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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 2  |  Issue : 2  |  Page : 7-15

The relation between interleukin-6 and different categories of acute coronary syndrome


1 Department of Cardiology and Angiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Date of Submission01-Feb-2015
Date of Acceptance01-Mar-2015
Date of Web Publication30-Dec-2016

Correspondence Address:
Atef Abdel Aziz Mahrous
Lecturer of Critical Care Medicine, Faculty of Medicine, University of Alexandria, 66 Masged Badr st from Moustafa Kamel sr, Sidi Bishr, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.161311

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  Abstract 

Background
Inflammation is now recognized to play a key role in the pathogenesis of atherosclerotic cardiovascular disease. Two circulating markers of inflammation, C-reactive protein (CRP) and interleukin (IL)-6, have emerged as predictors of future cardiovascular pathology and mortality in epidemiologic studies of (middle aged women) midlife healthy men and women, postmenopausal women, and older adults.
The aim of the present study was to study the changes in IL-6 in acute coronary syndrome (ACS) and to clarify whether IL-6 release is a factor initiating the inflammatory process in ACS or whether it is predominantly a response to this clinical condition, and to assess its correlation with CRP, cardiac biomarkers troponin I, and CK-MB for risk prediction in ACS.
Patients and methods
The study included 60 patients admitted by ACS who were categorized randomly into three groups: group I included 20 patients admitted for unstable angina, group II included 20 patients admitted for ST-segment elevation myocardial infarction with successful thrombolytic therapy, and group III included 20 patients admitted for ST-segment elevation myocardial infarction with failed thrombolytic therapy. The study also included 12 healthy control patients matched for age and sex (group IV). Blood levels of IL-6, CRP, and cardiac troponin I were measured; all samples of groups II and III were obtained after thrombolytic therapy whereas samples of group I were obtained on admission.
Results
IL-6 was significantly higher in group II, with a mean of 87.10, and ranged from 3.0 to 550.0; on exclusion of two patients who had an IL-6 level of 220 and 550 we obtained a mean of 54. In group III, the mean level was 52.36, ranging from 5.0 to 120.0, compared with control group IV, in which it ranged from 3.0 to 5.0, mean 3.67 (P < 0.001*). There was a positive correlation between IL-6 and CRP levels in group I (r = 0.385, P = 0.094) and group II (r = 0.166, P = 0.483), but this was statistically nonsignificant, and in group III, there was a statistically significant correlation (r = 0.638, P = 0.0002). IL-6 serum levels did not correlate with cardiac troponin levels in any of the patient groups I (r = 0.049, P = 0.836), in group II (r = 0.151, P = 0.524), and in group III (r = 0.079, P = 0.741). IL-6 did not correlate with any of the risk factors such as history of IHD, HTN, DM, and smoking. There was no statistically significant correlation between IL-6 and complications, except for the development of shock. The CRP level was significantly increased in ACS in comparison with the control group. CRP showed a significant increase in group III, ranging from 10.70 to 181, mean 84.25, and ranging from 2.47 to 155, mean 54.37 in group II compared with a mean level of 50.44 in group I and a mean of 1.96 in the control group, group IV (P = 0.0001*).
Conclusion
Atherosclerosis is currently considered a systemic inflammatory disease and IL-6 is an inflammatory cytokine. The IL-6 serum level was significantly increased in patients with ACS and in patients with successful thrombolytic therapy. There was a statistically significant positive correlation between IL-6 and CRP in ACS patients with failed thrombolytic therapy; IL-6 serum levels did not correlate with cardiac troponin levels in any of the ACS patient groups.

Keywords: Acute coronary syndrome, C-reactive protein, interleukin-6


How to cite this article:
Elbadawy TH, Mahrous AA, El Samnody HH. The relation between interleukin-6 and different categories of acute coronary syndrome. Res Opin Anesth Intensive Care 2015;2:7-15

How to cite this URL:
Elbadawy TH, Mahrous AA, El Samnody HH. The relation between interleukin-6 and different categories of acute coronary syndrome. Res Opin Anesth Intensive Care [serial online] 2015 [cited 2017 Jun 27];2:7-15. Available from: http://www.roaic.eg.net/text.asp?2015/2/2/7/161311


  Introduction Top


Almost all regional acute myocardial infarcts are caused by thrombosis developing on a culprit coronary atherosclerotic plaque [1].

The fully developed human fibrolipid plaque has a core of lipid surrounded by a capsule of connective tissue [2]. The core is an extracellular mass of lipid containing cholesterol and its esters; the core is surrounded by numerous macrophages, and these macrophages are derived from monocytes that cross the endothelium from the arterial lumen. They are not inert or end-stage cells, but are highly activated, producing procoagulant tissue factor and a host of inflammatory cell mediators such as tumor necrosis factor a (TNFa), interleukins (ILs), and metalloproteinases [3],[4].

The inflammation (vascular or extravascular) gives rise to cytokines (local and systemic), which in turn elicit the expression of acute-phase reactants such as C-reactive protein (CRP) and fibrinogen and of other effector molecules in the inflammatory response, such as adhesion molecules for leukocytes, procoagulants, and messenger cytokines such as IL-6, which induces the hepatic production of acute-phase reactants such as CRP [5],[6].

CRP is one of the substances present in the atherosclerotic lesion, more specifically in the vascular intima, where it colocalizes with monocytes, monocyte-derived macrophages, and lipoproteins [7]. This localization makes a direct contribution toward the atherosclerotic process possible.

The link between systemic markers of chronic inflammation and acute coronary events may, however, be more complex. There is experimental evidence that upregulation of systemic inflammation will exert a secondary effect of enhancing inflammatory activity in the plaque [8]. Inflammation is now recognized as playing a key role in the pathogenesis of atherosclerotic cardiovascular disease [9]. Two circulating markers of inflammation, CRP and IL-6, have emerged as predictors of future cardiovascular pathology and mortality in epidemiologic studies of midlife healthy men and women, postmenopausal women, and older adults [10],[11].

Irrespective of the source of the inflammatory cytokines, emerging work on serum inflammatory markers supports the notion of a 'pathway' of inflammatory activation related to acute coronary events [12].

During inflammation, the inflammatory cytokines TNF-α, IL-1, and IL-6 are secreted, in that order [13]. IL-6 then inhibits the secretion of TNF-α and IL-1 [14], activates the production of acute-phase reactants from the liver [15], and stimulates the hypothalamic-pituitary-adrenal axis [16] to help control the inflammation. In this sense, IL-6 is both a proinflammatory and an anti-inflammatory cytokine. IL-6 is of particular interest to physicians because of its marked pleiotropy and its involvement not only in inflammation but also in the regulation of endocrine and metabolic functions [15],[16],[17].

Overproduction of IL-6 may contribute toward illness during aging and chronic stress. Finally, administration of recombinant human IL-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis. IL-6 is expressed at the shoulder region of atherosclerotic plaques and may increase plaque instability by driving the expression of matrix metalloproteinase, MCP-1, and TNF-α [18].


  Aim of the work Top


The aim of this work was as follows:

  1. To study the changes in IL-6 in different categories of acute coronary syndrome (ACS).
  2. To assess the correlation between the level of IL-6 and other cardiac biomarkers for risk prediction in ACS.



  Participants Top


A minimum sample size required was calculated in the biostatistics department of the high institute of public health, university of Alexandria, to be 20 patients for each group to achieve a power of 80% and an α of 0.05. This study included 60 adult patients of both sexes fulfilling the American Heart Association criteria for the diagnosis of ACS [19] from among patients admitted to the ICU, Critical Care Medicine Department, Faculty of Medicine, and Alexandria University. Approval for the study was obtained from the ethical committee of the faculty medicine, university of Alexandria. An informed consent was obtained from the next of kin of every patient included in the present study.

Approval of the study was obtained from the ethical committee of the faculty medicine, University of Alexandria. An informed consent was obtained from the next of kin of every patient included in the present study.

Exclusion criteria

  1. Recent myocardial infarction (MI) in the last 3 months.
  2. Recent cardiological intervention in the last 3 months.
  3. Recent ischemic cerebrovascular stroke in the last 3 months.
  4. Acute infectious diseases.
  5. Active immunological diseases.


Patients were classified into the following groups:

Group I: unstable angina.

Group II: ST-segment elevation myocardial infarction with successful thrombolytic therapy.

Group III: ST-segment elevation myocardial infarction with failed thrombolytic therapy.

The study also included 12 healthy control patients of the same age and sex (group IV).


  Patients and methods Top


The following data were obtained from all participants (patients and control) and included in the current work:

  1. Personal data: name, age, sex, occupation, and specific habits (e.g. smoking).
  2. Historical data of the present condition in terms of onset, nature, duration, course, progression, characteristic site, and radiating areas of the chest pain, relieving and aggravating factors, associated symptoms [such as diaphoresis (excessive sweating), nausea, vomiting, dyspnea, and palpitation], and medication received.
  3. Medical history of diabetes mellitus (DM): type and medications received, hypertension (HTN): medications received and history of ischemic heart disease (IHD).
  4. Family history of DM, HTN, and IHD.


Each patient was subjected to the following:

  1. Thorough clinical examination including chest and heart auscultation.
  2. ECG, which was used to differentiate between S-T segment elevation myocardial infarction (STEMI) and NSTEMI.
  3. Blood levels of IL-6, CRP, and cardiac troponin I were measured. All samples of groups II and III were obtained after the thrombolytic therapy whereas samples of group I were obtained on admission; 5 ml blood samples were collected from all participants using disposable syringes, and serum was separated and used to determine the following:

    1. Cardiac enzymes: creatine kinase-myocardial band and biochemical markers such as troponin I by dimension RXL.
    2. Serum CRP: by Nephelometry Dade Behring.
    3. Serum IL-6: by ELISA.


All the samples were stored and the study was carried out in one setting by a clinical pathologist who was unaware of the nature of the samples.

Principle

Orgenium Laboratories' (Tiilitie, Vantaa, Finland). The Human IL-6 ELISA kit is an in-vitro enzyme-linked immunosorbent assay (competitive or sandwich technique) for the quantitative measurement of human IL-6 in serum, plasma, cell culture supernatants, and urine. This assay uses an antibody specific for human IL-6 coated on a 96-well plate. Standards, samples, and biotinylated anti-human IL-6 are pipetted into the wells and IL-6 present in a sample is captured by the antibody immobilized to the wells and by the biotinylated IL-6-specific detection antibody. After washing away unbound biotinylated antibody, HRP-conjugated streptavidin is pipetted into the wells. The wells are washed again. Following this second wash step, a TMB substrate solution is added to the wells, resulting in color development proportional to the amount of IL-6 bound. The stop solution induces a change in color from blue to yellow and the intensity of the color is measured at 450 nm.

Statistical analysis

The data were analyzed statistically using statistical package for social science, version 17 (SPSS Statistics acqured by IBM 2009, www.ibm.com/software/analytics/spss/). Means and standard deviation were used to describe the data distribution. Analysis of (ANOVA or F-test) was used for the comparison of more than two means. Least significant difference is basically a t-test, used only when the F-value is significant to detect the presence of significance between each two groups. The test was considered significant if the P-value was less than 0.05.


  Results Top


The current study was carried out on 60 patients presenting with chest pain to the critical care medicine department of the Alexandria Main University and Military Forces Hospital.

Demographic characteristics of the groups studied

There was no statistically significant difference between the four groups studied in terms of age (P = 0.772) and sex (χ2 = 0.491) [Table 1].
Table 1 Demographic data of the patients studied

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Smoking in different studied groups

In group I, there were 11 smokers (55%) and only nine nonsmokers (45%). In group II, there were nine smokers (45%) and 11 nonsmokers (55%). In group III, there were eight smokers (40%), two exsmokers (10%), and 10 nonsmokers (50%). In group IV, all participants were nonsmokers (MCP = 0.006) [Figure 1].
Figure 1: Comparison between the different groups studied in smoking.

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Relation between smoking and different markers

There was no statistically significant difference between smokers and nonsmokers in troponin (P = 0.618), CRP (P = 0.280), and IL-6 (P = 0.383) [Table 2].
Table 2 Relation between smoking and different markers

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Troponin level in the different groups studied

Troponin showed a significant increase in group III, ranging from 3.0 to 92.50, mean 36.20, ranging from 14.2 to 87.90, mean 40.95 in group II, and ranging from 0.0 to 0.05, mean 0.02 in group I, compared with the controls (group IV), in whom it ranged from 0.00 to 0.03, mean 0.001 (P < 0.0001*) [Table 3].
Table 3 Atatistical analysis of troponin level between the different groups studied

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C-reactive protein level in the different groups studied

There was a significant increase in group III, ranging from 10.70 to 181, mean 84.25, ranging from 2.47 to 155, mean 54.37 in group II, and ranging from 2.47 to 190, mean 50.44 in group I compared with the controls (group IV), in whom it ranged from 1.10 to 3.0, mean 1.96 (P = 0.0001*) [Table 4].
Table 4 C-reactive protein level in the different groups studied

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Interleukin-6 level between the different groups studied

IL-6 showed a significant increase in group I, ranging from 2.0 to 140.0, mean 33.10, and ranging from 3.0 to 550.0, mean 87.10 in group II. On excluding two patients who had IL-6 levels of 220 and 550, we obtained a mean of 54. In group III, IL-6 ranged from 5.0 to 120.0, mean 52.36, compared with the controls (group IV), in whom it ranged from 3.0 to 5.0, mean 3.67 (P < 0.001*) [Figure 2], [Table 5].
Figure 2: Interleukin 6 (IL-6) level between the different groups studied.

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Table 5 Interleukin 6 levels between the different groups
studied


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Correlation between interleukin-6 and troponin

There was no correlation between IL-6 and troponin in group I (r = 0.049, P = 0.836), group II (r = 0.151, P = 0.524), and group III (r = 0.079, P = 0.741) [Table 6].
Table 6 Correlation between interleukin 6 and troponin

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Interleukin-6 and C-reactive protein

There was a positive correlation between the IL-6 and CRP in group I (r = 0.385, P = 0.094) and group II (r = 0.166, P = 0.483), but statistically nonsignificant, and in group III, there was a statistically significant correlation (r = 0.638, P = 0.0002) [Table 7].
Table 7 Correlation between interleukin 6 and C-reactive
protein


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Relation between different markers and a history of ischemic heart disease

There was no statistically significant difference between patients with a history of IHD and those without a history of IHD in IL-6 (P = 0.152), but there was a statistically significant correlation between IL-6 and a history of IHD in group II (P = 0.033), troponin (P = 0.060), but there was a statistically significant difference in CRP (P = 0.001) [Table 8].
Table 8 Relation between different markers and medical
history of ischemic heart disease


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Relation between different markers and medical history of diabetes mellitus

There was no statistically significant difference between patients with DM and those without DM in IL-6 (P = 0.390), but there was statistically significant difference in CRP (P = 0.010) and troponin (P = 0.016) [Table 9].
Table 9 Relation between different markers and medical
history of diabetes mellitus


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Relation between different markers and incidence of arrhythmia

There was no statistically significant difference in the incidence of arrhythmia for IL-6 (P = 0.297) and troponin (P = 0.734), but there was a statistically significant difference in CRP (P = 0.013) [Figure 3].
Figure 3: Relation between different markers and mean of arrhythmia. CRP, C-reactive protein; IL-6, interleukin 6.

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There was a statistically significant difference in the incidence of shock for IL-6 (P = 0.020), whereas there was no difference in troponin (P = 0.582) and CRP (P = 0.563) [Table 10].
Table 10 Relation between different markers and incidence of shock

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Relation between different markers and incidence of pulmonary edema

There was no statistically significant difference in the incidence of pulmonary edema for IL-6 (P = 0.802), CRP (P = 0.070), and troponin (P = 0.101) [Figure 4].
Figure 4: Relation between different markers and incidence of pulmonary edema.

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  Discussion Top


IL-6 is an inflammatory cytokine produced by endothelial cells, smooth muscle cells, fibroblasts, lymphocytes, and macrophages. Atherosclerosis is currently considered a systemic inflammatory disease and increased levels of IL-6 have been associated with the progression of coronary artery disease [10].

Previous studies have reported increased proinflammatory cytokine concentrations and decreased anti-inflammatory cytokine concentrations in patients with ACS. However, the role of anti-inflammatory cytokines remains unclear and this was the focus of interest of our investigations [11],[18].

In the current study, the mean age of all patients was 55.41 years. There was no statistically significant difference between the three groups studied and the control group.

According to sex, men were affected more (70%), with a mean age of 56.66 years, than women (30%), with a mean age of 53.90 years. This may have been because of the high incidence of cigarette smoking among men compared with women and the protective effect of female sex hormones in the prevention of ACS.

Smoking

In terms of the correlation between smoking and different markers including troponin, CRP, and IL-6, there was no statistically significant difference. In the nonsmoker group, the mean CRP level was 54.03 mg/l and the mean IL-6 level was 37.48 pg/ml. In the smoker group, the mean CRP level was 48.35 mg/l (lower than nonsmokers) whereas the mean IL-6 level was 63.86 pg/ml (higher than nonsmokers). Although there was no statistically significant difference, this data showed the enhancing effect of smoking in the inflammatory process, where IL-6 was significantly higher in smokers and a significant reduction of CRP reflects a modest anti-inflammatory activity. This finding was in agreement with the result reported by Sunyer et al. [20], who found a potential role of the IL-6 genes changed in the inflammatory response associated with smoking.

Medical history

In the current study, there was a significant difference between groups in the risk factors including DM, HTN, and IHD (P = 0.01). The risk factors were more prevalent in the patients in group III compared with those in group II, more than group I, because these factors enhance the process of atherosclerosis. In terms of the correlation between medical history and different markers, there was a statistically significant difference between medical history including DM, HTN, and IHD and different markers including CRP, but not in IL-6. In diabetic patients, the mean CRP level was 60.59 mg/l whereas the mean IL-6 level was 52.59 pg/ml, and in nondiabetic patients, the mean CRP level was 42.60 mg/l whereas the mean IL-6 level was 43.19 pg/ml.

Cardiac troponins

In this study, troponin I level was measured in all patients; there was a significant correlation between its level and group stratification of our patients. It was significantly increased in group II and group III (P = 0.00001). The level of troponin I was higher in groups II and III than group I; thus, there was a significant difference between the three groups in the troponin level.

In addition to its use in the diagnosis of MI, an increased troponin level can identify patients at high risk for adverse cardiac events [21]. However, the current study showed that an increased troponin level at baseline was not a statistically significant predictor of mortality, even in patients with chest pain and acute MI with ST-segment elevation who were eligible for reperfusion therapy. However, it appeared to be significantly increased in DM, HTN, and in shocked patients.

Inflammatory marker C-reactive protein

CRP is one of the substances present in the atherosclerotic lesion, more specifically in the vascular intima, where it colocalizes with monocytes, monocyte-derived macrophages, and lipoproteins [7]. This localization makes a direct contribution toward the atherosclerotic process possible.

CRP reflects systemic inflammation, and these results support the hypothesis that chronic inflammation may play a role in the pathogenesis and progression of atherosclerosis [22]. A crucial point in understanding the clinical and pathophysiologic significance of an increase in CRP in ACS is whether CRP release is predominantly a response to small amounts of myocardial necrosis or whether it is an independent indicator of the inflammatory process occurring in this clinical condition.

In the current study, the difference between the levels of CRP in the groups studied and the control group was statistically significant (P < 0.001). CRP was increased in MI more than unstable angina, but its level was normal in the control group, and this was in agreement with the inflammatory theory of atherosclerosis. The mean CRP level in group I was 50.44 mg/l and the mean level in group II was 54.37 mg/l, whereas the mean level was 84.25 mg/l in group III and 1.96 mg/l in group IV.

The level of CRP in the patient groups was higher in STEMI groups than that in the unstable angina group and was higher in the STEMI group with failed thrombolytic therapy than the STEMI group with successful thrombolytic therapy. These findings indicated the relation among the presence of myocardial damage, degree of inflammation, and CRP level.

The level of CRP was high in ischemic than perfused myocardium; this may be attributed to the prolonged expression of IL-6 in ischemic myocardium without reperfusion with a high level of CRP [23].

Most clinical studies report that CRP is an independent predictor of the risk of atherosclerosis [24], cardiovascular events [25], atherothrombosis [26], HTN [27], and myocardial infarction [28], even after considering other cardiovascular risk factors such as age, smoking, obesity, diabetes, hypercholesterolemia, and HTN. However, the absence of a relationship between CRP and the risk of myocardial infarction has been reported as well, especially after comprehensive adjustment for established risk factors [29].

In terms of the relation between CRP level and the development of complications, 40 patients did not develop any complications whereas 20 patients developed complications. There was a significant relation between CRP level and arrhythmia (P = 0.013), but no significant relation between CRP level and the development of pulmonary edema (P = 0.070), shock (P = 0.563), and death (P = 0.681).

In ACS, pulmonary edema may develop as a result of different mechanisms such as pump failure because of loss of muscle mass, which results in cardiogenic shock, diastolic dysfunction because of loss of myocardial compliance as a result of ischemia, mechanical factors such as acute mitral regurge, or because of tachyarrhythmia. Thus, the relation between the level of CRP and pulmonary edema needs to be investigated separately.

There have been several recent studies of elevated levels of CRP in patients with ACS [30],[31],[32]. They found that CRP in patients with ACS was predictive of adverse clinical outcomes. Because the present study included a large high-risk patient group, we expected CRP to be a significant predictor of increased cardiac risk. However, in our work, the predictive value of CRP was correlated with an increased risk of arrhythmia, but not correlated with pulmonary edema, shock, and death.

Anti-inflammatory marker interleukin 6

In the present study, the mean level of IL-6 was 33.10 pg/ml in group I and 87.10 pg/ml in group II, and on excluding two patients who had IL-6 levels of 220 and 550, we found that mean = 54, a mean of 52.36 pg/ml in group III and a mean of 3.67 pg/ml in group IV.

The present work showed that serum IL-6 concentrations were significantly higher in patients in groups II and III, than in group I and controls (P = 0.00001) (the normal range in our kit was 7.8-500 pg/ml).

A few studies have reported that the increase in IL-6 observed in ACS might be a result of myocardial necrosis rather than plaque rupture [33].

To explain the higher level of IL-6 in the STEMI group with failed thrombolytic therapy and according to some authors, it was found that IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury by downregulating the concentrations of proinflammatory cytokines such as IL-6. However, in ischemic myocardium without reperfusion, the expression of IL-6 is prolonged [34]. In other words, increased levels of IL-10 suggest good reperfusion, whereas low levels of IL-10 indicate ischemic but not reperfused myocardium and are accompanied by increased levels of IL-6.

The control group had no inflammation, and thus no inflammatory or anti-inflammatory cytokines, and their levels were normal. The results of the present study are in agreement with recent in-vitro and in-vivo studies in animals, which have suggested a protective role of IL-6 in both atherosclerotic lesion formation and stability.

Increased IL-6 levels were also observed in a subgroup of patients who gained the greatest benefit in terms of mortality from an early invasive strategy. These results suggest that an increased level of IL-6 may identify patients with a more severe index event, who would therefore benefit from more aggressive treatment. Currently, however, the large circadian variations in IL-6 levels and the lack of confirmatory studies limit the applications of IL-6 as a biomarker in ACS.

The current study found that IL-6 serum levels did not correlate with cardiac troponin levels in all patient groups and this means that the levels of IL-6 are not related to the extent of myocardial damage.

In terms of the associated risk factors, it was found that IL-6 showed no association with D.M, HTN, or IHD. Some studies have found higher levels of IL-6 in patients with DM compared with non diabetics [35],[36], whereas others have found no association of IL-6 with diabetes [37],[38].

Also, IL-6 did not correlate with any of the risk factors such as history of IHD, a medical history of HTN, and also smoking. There was no statistically significant correlation between IL-6 and complications, except in shocked patient. It was reported that once multiple organ failure is present, patients with cardiogenic shock will show similarly high IL-6 levels as patients with septic shock. High IL-6 levels in cardiogenic shock patients were associated with a progression to multiple organ failure [39].

Correlation between interleukin 6 and C-reactive protein

We found a statistically significant positive correlation between the IL-6 and CRP in group III (P = 0.002), a positive correlation, but not significant, in group I (P = 0.094), and no correlation in group II (P = 0.483). Vasan et al. [40] found that serum IL-6 levels were related to CRP levels. This result was not surprising as IL-6 is a central mediator of the acute-phase response and a primary determinant of the hepatic production of C-reactive [5].

According to several authors, the ratio of inflammatory and anti-inflammatory markers is the most powerful predictor of the development of a new coronary event during both the first 6 months and the 1-year follow-up period [41]. As we have mentioned earlier, the role of anti-inflammatory cytokines remained unclear despite recent studies and we thus focused on this topic in our investigation.

Undoubtedly, the association between inflammation, coronary plaque instability, and clinical presentation is extremely complex. Our investigation represents a small observational study and it was beyond the scope of the study to assess the relationship between IL-6 and patient outcome. However, our results suggest that increased levels of IL-6 may lead to an increase in the risk for atherosclerosis and the development of ACS.


  Conclusion Top


CRP is a useful prognostic indicator in patients with ACS. IL-6 is an anti-inflammatory cytokine. ACS patients have increased circulating levels of IL-6 compared with those patients who have unstable angina. The level of IL-6 is not affected by the extent of myocardial damage and necrosis. The use of serum IL-6 level as a predictive test for subsequent adverse cardiac events can be recommended. It is important to speculate that therapeutic interventions that increase endogenous IL-6 serum levels or even exogenous administration of IL-6 may represent novel therapeutic strategies to improve clinical outcome after ACS, specifically in patients with increased ongoing inflammatory activity.

Further studies with a larger sample of patients and long-term follow-up are needed to confirm our results and to study the prognostic value of IL-6 in ACS.

Study limitations

These results are interpreted on the basis of a small number of patients and a short-term follow-up.


  Acknowledgements Top


Conflicts of interest

None declared.

 
  References Top

1.
Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Jr, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995; 92:1355-74.  Back to cited text no. 1
    
2.
Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999; 340:115-26.  Back to cited text no. 2
    
3.
Davies MJ, Woolf N, Rowles PM, Pepper J. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Br Heart J 1988; 60:459-64.  Back to cited text no. 3
    
4.
Mach F, Schönbeck U, Fabunmi RP, Murphy C, Atkinson E, Bonnefoy JY, et al. T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism: implications for tubule formation. Am J Pathol 1999; 154:229-38.  Back to cited text no. 4
    
5.
Danenberg HD, Szalai AJ, Swaminathan RV, Peng L, Chen Z, Seifert P, et al. Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice. Circulation 2003; 108:512-5.  Back to cited text no. 5
    
6.
Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, et al. C-reactive protein in cardiovascular disease. JAMA 2008; 294:2866-90.  Back to cited text no. 6
    
7.
Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001; 103:1194-7.  Back to cited text no. 7
    
8.
Moreno PR, Fuster V. The year in atherothrombosis. J Am Coll Cardiol 2004; 44:2099-110.  Back to cited text no. 8
    
9.
Moreno PR, Purushothaman KR, Fuster V, Echeverri D, Truszczynska H, Sharma SK, et al. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability. Circulation 2004; 110:2032-8.  Back to cited text no. 9
    
10.
Davies MJ, Woolf N, Rowles PM, Pepper J. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Br Heart J 1988; 60:459-64.  Back to cited text no. 10
    
11.
Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990; 82(Suppl):38-46.  Back to cited text no. 11
    
12.
Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6:131-8.  Back to cited text no. 12
    
13.
Fong YM, Marano MA, Moldawer LL, Wei H, Calvano SE, Kenney JS, et al. The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest 1990; 85:1896-904.  Back to cited text no. 13
    
14.
Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993; 329:1246-53.  Back to cited text no. 14
    
15.
Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332:1351-62.  Back to cited text no. 15
    
16.
Besedovsky HO, del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 1996; 17:64-102.  Back to cited text no. 16
    
17.
Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993; 77:1690-4.  Back to cited text no. 17
    
18.
Stouthard JM, Romijn JA, Van der Poll T, Endert E, Klein S, Bakker PJ, et al. Endocrinologic and metabolic effects of interleukin-6 in humans. Am J Physiol 1995; 268(Pt 1):813-9.  Back to cited text no. 18
    
19.
Braunwald E, Antaman E, Beasley J, Califf R, et al. ACC AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction. Circulation 2000; 102:1193-1209.  Back to cited text no. 19
    
20.
Sunyer J, Forastiere F, Pekkanen J, Plana E, Kolz M, Pistelli R, et al. Interaction between smoking and the interleukin-6 gene affects systemic levels of inflammatory markers. Nicotine and tobacco research 2009;11:1337-43.  Back to cited text no. 20
    
21.
Zethelius B, Berglund L, Sundström J, Ingelsson E, Basu S, Larsson A, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008; 358:2107-16.  Back to cited text no. 21
    
22.
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135-43.  Back to cited text no. 22
    
23.
Alam SE, Nasser SS, Fernainy KE, Habib AA, Badr KF. Cytokine imbalance in acute coronary syndrome. Curr Opin Pharmacol 2004; 4:166-70.  Back to cited text no. 23
    
24.
Pepys MB, Hirschfield GM. C-reactive protein and atherothrombosis. Ital Heart J 2001; 2:196-9.  Back to cited text no. 24
    
25.
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101:1767-72.  Back to cited text no. 25
    
26.
Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003; 290:2945-51.  Back to cited text no. 26
    
27.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557-65.  Back to cited text no. 27
    
28.
Doggen CJ, Berckmans RJ, Sturk A, Manger Cats V, Rosendaal FR. C-reactive protein, cardiovascular risk factors and the association with myocardial infarction in men. J Intern Med 2000; 248:406-14.  Back to cited text no. 28
    
29.
Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349:462-6.  Back to cited text no. 29
    
30.
Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331:417-24.  Back to cited text no. 30
    
31.
Benamer H, Steg PG, Benessiano J, Vicaut E, Gaultier CJ, Boccara A, et al. Comparison of the prognostic value of C-reactive protein and troponin I in patients with unstable angina pectoris. Am J Cardiol 1998; 82:845-50.  Back to cited text no. 31
    
32.
Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon CP, Braunwald E. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998; 31:1460-5.  Back to cited text no. 32
    
33.
Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 2000; 101:1372-8.  Back to cited text no. 33
    
34.
Frangogiannis NG, Mendoza LH, Lindsey ML, Ballantyne CM, Michael LH, Smith CW, Entman ML. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury. J Immunol 2000; 165:2798-808.  Back to cited text no. 34
    
35.
Temelkova-Kurktschiev T, Henkel E, Koehler C, Karrei K, Hanefeld M. Subclinical inflammation in newly detected type II diabetes and impaired glucose tolerance. Diabetologia 2002; 45:151.  Back to cited text no. 35
    
36.
Ford ES. Body mass index, diabetes, and C-reactive protein among U.S. adults. Diabetes Care 1999; 22:1971-7.  Back to cited text no. 36
    
37.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286:327-34.  Back to cited text no. 37
    
38.
Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50:2384-9.  Back to cited text no. 38
    
39.
Geppert A, Steiner A, Zorn G, Delle-Karth G, Koreny M, Haumer M, et al. Multiple organ failure in patients with cardiogenic shock is associated with high plasma levels of interleukin-6. Crit Care Med 2002; 30:1987-94.  Back to cited text no. 39
    
40.
Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, et al. Framingham Heart Study. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003;107:1486-91.  Back to cited text no. 40
    
41.
Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol 2003; 41(Suppl S):7S-14S.  Back to cited text no. 41
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]


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