with an onset ≥ 6 h than in patients with an onset < 6 h (14.1 ± 16.5 mg/L vs 2.7 ± 2.3 mg/L, p < 0.0001).

Conclusions: Serum levels of hs-CRP were significantly higher in patients with an onset of AMI < 6 h than in healthy subjects and in patients with angina pectoris undergoing PCI. The inflammatory process has been proved as one of the mechanisms causing plaque rupture. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.

Key Words: acute myocardial infarction • high-sensitivity C-reactive protein


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A growing number of studies123456 report that inflammation plays a crucial role in the cell biology of atherosclerosis. Pathologic and immunohistochemical staining studies789 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.101112 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,1314 and the level of this CRP has been reported to be associated with poor prognosis after acute myocardial infarction (AMI).1516 However, CRP is primarily synthesized and secreted rapidly in liver 6 h after an acute inflammatory stimulus.1718 Thus, serum levels of CRP within 6 h after 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.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
In our hospital, all patients 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 after vascular puncture before coronary angiography 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 months, 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 if fever (body temperature > 37.5°C) 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 < 12 h in duration undergoing primary PCI in our hospital. Fourteen of the 171 patients (8.2%) were subsequently excluded due to fever (3 patients), infection (2 patients), malignancy (2 patients), or renal function impairment (7 patients).

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 < 6 h and ≥ 6 h but < 12 h. Therefore, the remaining 106 patients constituted the study population. Thirty subjects who underwent PCI due to angina matched with respect to age, gender, hypertension, diabetes mellitus, current smoking, and hypercholesterolemia served as coronary artery disease control subjects. We also studied 30 age- and gender-matched healthy volunteers. Informed consent was obtained from all study subjects. The study protocol was approved by the Institutional Review Committee on Human Research in our institution.

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 < 0.10 mg/L. We assessed the intraindividual variability of serum hs-CRP levels in study patients, angina subjects, and healthy subjects. The mean intraassay coefficients of variance were 2.83%, 2.79%, and 2.96%, respectively.

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 inferior leads. Detailed in-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 {chi}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 < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
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.


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

 
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 < 6 h
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 < 6 h (Table 2 ). Laboratory investigation demonstrated no significant differences in serum levels of hs-CRP or WBC counts among these patients. Angiographic results also demonstrated no significant differences in multiple vessel disease, pre-PCI thrombolysis in myocardial infarction (TIMI) flow grades, or intercoronary collaterals.


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  		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 < 6 h*

 
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.


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

 
Comparison of Baseline Characteristics, Clinical Variables, Laboratory Findings, and Angiographic Results Between Patients With Onset of AMI < 6 h and Patients With Onset of AMI ≥ 6 h
There were no significant differences in terms of male sex, coronary artery disease risk factors, previous stroke or myocardial infarction, BMI, body temperature, preinfarction angina, anterior wall infarction, or cardiogenic shock on hospital admission between patients with onset of AMI < 6 h and patients with onset of AMI ≥ 6 h (Table 4 ). However, patients with onset of AMI ≥ 6 h were older than those with onset of AMI < 6 h. Laboratory findings demonstrated there were no significant differences in terms of WBC counts and creatinine levels between these two groups of patients. However, the serum level of hs-CRP was markedly higher in patients with onset of AMI ≥ 6 h than in those with onset of AMI < 6 h. Angiographic results demonstrated that the incidences of multiple-vessel disease, pre-TIMI flow grades, and intercoronary collaterals were similar between these two groups of patients. The mean time from onset of chest pain to blood sampling was substantially longer in patients with onset of AMI ≥ 6 h than in patients with onset of AMI < 6 h.


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  		Table 4.. Comparison of Baseline, Clinical Characteristics, Laboratory Findings, and Angiographic Results Between Patients With Onset AMI of < 6 h and Patients With Onset of AMI ≥ 6 h*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
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 < 6 h. However, there was no difference between patients with onset of AMI ≤ 3 h and those with an onset > 3 h but < 6 h. Our finding suggests that these substantially increased serum hs-CRP levels in the clinical setting of AMI of onset ≥ 6 h are due to the results of myocardial damage. However, hs-CRP levels within 6 h of onset of AMI, before they can be affected by myocardial damage, reflect the baseline levels of serum hs-CRP in these patients. Previous studies1718 have demonstrated that the circulating concentration of human CRP, the classical acute phase protein, is always increased after AMI, starting approximately 6 h after onset of symptoms and reaching a peak after approximately 50 h.1314 Therefore, according to our study and other studies,13141718 serum hs-CRP can be categorized into two different intervals in the clinical setting of AMI. This is clinical importance because it may provide eligible information for assessment of the possible impact of hs-CRP levels on coronary atherosclerotic lesions and on clinical outcomes of patients with AMI undergoing variable strategic managements.

CRP has been believed to directly participate in initiation and propagation of atherosclerosis.62021 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,1112 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.10111216222324 This clinical observation10121622 is further corroborated by growing evidence from in vitro studies17182021 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 monocyte 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 < 6 h, risk control subjects, and normal subjects.

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 < 6 h than in normal control subjects. Another important finding was that the serum hs-CRP was significantly higher in patients with AMI of onset < 6 h than in patients with angina pectoris undergoing elective PCI. Therefore, our findings extend the findings from Tomoda and Aoki,19 and suggest that significantly increased hs-CRP or a spike in serum hs-CRP may be a fundamentally important prerequisite for an atherosclerotic plaque to rupture. This, as a consequence, leads to AMI. An autopsy study from Burke et al9 demonstrated that there is a strong correlation between hs-CRP levels and increased numbers of thin atheromas in the coronary tree. Moreover, a positive correlation between the intensity of CRP staining in plaque and serum levels of hs-CRP was also found in their study.9 Therefore, they suggested that hs-CRP levels were highest in hearts harboring acute rupture and erosion. Our suggestion based on laboratory data and clinical observations is corroborated by Burke et al,9 and further correspond with the results from other basic studies.172021

Our study has 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. Therefore, 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 after 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 be impossible to measure serial changes in hs-CRP level in patients before an AMI.

In conclusion, hs-CRP might not only mirror an inflammatory stimulus, but also have direct effect promoting atherosclerotic propagation and destabilizing plaque. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.


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

Received for publication March 10, 2004. Accepted for publication June 8, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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