C-reactive protein elevation and disease activity in patients with coronary artery disease

Ramón Arroyo-Espliguero, Pablo Avanzas, Juan Cosín-Sales, Guillermo Aldama, Carmine Pizzi and Juan Carlos Kaski*

Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK

* Corresponding author. Tel.: +44-20-8725-5901; fax: +44-20-8725-3328
E-mail address: jkaski{at}sghms.ac.uk

Received 2 February 2003; revised 14 December 2003; accepted 18 December 2003

Abstract

Aims We sought to assess (1) whether C-reactive protein (CRP) is an independent predictor of future cardiovascular events after adjustment for coronary artery disease (CAD) severity and (2) whether CRP levels correlate with number of angiographically complex coronary artery stenosis.

Methods and results We studied 825 consecutive angina patients (mean age 63±10 years, 74% men), 700 with chronic stable angina (CSA) and 125 with acute coronary syndromes without ST-segment elevation (ACS). The composite endpoint of non-fatal acute myocardial infarction, hospital admission with class IIIb unstable angina and cardiac death was assessed at one year follow-up. Hs-CRP level was higher in CSA patients with the combined end-point () after adjustment for number of diseased coronary arteries. Hs-CRP was also significantly higher in patients with ACS compared to CSA () and correlated with number of complex angiographic stenoses (, ). Hs-CRP was also increased in patients with NYHA functional class III or IV compared to those in class I or II ().

Conclusions CRP levels predict future cardiovascular events independently of CAD severity and correlate with number of angiographically complex coronary artery stenosis in patients with ACS. Thus, CRP levels are a marker of atheromatous plaque vulnerability and CAD activity.

Key Words: Inflammation • Coronary artery disease • C-reactive protein • Angina • Plaque complexity

Introduction

The acute-phase reactant C-reactive protein (CRP) has been shown to be a strong independent predictor of future cardiovascular events,1 i.e., myocardial infarction (MI), stroke and death in patients with angina2,3 and in apparently healthy subjects.4 Whether in angina patients elevated CRP levels simply represent a surrogate of atherosclerotic burden rather than a marker of coronary artery disease (CAD) activity is controversial.1–6 We hypothesized that irrespective of CAD extent and severity, serum CRP levels are an index of atheromatous plaque activity and vulnerability. In the present study, we assessed whether CRP is a marker of CAD extent and an independent predictor of future cardiovascular events after adjustment for number of diseased coronary vessels.

Increased CRP levels may portend the vulnerability of an atherosclerotic plaque and also contribute to plaque disruption.7 Systemic inflammation has been shown in angiographic, angioscopic and intravascular ultrasound (IVUS) studies to predispose the individual to multifocal plaque disruption and the development of acute coronary syndromes (ACS).8–10 Moreover, it has been suggested that CRP may not only be a marker of generalized inflammation but directly and actively participates in both atherogenesis11–13 and atheromatous plaque disruption.14 In this study we tested the hypothesis that high CRP levels correlate with the presence of complex angiographic stenoses, which are known to represent high-risk coronary plaques.15,16

Methods

Patient selection
We studied 825 consecutive patients (mean age 63±10 years, 74% men) admitted to our unit for the assessment of angina chest pain. One hundred and twenty five (15%) patients had ACS without ST-segment elevation and 700 (85%) had chronic stable angina (CSA). CSA was defined as typical exertional chest pain brought on by exertion and relieved by rest, sublingual nitrates or both with symptoms stable for at least three months before study entry. All CSA patients had a positive ECG exercise stress test response (1 mm ST-segment depression) or reversible perfusion defects during myocardial perfusion scintigraphy and underwent coronary arteriography.

ACS was defined as prolonged (20 min) ischemic chest pain in the preceding 24 h associated with transient ischemic ECG changes with or without raised levels of markers of myocardial damage. The clinical management of ACS and the decision to proceed to angiography was left to the discretion of the managing cardiologist who was unaware of results regarding inflammatory markers. Sixty three ACS patients (50%) underwent coronary angiography during hospital admission.

Patients with recent (12 weeks) acute myocardial infarction (AMI), life-threatening arrhythmias, cardiac valve disease, acute or chronic liver disease, infectious diseases or other conditions likely to cause death within one year were not included in the study. None of the patients included in the study had ongoing systemic or cardiac inflammatory processes. All patients gave written informed consent before study entry and the study was approved by the local research ethics committee.

Clinical characterization and study end-points
At study entry, the data acquired included age, gender, body mass index (BMI), blood pressure, and assessment of risk factors including a history of MI and a previous percutaneous transluminal coronary angioplasty (PTCA). During baseline evaluation, symptoms of congestive heart failure (CHF) were assessed using the New York Heart Association (NYHA) CHF functional classification.17 The patients ability to perform a variety of every day tasks, i.e., personal care, housework, occupational and recreational activities was systematically assessed and consequently assigned to a specific NYHA functional class as appropriate. Canadian Cardiovascular Society (CCS) functional class was also recorded at study entry. Cardiac medications taken at study entry, specifically aspirin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, ß-blockers, angiotensin-converting enzyme inhibitors (ACEIs), digoxin, diuretics and nitrates were recorded.

After recruitment and baseline characterization all patients were followed up for one year. Major clinical events during follow-up were: non-fatal AMI, defined according to World Health Organization criteria, readmission to the coronary care unit (CCU) with Braunwald’s class IIIb unstable angina requiring treatment and/or urgent revascularization18 and cardiac death.

High sensitivity C-reactive protein measurements
Fasting blood samples were obtained from CSA patients at the time of diagnostic coronary angiography. In ACS patients blood samples were drawn at admission to the CCU. CRP measurements were performed on the COBAS Integra (Roche Diagnostics Limited, Lewes, East Sussex, UK.) using the CRP-Latex assay in both the high sensitivity application (analytical range 0.2–12 mg/L) and the normal application (analytical range 2–160 mg/L). Analytical precision of the high sensitivity CRP-Latex assay was 7.6% at a level of 1.02 mg/L, 3.3% at 1.79 mg/L and 1.3% at a level of 4.36 mg/L. Samples outside the analytical range of the high sensitivity CRP-Latex assay were analyzed by the CRP-Latex assay in the normal application. The analytical precision of the normal CRP-Latex assay was 2.4% at a level of 29.5 mg/L and 1.3% at a level of 113 mg/L.

Angiographic analyses
Images of the coronary tree were obtained with the digital Philips Integris 3000 system (Philips, Holland), using an automated quantitative coronary artery stenosis assessment process in all patients. Two experienced cardiologists who had no knowledge of the patients’ clinical characteristics and biochemical results reviewed all angiographic images to assess the extent of CAD and morphology of all coronary artery stenoses with >=30% reduction in diameter.

Angiographic scoring system
As described in previous studies from our group,19 coronary angiograms were assessed and scored according to Sullivan et al.,20 which includes vessel score, stenosis score and extension score. Vessel score is based on the number of coronary arteries showing 75% reduction in lumen diameter. Stenosis score is aimed at reflecting the most severe stenosis observed in each of the main coronary vessels assessed. Extension score refers to the proportion of the coronary artery tree showing angiographically detectable atheroma.

Angiographic coronary stenosis morphology
As in previous work from our unit,19 complex coronary lesions were defined by the following features: (1) irregular morphology or scalloped borders, or both; (2) overhanging or abrupt edges perpendicular to the vessel wall; (3) ulceration (i.e., outpouchings within the stenosis); and/or (4) the presence of filling defects consistent with intracoronary thrombus. When discrepancies arose regarding the morphologic appearance of a lesion, a third experienced observer was involved and the lesion was classified by consensus.

Statistical analysis
Results of normally distributed continuous variables are expressed as the mean value±SD. Continuous variables with a non-normal distribution are presented as median value (interquartile interval) and qualitative variables are presented as frequencies. Analysis of normality of the continuous variables was performed with the Kolmogorov–Smirnov test. Differences between ACS and CSA patients were assessed by unpaired t test and the Mann–Whitney U test for continuous variables, as appropriate, and testing was used for discrete variables. Logistic regression was used to assess the univariate associations between continuous baseline characteristics and the probability of having an event. Correlations between continuous variables were analyzed with two-way Pearson or Spearman correlation tests, as appropriate. The Kruskal–Wallis test for two-way analysis of variance was used to evaluate differences in hs-CRP levels between NYHA functional classes. Moreover, for the purpose of analysis, and for clinical relevance, NYHA and CCS functional classes were dichotomized into binary predictors: I–II vs. III–IV. Information regarding the development of combined end-point was available in all patients included in the study. Multivariate analysis used linear regression analysis for a continuous dependent variable and binary logistic regression analysis for a discrete variable. Backward stepwise selection was used to derive the final model for which significance levels of 0.1 and 0.05 were chosen to exclude and include terms, respectively. Variables included in multivariate analysis were those which showed a correlation in univariate analysis that was significant at the 20% significance level. The relationship between hs-CRP levels and the endpoint was not of linear nature. Therefore, hs-CRP was logarithmically transformed before entering the logistic regression analysis. In the same way, in order to fulfill the statistical requirement for multiple regression analysis (normal distribution and constant variance of the residuals) a logarithmical transformation of hs-CRP levels was performed. Differences were considered to be statistically significant if the null hypothesis could be rejected with 95% confidence. All values are two-tailed. The SPSS 11.0 statistical software package (SPSS Inc., Chicago, IL) was used for all calculations.

Results

Hs-CRP levels and clinical events during follow-up in patients with CSA
Baseline characteristics of the 700 patients with CSA are shown in Table 1. Sixty eight CSA patients (10%) suffered the combined end-point (Table 2), whereas 632 patients had no events. Hs-CRP levels increased the probability of having an event () (Table 3). Univariate analysis also revealed that a history of previous MI (), number of diseased vessels (>=50% diameter reduction) () and a NYHA functional class III or IV () were significantly different in patients with events and those without events. Of interest, 320 (46%) patients underwent scheduled coronary revascularization in the one year follow-up (103 [32%] patients underwent PTCA and 217 [68%] coronary artery by-pass grafting (CABG)). No significant differences in serum hs-CRP concentrations were found between patients with and those without revascularization. However, CSA patients who underwent coronary revascularization had significantly fewer major events than those without revascularization (6% vs. 13%; ). After adjustment using backward stepwise binary logistic regression, hs-CRP serum concentration (), number of diseased vessels (>=50% diameter reduction) () and scheduled coronary revascularization () remained significantly different (Table 4).


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Table 1 Baseline characteristics of 700 patients with chronic stable angina and 125 patients with acute coronary syndromes without ST-segment elevation

 

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Table 2 Major cardiovascular events during one year follow-up in 700 patients with chronic stable angina

 

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Table 3 Baseline characteristics of 700 patients with chronic stable angina included in the study: comparison between patients with and without cardiovascular events

 

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Table 4 Multivariate predictors of the combined end-point of cardiac death, non-fatal myocardial infarction, class IIIb unstable angina in the 700 patients with chronic stable angina included in the study

 
Clinical and angiographic predictors of serum hs-CRP level distribution in patients with CSA
Baseline serum hs-CRP concentrations were higher in women (), patients with a history of MI () or a previous PTCA (), smokers () and hypertensive patients (). Baseline serum hs-CRP levels were higher in patients with NYHA functional class III or IV () (Table 5) and with CCS functional class III or IV (). Higher serum hs-CRP levels were also found in patients receiving treatment with ACEI (), diuretics () and digoxin (). Significant correlations were also found between hs-CRP levels and age (, ), BMI (, ) and serum triglyceride levels (, ). Hs-CRP levels, however, were not significantly associated with total cholesterol serum levels (), diabetes mellitus or treatment with aspirin or HMG-CoA reductase inhibitors in the univariate analysis. Moreover, hs-CRP was not significantly correlated with CAD extent or severity, as assessed by the number of coronary vessels with >=50% lumen reduction, vessel, stenosis and extension scores (Table 6). No significant association was found between hs-CRP levels and number of complex plaques in patients with CSA (; ).


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Table 5 C-reactive protein levels found in relation to NYHA functional class in 700 patients with chronic stable angina

 

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Table 6 Correlation between serum C-reactive protein levels and angiographic data of 700 patients with chronic stable angina

 
Interestingly, serum hs-CRP levels showed a weak, albeit significant, correlation with left ventricular ejection fraction (LVEF) (; ). After adjustment using backward linear multiple regression analysis, only age (), gender (), BMI (), smoking status (), serum triglyceride levels () and NYHA functional class III or IV () were independent predictors of serum CRP concentrations (Table 7).


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Table 7 Multivariate predictors of C-reactive protein levels in 700 patients with chronic stable angina

 
Hs-CRP levels and number of complex coronary lesions in patients with ACS
Baseline characteristics of patients with ACS () are shown in Table 1. Serum hs-CRP levels were higher in patients with ACS than in CSA (). After binary logistic regression hs-CRP remained significantly different when CSA and ACS patients were compared (OR 3.4 [1.4–8.4] CI 95%, ).

Hs-CRP levels showed a significant correlation with the number of angiographically complex coronary artery lesions (, ) but did not significantly correlate with number of smooth lesions (; ). Univariate analysis revealed that age (, ), number of diseased vessels with >=50% lumen reduction (, ) and low-density lipoprotein (LDL) cholesterol levels (, ) were also significantly correlated with the number of complex lesions. After backward stepwise multiple regression analysis, independent predictors of the number of complex lesions were number of vessels with >=50% lumen reduction () and hs-CRP levels ().

Discussion

We found that CRP concentrations predict future cardiovascular events in patients with CSA, independently of CAD severity. We also found that CRP concentrations are higher in patients with ACS and correlate with number of complex lesions in these patients. These findings indicate that serum CRP is a marker of disease activity and this concept is endorsed by studies showing that CRP levels correlate with cardiovascular risk in ACS patients.

Our results thus give further support to the increasingly accepted hypothesis that CRP is not merely a marker of systemic inflammation but may also be a pathogenic mechanism in ACS.11,14,21

Clinical and angiographic potential determinants of hs-CRP distribution in CSA patients
The present study also confirms previous findings that CRP concentrations raise with increasing age and with smoking status.5,22,23 The mechanism whereby smoking is related to CRP concentration is unclear, but it may be multifactorial, involving bronchial injury, endothelial activation and systemic inflammation.5,22 Increased serum CRP concentrations have been reported to be associated with metabolic disorders such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes,23 suggesting that low-grade systemic inflammation may underlie these metabolic disorders. In fact, it has been suggested that obesity could be an inflammatory disorder and elevated serum levels of inflammatory markers have been described in overweight and obese children and adults.24 This hypothesis is further endorsed by the observation in this study and others22,23 that a significant correlation exists between serum CRP concentration and both BMI and serum triglyceride levels. Inflammation could be the common link between obesity and cardiovascular disease.24

Another important finding of the present study is the higher serum CRP levels in CSA patients with NYHA functional class III or IV compared to patients with class I or II. The effect of CRP in NYHA functional class was independent of other potential confounding variables, such as age, gender, BMI, LVEF, number of diseased coronary vessels and treatment with ACEI, digoxin, diuretics and ß-blockers. The higher serum CRP levels seen in patients under treatment with ACEI, digoxin and diuretics may be reflecting the worse NYHA functional class of these patients. These findings are in agreement with a recently published report which showed higher levels of CRP with increasing NYHA functional class, especially in patients with ischemic cardiomyopathy,25 and a trend to decreasing values of LVEF in relation to higher CRP levels. The significant relationship between CRP and both LVEF and NYHA CHF functional class in patients with CSA suggests the implication of inflammatory mechanisms in left ventricular dysfunction and in the pathogenesis of CHF, independently of the underlying atherosclerotic burden. CRP may exert a negative inotropic or cytotoxic effect on cardiac myocytes and, thus, play an important role in the pathogenesis of cardiac dysfunction and remodeling.26

Our study showed that CRP does not correlate with the extent or severity of CAD. The relation between CRP and CAD severity/extent is a controversial issue. Some studies have shown a correlation between CRP and the extent of atherosclerosis,1,5 whereas others have not found such a correlation.6 Zebrack et al.1 recently reported a correlation between CRP and the extent of CAD using a CAD score, but correlation coefficients were low indicating a weak relationship and there was no correlation between CRP and the number of moderate and severe lesions. Our results showed that serum CRP concentration did not correlate with severity or extent of CAD. These findings are in agreement with results reported by Azar et al.6 Our findings showing a correlation between CRP levels and both cardiovascular events and complex coronary stenoses suggest that CRP is not merely a marker of angiographic atherosclerosis burden but a marker of CAD activity. In our study CRP and angiographic severity of CAD were independent markers of risk and each provided complementary information.

Hs-CRP and inflammatory activity in the coronary atheromatous plaque
The relation of serum CRP concentrations with adverse cardiovascular events during follow-up in CSA patients in the present study suggests that clinical "stability" does not always indicate atheromatous plaque stability.27 Increased serum CRP levels in patients with CSA may be a reflection of ongoing inflammation in the atheromatous plaque, which may lead to plaque vulnerability and progression to unstable syndromes. In several atherectomy investigations, considerable amounts of inflammatory cells were found in culprit lesions of CSA patients and the presence of thrombus was documented in substantial numbers of apparently stable plaques.27 It has been recently reported that CRP correlates with the number of vulnerable atherosclerotic plaques with superficial foam cells, large necrotic cores and thin fibrous cap atheroma.21 These findings suggest that the increased risk of future coronary events observed in patients with elevated serum CRP is directly related to the increased number of vulnerable plaques prone to rupture,21 strengthening the role of CRP as a major risk factor for the development of clinical manifestations of CAD.

CRP has been shown to actively participate in both atheromatous lesion formation11–13 and plaque disruption.14 CRP increases the expression of endothelial adhesion molecules and monocyte chemoattractant protein-1 (MCP-1),12,28 facilitates native LDL uptake into macrophages,13 promotes monocyte activation29 and a procoagulant effect by inducing monocytes to synthesize tissue factor.30 CRP can also activate the classic pathway of complement activation31 and has been demonstrated to colocalize with terminal complement complexes in established coronary plaques.32

Our finding that hs-CRP serum level is increased in patients with ACS and correlates with number of complex lesions in these patients provides support to a role of CRP in plaque vulnerability. The fact that a large proportion of patients with ACS in our study had multiple complex stenosis is compatible with recent angioscopic and IVUS imaging studies suggesting a pan-coronary involvement in ACS.8,9 Recently, it has been reported that several vulnerable plaques other than the "culprit" stenosis can be found in individual patients with MI8,9 and that multiple plaque disruption occurs in patients with ACS.10 These findings are likely to be the result of a diffuse inflammatory process that leads to multifocal plaque instability. CRP may thus be a marker of this process.

However, no significant association was found between hs-CRP levels and number of complex plaques in patients with CSA. Given the fact that this same relationship was statistically significant in patients with ACS, the lack of association between CRP and number of complex plaques in the CSA setting is intriguing. The reasons for the discrepancy are speculative but the relatively small patient sample size may account, at least partially, for these findings. Further studies are required to clarify the issue.

Limitations of the study
We have used coronary arteriography to characterize plaque complexity. Angiography depicts coronary anatomy from a planar two-dimensional silhouette of the lumen and cannot detect early signs of atherosclerosis or disease activity. Both IVUS and angioscopy are likely to provide more accurate information regarding atherosclerotic burden. However, even with the limitations imposed by angiography, our results are in agreement with studies with angioscopy and IVUS regarding the presence of vulnerable plaques in CAD patients.

Conclusion

CRP levels predict future cardiovascular events in patients with CSA independently of CAD severity. CRP concentrations are also higher in patients with ACS and correlate with number of complex vulnerable plaques in these patients. These findings indicate that serum CRP levels are a marker of CAD activity and may be a biochemical marker of the diffuse inflammatory process that leads to multifocal plaque instability.

Acknowledgments

We are grateful to M. Lacalle and J.M. Bellón from Department of Preventative Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain for expert statistical advice.

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