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Eur J Cardiothorac Surg 2007;31:685-690. doi:10.1016/j.ejcts.2006.12.029
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis

Tullio Palmerinia,*, Antonio Marzocchia, Cinzia Marrozzinia, Letizia Bacchi Reggiania, Carlo Savinib, Giuseppe Marinellib, Roberto Di Bartolomeob, Angelo Branzia

a Department of Cardiology, Policlinico S. Orsola, University of Bologna, Italy
b Department of Cardiac Surgery, Policlinico S. Orsola, University of Bologna, Italy

Received 16 October 2006; received in revised form 20 December 2006; accepted 22 December 2006.

* Corresponding author. Address: Department of Cardiology, University of Bologna, Policlinico S. Orsola, Via Massarenti 9, 40 138 Bologna, Italy. Tel.: +39 051 349858; fax: +39 051 344859. (Email: tulliopalmerini{at}hotmail.com).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitation
 References
 
Objective: Preprocedural levels of C-reactive protein predict mid-term mortality after percutaneous coronary intervention for the treatment of unprotected left main coronary artery stenosis. However, there are no data regarding the impact of C-reactive protein on mid-term mortality in patients with unprotected left main coronary artery stenosis treated with coronary artery bypass graft. Methods: The predictive value of preoperative C-reactive protein levels, leukocyte counts, and fibrinogen levels were evaluated in a series of 108 patients who underwent coronary artery bypass graft surgery at our Institution from 1st January 2002 to 31st April 2005. Patients were divided in two groups: Group 1 included patients with C-reactive protein levels in quartiles IV (C-reactive protein levels ≥1.22 mg/dl) and Group 2 included patients with C-reactive protein levels in quartiles I + II + III. Results: At 9-month follow-up the rate of mortality was 25.9% in Group 1 and 4.9% in Group 2 (hazard ratio = 5.86, 95% confidence intervals = 1.71–20.03; p = 0.005). In all patients who had cardiac mortality, C-reactive protein levels were >0.5 mg/dl. In the multivariate analysis age >75 years, peripheral vascular disease and C-reactive protein quartiles were the only independent predictors of mortality. Conclusions: Elevated preoperative levels of C-reactive protein indicate an increased risk of death after coronary artery bypass graft surgery for the treatment of unprotected left main coronary artery stenosis. Inflammatory risk assessment in patients with unprotected left main coronary artery stenosis provides incremental prognostic value for adequate preoperative patient stratification.

Key Words: Coronary artery bypass • Left main • Inflammation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 5. Limitation
 References
 
Besides traditional risk factors, inflammatory markers are now emerging as independent predictors of adverse cardiovascular events. There is a wealth of evidence demonstrating that C-reactive protein (CRP) is an independent predictor of mortality and myocardial infarction (MI) in healthy subjects [1], in patients with acute coronary syndromes [2] and in patients undergoing percutaneous coronary intervention [3]. The association between elevated levels of CRP and postoperative outcome in patients treated with coronary artery bypass graft (CABG) surgery is controversial. Some studies have reported a correlation between elevated levels of CRP and adverse prognosis after CABG surgery [4], while others have refuted this association [5]. Furthermore, no studies have been focused on patients with unprotected left main coronary artery stenosis.

We have recently reported that elevated preprocedural levels of CRP and leukocyte counts predict 9-month mortality after percutaneous coronary intervention of the unprotected left main coronary artery stenosis, raising the hypothesis that inflammatory markers could be an effective tool in discriminating the strategy of revascularization in this subset of patients [6]. However, in that paper we were not able to determine whether adverse prognosis was a specific characteristic of the combination of elevated inflammatory markers with percutaneous coronary intervention or whether adverse outcome was dependent on the inflammatory status of patients, regardless of the treatment used. Therefore, in this study, we investigated the prognostic impact of CRP, leukocyte counts, and fibrinogen levels in patients with unprotected left main coronary artery stenosis undergoing CABG surgery.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 5. Limitation
 References
 
2.1 Patients
Since January 2002, all patients with a de novo ≥50% unprotected left main coronary artery stenosis treated with either percutaneous coronary intervention or CABG have been prospectively collected in a specific database (Bologna Registry for the treatment of unprotected left main coronary artery stenosis). In this study, selection of patients was done solely accordingly to CABG treatment and availability of preoperative CRP. Exclusion criteria were acute MI with ST segment elevation, hemodynamic instability, previous CABG, previous percutaneous coronary intervention, MI or cerebrovascular accident during the year prior to the study, intercurrent inflammatory condition, or history of a neoplastic condition. All patients had 9-month follow-up by telephone interview. The use of the Registry and subsequent data analysis were approved by the institutional ethics committee and patients provided written, informed consent to participate in the study.

2.2 Laboratory assay
Fasting blood samples were collected from a peripheral vein at a median time of 6 days (range 0–15 days) before the operation. Determination of CRP levels, leukocyte counts, and fibrinogen levels was done the same day. CRP was measured by the high sensitivity nephelometric method (Dade Behring, Marburg, Germany). Fibrinogen was measured with the Clauss method [7] (Sysmex Corporation, Dade Behring). Leukocyte count was determined with an automated counter (ADVIA 120, Hematology System, Bayer, Milano, Italy).

As previously defined [2], a CRP level ≥ 0.3 mg/dl (i.e. 90th percentile of normal distribution) was considered elevated. Fibrinogen levels >400 mg/dl and leukocyte counts >8500/µl (upper limits of the normal values for our laboratory) were considered elevated.

2.3 Definitions
Hemodynamic instability was defined as the need to use inotropic drugs or intra-aortic balloon pump to keep the systolic pressure to at least 90 mmHg in the presence of symptoms of low cardiac output. Acute coronary syndrome was defined as either unstable angina or non-ST elevation MI. The diagnosis of non-ST elevation MI was based on the presence of typical symptoms and an increase of either CPK, with the isoenzyme MB > 10% of the total value, or troponin I. The diagnosis of perioperative MI was made if, in the first 7 days after the intervention, there was documentation of new abnormal Q waves and either a ratio of serum creatine kinase MB isoenzyme to total cardiac enzyme that was greater than 10% or a CK–MB value that was five times the upper normal limit. Beginning 8 days after the intervention either abnormal Q waves or enzymatic changes as previously specified were sufficient for a diagnosis of MI. Renal dysfunction was defined as creatinine levels >1.2 mg/dl. Poor candidates for surgery were defined as those patients with at least one of the following characteristics: age >75 years, severe obstructive pulmonary disease, serum creatinine ≥2 mg/dl, left ventricular ejection fraction (LVEF) ≤30%, severe peripheral vascular disease, or previous stroke. The surgical procedure was considered as a complete revascularization if all lesions occupying >50% diameter with a reference diameter of >1.5 mm potentially amenable to treatment had been treated according to the surgical report. Deaths were classified as either cardiac or non-cardiac. Deaths that could not be classified were considered cardiac.

2.4 Statistics and end point of the study
The primary object of the study was 9-month mortality. CRP values, fibrinogen levels, and leukocyte counts, which were not normally distributed (Smirnov Kolmogorov test), were grouped in quartiles for data analysis. Patients were divided in two groups: Group 1 included patients with CRP levels in quartile IV (CRP levels ≥1.22 mg/dl) and Group 2 included patients with CRP levels in quartiles I + II + III (CRP levels <1.22 mg/dl). The same division in quartiles was done for leukocyte counts (quartile IV: leukocyte counts ≥8755/µl) and fibrinogen levels (quartile IV: fibrinogen levels ≥439 mg/dl). Correlations were determined using Spearman's rank correlation test. Categorical variables were compared by chi-square statistics or Fisher exact test as appropriate. The relation between CRP levels and mortality was analyzed also by means of a receiver operator characteristic (ROC) curve analysis. Kaplan–Meier curves were generated for total mortality by CRP quartiles and compared with log rank test. Cox regression analysis was performed to determine predictors of death at 9-month follow-up. Non-correlated variables with p ≤ 0.05 at the univariate Cox analyses were included in the multivariate analysis. Statistical analyses were performed using the Statistical Package for Social Sciences software (SPSS 12.0 for Windows, SPSS Inc., Chicago, Illinois). p values <0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 5. Limitation
 References
 
3.1 Baseline clinical, angiographic, and laboratory characteristics
From 1st January 2002 to 31st April 2005, we identified 146 patients who met the criteria defined by the study. In 38 patients, CRP values were not available and therefore the final study cohort consisted of 108 patients. Clinical characteristics of the patients according to CRP levels distribution are listed in Table 1 . Patients enrolled in the study presented a rather high-risk profile compared to previous studies: 61% had an acute coronary syndrome, 29% were older than 75 years, 15% had renal dysfunction, 2.8% had previous stroke, 35% had an abnormal (≤50%) LVEF and 16% had LVEF ≤ 40%, 36% had a Parsonnet score > 15 [8], 45% had a Euroscore > 5 [9], and 59% were considered poor candidates for surgery. Patients with CRP levels in quartile IV were more likely to be in NYHA class III, to have insulin-treated diabetes, an acute coronary syndrome and lower LVEF than patients with CRP levels in quartile I + II + III.


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  		Table 1 Clinical characteristics according to CRP quartiles
 
Angiographic findings and the main procedural variables are presented in Table 2 .


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  		Table 2 Angiographic and procedural characteristics according to CRP quartiles
 
Preprocedural CRP levels were elevated in 65 patients. Elevated levels of leukocyte counts and fibrinogen were found in 31 and 44 patients, respectively. CRP levels were correlated both with leukocyte counts (r = 0.5; p = 0.0001) and with fibrinogen levels (r = 0.6; p = 0.0001).

3.2 Clinical outcome at 9-month follow-up
All patients had 9-month follow-up. Eleven patients died: four patients died at 30-day follow-up and seven died thereafter. The rate of mortality, cardiac mortality, and MI were 10%, 7%, and 0.9%, respectively. Mortality and cardiac mortality were 26% and 22% in Group 1 and 4.9% and 2.5% in Group 2 (for mortality: hazard ratio (HR) = 5.86, 95% confidence interval (CI) = 1.71–20.03, p = 0.005; for cardiac mortality: HR = 10.04, 95% CI = 2.02–49.82, p = 0.005). Median CRP values were 3.24 mg/dl among the 11 patients who died and 0.34 mg/dl among the 97 patients who were alive at the end of follow-up (p = 0.004). The area under the ROC curve was 0.77 (0.59–0.94, p = 0.004).

In all patients who died of cardiac causes, CRP levels were >0.5 mg/dl (median CRP levels = 3.34 mg/dl; range 0.6–16.4 mg/dl). The same results were observed when we considered quartiles of leukocyte counts and fibrinogen levels (Table 3 ). Among patients with acute coronary syndrome, 25 patients had CRP levels in quartile IV and 41 in quartiles I + II + III. Mortality was 25% in those with CRP levels in quartile IV and 5% in those with CRP levels in quartiles I + II + III (p = 0.021).


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  		Table 3 Predictors of death in the Cox univariate and multivariate analysis at 9-month follow-up a
 
Fig. 1 shows survival at 9-month follow-up according to Kaplan–Meier analysis, with respect to CRP distribution (quartile IV vs quartiles I + II + III). The difference in mortality between the two groups was already evident after 30-day follow-up and continued to increase during the 9-month follow-up (log rank test: p = 0.001).


Figure 1
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  		Fig. 1. Survival at 9-month follow-up by preprocedural levels of C-reactive protein levels according to Kaplan–Meier analysis. Patients with preprocedural levels of C-reactive protein in quartile IV (CRP levels ≥1.22 mg/dl) had a significantly lower survival rate than patients in quaritiles I + II + III (log rank test: p = 0.001).

 
3.3 Multivariate analysis
In the univariate analysis (Table 3) age > 75 years, NYHA classes III + IV, diabetes, peripheral vascular disease, complete revascularization, LVEF ≤ 40%, Euroscore > 5, Parsonnet score > 15, quartiles of CRP, fibrinogen, and leukocyte counts were associated with increased risk of total mortality. However, in the multivariate analysis (Table 3) age >75 years (HR = 3.89, 95% CI = 1.16–13.08, p = 0.028), peripheral vascular disease (HR = 10.64, 95% CI = 2.27–49.91, p = 0.003), and CRP quartiles (HR = 5.87, 95% CI = 1.67–20.62, p = 0.006) were the only independent predictors of death at 9-month follow-up. When we performed a second multivariate analysis using CRP levels as a continuous variable (log transformation), similar results were obtained (Table 3).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
5. Limitation
 References
 
Identification of independent predictors of postoperative mortality after CABG surgery is of the utmost importance for adequate preoperative patient stratification, optimization of patients condition, and evaluation of quality of treatment. To our knowledge, this study is the first to provide evidence that elevated pretreatment levels of CRP are closely associated with the risk of death after CABG surgery for the treatment of unprotected left main coronary artery stenosis. Assessment of the inflammatory status of these patients, therefore, provides incremental prognostic information beyond that defined by traditional risk factors.

We have recently reported that elevated levels of CRP and leukocyte counts predict mortality after percutaneous coronary intervention of unprotected left main coronary artery stenosis raising the important question whether CRP levels could be a discriminating tool in selecting the strategy of revascularization in this subset of patients [6]. In that study, in fact, we were not able to determine whether the relation found was specific to the association between CRP and percutaneous coronary intervention or whether it was linked only to the inflammatory status of the patient. In this study, we observed that also in patients treated with CABG surgery CRP levels were a strong and independent predictor of poor postoperative outcome. In the multivariate analysis, patients in quartile IV (CRP ≥ 1.22 mg/dl) had an HR of death = 5.87 (p = 0.006) compared to patients belonging to quartiles I + II + III. Even among patients with acute coronary syndrome, mortality was significantly higher in those with CRP levels in quartile IV than in those with CRP levels in quartiles I + II + III (p = 0.021).

The association between CRP levels and cardiac mortality was even more striking. All patients who died of cardiac causes, in fact, had CRP levels >0.5 mg/dl. Furthermore, cardiac mortality was 22% in Group 1 and 2.5% in Group 2 (p = 0.004). Since CRP levels were correlated both with leukocyte counts and fibrinogen levels, the same distribution of deaths was noticed when they were analyzed by leukocyte and fibrinogen quartiles. Systemic activation of the inflammatory system before CABG surgery, therefore, represents a risk factor of poor postoperative outcome in patients with unprotected left main coronary artery stenosis.

Whether preprocedural activation of inflammatory system is just a marker of poor postoperative outcome or, instead, it plays a direct role in vascular disease, remains to be established. Although patients with CRP levels in quartile IV presented a higher risk profile having more frequently an acute coronary syndrome, a lower LVEF, and being more often in NYHA class III than patients with CRP levels in quartile I + II + III, in the multivariate analysis CRP levels, peripheral vascular disease, and age >75 years were the only independent predictors of death. Furthermore, there is a wealth of evidence that CRP, leukocyte counts, and fibrinogen may have direct vascular effects that contribute to vascular damage.

It has been shown that CRP may have both proinflammatory and prothrombotic effects by activating tissue factor [10], stimulating cytokine release such as interleukin 1, interleukin 6 and tumor necrosis factor [11], and favoring oxidized LDL uptake [12]. Furthermore, CRP has been shown to induce adhesion molecule expression in human endothelial cells [13], and to produce monocyte chemoattractant protein 1 [14]. The possible biological relevance of CRP in thrombosis is confirmed by a recent experimental study in which it was shown increased thrombosis of the femoral artery after wire injury in transgenic mice producing human CRP [15].

Leukocytes have been demonstrated to propagate thrombosis producing tissue factor [16], providing a catalytic surface for thrombin generation, and forming platelet–leukocyte aggregates [17]. They may also exert vascular effects compromising the microvasculature by adhesion, aggregation, and platelet recruitment [18], releasing proinflammatory and vasculotoxic factors and contributing to intimal hyperplasia after vascular injury [19].

The notion that fibrinogen is related to coronary risk relies on several epidemiological studies and clinical observations [20]. There are several potential pathophysiologic mechanisms by which elevated fibrinogen levels could mediate coronary risk: it forms the substrate for thrombin and represents the final step in the coagulation cascade, it is essential for platelet aggregation [21], it modulates endothelial function [22], it promotes smooth muscle cell proliferation and migration [23].

The association between CRP levels and postoperative cardiovascular events after CABG surgery is controversial. Some studies have reported a significant correlation between CRP levels and poor postoperative outcome [4], while others have refuted this association [5]. Differences in sample size of patients, in event rates, in the specified end point of the study, in the sensitivity of the assays used to determine CRP levels and in the cut-off point of CRP levels chosen may account for discrepancies of results. However, in the study by Biancari et al. [4], which presents the largest series of patients in which this relationship has been investigated, preoperative CRP levels were a strong predictor of postoperative outcome.

Our study extends those findings to patients with unprotected left main coronary artery stenosis and confirms that CRP levels may be applied clinically as a screening tool for identifying high-risk patients.

Our findings raise the important question whether anti-inflammatory therapy associated with CABG surgery may improve the postoperative outcome of patients with unprotected left main coronary artery stenosis. Although generally used as lipid-lowering drugs, statins have been recently shown to have pleiotropic anti-inflammatory properties and it is now believed that part of their beneficial effect is due to these characteristics [24]. In this context, it has been shown that preoperative statin therapy may reduce the risk of mortality after CABG surgery for disease of the remote coronary tree [25]. Whether this finding could also apply to patients with unprotected left main coronary artery stenosis deserves further investigations.


   5. Limitation
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitation
References
 
A limitation of this study is represented by its partially retrospective nature. In fact, even though clinical and procedural data were prospectively collected, CRP levels were retrospectively retrieved and therefore they were not present in all patients of the Registry. However, patient population selected in this study presented the same clinical characteristics and the same clinical outcome as the whole population of the Registry and, therefore, it is unlikely that selection biases were introduced.


   Acknowledgments
 
This research was supported by the funds of Fondazione Fanti Melloni, Bologna, Italy.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitation
 References
 

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