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Cardiovascular Research 2003 60(1):136-140; doi:10.1016/S0008-6363(03)00355-9
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Preprocedural serum levels of acute-phase reactants and prognosis after percutaneous coronary intervention

Braim M. Rahela,*, Frank L.J. Visserenb, Maarten-Jan Suttorpa, Thijs H.W. Plokkera, Johannes C. Keldera, Bartelt M. de Jonghc, K.Paul Bouterd and Rob J.A. Diepersloote

aDepartment of Cardiology, Heart Lung Center Utrecht, Location: St Antonius Hospital Nieuwegein, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands
bDepartment of Internal and Vascular Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands
cDepartment of Microbiology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
dDepartment of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, The Netherlands
eDepartment of Microbiology, Diakonessen Hospital Utrecht, Utrecht, The Netherlands

*Corresponding author. Tel.: +31-30-609-2278; fax: +31-30-609-2277. Email address: b.rahel{at}antonius.net

Received 1 November 2002; accepted 26 March 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: In this study we evaluate the value of baseline concentrations of acute-phase reactants on prognosis after percutaneous coronary intervention (PCI). Methods: Blood samples were drawn immediately before PCI to measure baseline concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), lipoprotein(a) (Lp(a)), and fibrinogen. Follow-up data were collected at 8 months. Repeat PCI, CABG, myocardial infarction, and death were recorded as major adverse clinical events (MACE). Furthermore the recurrence of angina pectoris was noted. Results: The study included 600 consecutive patients after a successful PCI. Sixty-four percent of the patients were stented. The mean age was 61.6 years and 68.9% were male. CRP levels were significantly higher in patients who were to have repeat angina as compared with those who were not (P = 0.0322). IL-6 levels were not correlated with angina or MACE. Lp(a) and fibrinogen concentrations were both significantly related to MACE (P = 0.0337 and P = 0.0253, respectively). Conclusion: Our study clearly supports the role of inflammation in restenosis after PCI as measured in statistically higher levels of Lp(a) and fibrinogen in patients with MACE and CRP in patients with repeat angina.

KEYWORDS Angioplasty; Coronary disease; Endothelial function; Infection/inflammation; Restenosis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Case-control studies have established consistent associations between circulating inflammatory markers, in particular C-reactive protein (CRP), and the subsequent risk of cardiovascular events in healthy people [1,2] and in patients with established coronary heart disease [3–5]. Percutaneous coronary intervention (PCI) has been shown to elicit an inflammatory response by itself [6,7]. In addition, preprocedural CRP levels appear to predict outcome in patients undergoing balloon angioplasty and stent implantation [8,9]. Also other acute-phase reactants like interleukin-6 (IL-6), lipoprotein(a) (Lp(a)) and fibrinogen possibly play a role in the biologic response after PCI [10–12]. So far, there are only limited data on the prognostic value of these acute-phase reactants measured preprocedural.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
All consecutive patients scheduled for elective PCI in the St. Antonius Hospital in Nieuwegein, the Netherlands were eligible in the period between July 1998 and December 1999. Patients were included if there was a successful procedure of a de novo lesion with signs of ischemia related to this vessel (signs of ischemia found during an abnormal excercise test, defined as ST depression of at least 1.0 mm that is horizontal or down-sloping or upsloping ST depression of at least 2.0 mm or signs of ischemia found during nuclear imaging with excercise, dobutamine or adenosine). The minimum age for inclusion was 18 years. Exclusion criteria were acute coronary syndromes, prior PCI or CABG of the target lesion, current treatment for a malignancy or infection, or use of immunosuppressive drugs. The study was conducted according to the principles of the Declaration of Helsinki, and all patients gave written informed consent to use routinely drawn preprocedural blood samples for further analysis. The institutional ethics committee approved the study.

Hypertension was defined as a systolic tension higher than 140 mmHg and/or a diastolic tension higher than 90 mmHg or use of anti-hypertensive drugs. Diabetes mellitus was defined as fasting venous glucose concentrations ≥7.8 mmol/l or use of glucose lowering drugs. Hypercholesterolaemia was defined as a fasting plasma cholesterol level higher than 5.0 mmol/l or use of cholesterol lowering drugs. A positive family history was defined as the presence of coronary heart disease in a first degree family member before the age of 55 in male and 60 in female.

2.2. Blood samples and laboratory analysis
Blood samples were routinely drawn prior to each procedure, separated and serum and plasma samples kept frozen at –80°C until analysis of C-reactive protein (CRP-EIA (HS), ELISA set, Kordia BV, Leiden, the Netherlands), fibrinogen (FG-EIA fibrinogeen, ELISA set, Kordia), Lipoprotein(a) (Tint ELIZE Lp(a), Kordia), and IL-6 (M1916, Pelikine IL-6, Compact ELISA CLB, Amsterdam, the Netherlands).

The laboratory personnel were blinded for the clinical outcome. The clinical outcome investigators committee was blinded to the laboratory results.

2.3. Angioplasty procedure
Aspirin was started before the procedure and continued during the follow-up period. At the start of the procedure, patients received a bolus of 10 000 U of heparin intravenously. Percutaneous coronary intervention was performed from the femoral artery approach with standard techniques. Stents were used to the discretion of the operator. Procedural success was defined as a residual stenosis less than 20% at the angioplasty site. Before and after angioplasty, 100–500 µg intracoronary nitroglycerine was given and repeated if necessary. Directly following stent implantation patients received 300 mg clopidogrel and were instructed to take 75 mg clopidogrel once daily during 1 month.

2.4. Long-term follow-up
Clinical follow-up was performed at 8 months by mailing a questionnaire to the patient or relatives of the patient. In case of non-response patients were contacted by telephone. Repeat PCI, CABG, myocardial infarction (defined as the presence of new significant Q waves or an elevation of creatine kinase or its MB isoenzyme to at least two times the upper limit), or death (of all causes) were recorded as major adverse clinical events (MACE). Repeat angina was defined as chest pain recognised from cardiac origin by the patient.

2.5. Statistical analysis
Statistical analysis was done using the Statcalc module of Epi Info® and SAS version 8.2. The t-test was used to test differences in quantitative values. Variables are expressed as means (±standard deviation) unless otherwise stated. Variables are called independent after multivariate logistic regression analysis. The crude and adjusted odds ratios, as estimates for the relative risk, were calculated using unconditional logistic regression. Adjustment was made for the following potentially confounding factors: age and smoking.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The study included 600 consecutive patients scheduled for PCI. In 64% of the patients one or more stents were implanted. The baseline characteristics are shown in Table 1. Mean age was 61.6 years, 68.9% were male. Two patients were lost to follow-up (one patient emigrated to Brazil, one patient moved to the UK and could not be traced). Only 54 patients (9%) had a major adverse clinical event during follow-up (repeat PCI: 57%, CABG: 13%, myocardial infarction: 23%, death: 7%, all deaths are cardiac or presumed cardiac).


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  		Table 1 Baseline characteristics of 600 PCI patients

 
We found statistically significant higher fibrinogen levels in patients with developing MACE as compared with patients without MACE (P = 0.0253). Also Lp(a) levels were found higher in patients with MACE as compared to patients without MACE (P = 0.0337). C-reactive protein showed a trend towards higher levels in patients with MACE (Table 2).


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  		Table 2 MACE during 8 months follow-up

 
During 8 months follow-up 196 patients (32.7%) reported recurrence of anginal complaints. As shown in Table 3, CRP showed higher levels in the group with complaints as compared with patients without repeat angina (P = 0.0322).


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  		Table 3 Repeat angina pectoris at 8 months follow-up

 
Subanalysis of only stented patients yielded similar results. Comparison of stented patients versus patients with only balloon angioplasty showed no significant differences with respect to MACE or angina pectoris (P = 0.7629 and P = 0.1711, respectively). Also comparison of patients on statins versus patients without statins and diabetics versus non-diabetics yielded no significant differences in MACE or angina pectoris.

Multivariate subanalysis of the permutations of two or more acute-phase reactants yielded no additional risk factor for MACE or repeat angina.

Fibrinogen was found the strongest independent predictor for MACE. Even after adjustment of the acute-phase reactants (CRP, IL-6, Lp(a)), both single and in combinations (CRP and IL-6, CRP and Lp(a), IL-6 and Lp(a), CRP and IL-6 and Lp(a)) or after adjustment for stenting, age, statin treatment, or diabetes, we found no important change in the odds ratio's for fibrinogen (ranging between 1.6 and 2.4). Adjustment for the confounding factors age and smoking showed a significant increase in the odds ratio of fibrinogen (Table 4).


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  		Table 4 Odds ratios after adjustment for age and smoking

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
To our knowledge, this prospective study is the first investigating the independent and combined prognostic value of several acute-phase reactants in a large consecutive group of patients undergoing PCI. Of the acute-phase reactants C-reactive protein has been studied most extensively. An early study investigating this subject could not detect an association between preprocedural CRP levels and restenosis in a relatively small patient group [13]. However, more recently published data suggested that preprocedural CRP levels consistently were associated with adverse events after percutaneous coronary intervention [8,14,15]. Also in a cohort solely consisting of stented patients, preprocedural CRP appears to predict cardiovascular events, supporting the role of inflammation in neointimal hyperplasia [9]. Also in our population, CRP levels were higher in patients with MACE as compared with patients without MACE, but this difference reached no statistically significance. Looking at patients experiencing repeat anginal complaints however, we found significantly higher levels of CRP as compared to patients free of complaints.

The precise mechanisms by which elevated CRP levels lead to events remain to be elucidated. CRP is synthesised and secreted by hepatocytes in response to cytokines, especially IL-6. CRP levels reflect the degree of underlying inflammation, which in turn is known to be related to restenosis [16,17]. CRP has been shown to bind to damaged tissues and to act synergistically with lipopolysaccharide in the activation of endothelial cells and to induce tissue factor production by monocytes [18–20]. Considering that IL-6 is the principal regulator of CRP release by the liver and IL-6 can be produced by various cells, including endothelial cells, hepatocytes, monocytes, and smooth muscle cells, we hypothesised that raised IL-6 levels are the link between circulating CRP concentrations and coronary events. In this study we found no correlation between IL-6 levels and development of MACE after PCI. In two small studies a positive correlation between increased IL-6 levels and restenosis was shown [10,21]. This could partly be explained by the fact that we measured preprocedural IL-6 concentrations, whereas these two studies reported postprocedural IL-6 levels.

In our study Lp(a) levels were found significantly higher in patients with MACE as compared with patients without MACE. Previous data about Lp(a) and adverse events after percutaneous coronary intervention are inconsistent. In the FLARE study, in which 823 patients were followed after angioplasty, baseline Lp(a) failed to predict restenosis or major adverse cardiac events [22]. In the same year Chiarugi et al. showed significantly higher baseline levels of Lp(a) in patients developing restenosis. Earlier restenosis was observed with Lp(a) values >450 mg/l and >300 mg/l if associated with anticardiolipin antibodies [23]. Sirikci et al. found higher Lp(a) levels in patients with restenosis, but this difference was only statistically significant in a small subgroup of women [24]. The exact mechanism by which Lp(a) acts in smooth muscle cell hyperplasia is not fully understood. Lp(a) consists of two parts. One part is LDL cholesterol which could explain the development of atherosclerosis. The other part is apolipoprotein(a) which resembles plasminogen resulting in competition for fibrin and thus increasing basal clotting levels.

In the present study baseline fibrinogen levels also appeared to be significantly higher in patients with MACE as compared to patients without MACE. Montalescot et al. [25] also found a relation between elevated fibrinogen levels during follow-up after angioplasty and restenosis. Patients with a fibrinogen concentration exceeding 3.5 g/l at follow-up evaluation had higher restenosis rates than patients with a fibrinogen concentration below 3.5 g/l. This cut-off point fits well in the concentrations found in our study-groups. The rationale for fibrinogen as a risk factor for restenosis is supported by the results of Naito et al. who concluded that fibrin degradation products stimulate smooth muscle cell outgrowth leading to restenosis [26]. This could be in agreement with our own study on the effect of coumadin on restenosis [27]. Although Schumacher et al. also demonstrated higher fibrinogen levels in patients with restenosis versus patients without restenosis, the difference was not significant [28]. The combination of two or more of the discussed acute-phase reactants yielded no additional risk factor for MACE or repeat angina.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our study clearly supports the role of inflammation in restenosis after PCI as measured in statistically higher levels of Lp(a) and fibrinogen in patients with MACE and CRP in patients with repeat angina.


   Notes
 
Time for primary review 25 days.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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