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Original Article
Association of Inflammatory Cytokines/Biomarkers with Acute Coronary
Syndrome and Its Correlation with Severity and Hospital Outcome
Mohd Mahmudullah Razi1, MD, DM; Nasar Abdali1, MD; Mohammed Asif S1, MD;
MalikMohammed Azharuddin2, MD

1
Department of Cardiology, Objective: Coronary atherosclerosis is one of the major causes of coronary artery disease.

Abstract
LPS Institute of Cardiology,
GSVM, Kanpur, 2Department
of Medicine, JNMCH, AMU,
Aligarh, Uttar Pradesh, India
Received: November, 2016.
Accepted: January, 2017.
Atherosclerosis is an inflammatory process involving vascular wall cells, monocytes,
T‑lymphocytes, pro‑inflammatory cytokines, chemoattractant cytokines (chemokines), and growth
factors. The presence of inflammatory cells in the atherosclerotic lesion and elevated levels of
the inflammatory markers in peripheral circulation correspond to an active inflammatory process
in the body. In view of this background, this study was undertaken to evaluate the association
between activation of inflammatory cytokines and acute coronary syndrome (ACS). Furthermore,
the correlation of these factors with severity of ACS and in‑hospital mortality outcomes was
studied.
Study Design: It is a prospective case–control study, including forty cases of ACS (as per
the inclusion criteria listed below) and twenty controls. The levels of inflammatory markers
interleukin‑6 (IL‑6), tumor necrosis factor‑α (TNF‑α), and troponin I were estimated in cases
and controls. The levels of these markers in the peripheral circulation were also stratified on
the basis of the presenting ACS type (unstable angina, non‑ST‑elevation myocardial infarction,
and ST‑elevation myocardial infarction). All statistical data were analyzed using SPSS software
version 19 Statistical package for windows (Chicago, Inc., IL, USA).
Results: The levels of inflammatory markers such as IL‑6, TNF‑α, and troponin I were higher
in the ACS group than the control, and difference was statistically significant. Furthermore, there
was a statistically significant difference in the levels of these markers between the various ACS
groups.
Conclusions: The circulating levels of inflammatory markers such as IL‑6 and TNF‑α are
significantly elevated in patients with ACS, supporting the view that inflammatory cytokines
are associated with ACS. There is a direct correlation of the levels of IL‑6 and TNF‑α with the
severity of ACS and in‑hospital mortality in these cases.
Keywords: Acute coronary syndrome, interleukin‑6, tumor necrosis factor‑α

Introduction Pro‑inflammatory stimuli such as oxidatively modified

C oronary atherosclerosis is one of the major causes of
coronary artery disease (CAD). Atherosclerosis is an
inflammatory process involving vascular wall cells along with
activation of markers of inflammation such as the monocytes,
T‑lymphocytes, pro‑inflammatory cytokines, chemoattractant
cytokines (chemokines), and growth factors. Atherosclerotic
plaques are vulnerable to rupture and thereby associated with
serious complications. The presence of inflammatory cells in
the atherosclerotic lesions and elevated levels of inflammatory
markers in the peripheral circulation correspond to an
activation of the inflammatory process in the body.[1‑4]
The fatty streak is the early inflammatory lesion, consisting
mainly of monocyte‑derived macrophages and T‑lymphocytes.
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low‑density lipoprotein (LDL) cholesterol, free radicals,
cigarette smoke, elevated plasma homocysteine, and infectious
organisms cause endothelial dysfunction which leads to
compensatory responses that alter the normal properties of
the endothelium. A cascade of events ensues leading to the
development of isolated macrophages, foam cells, fatty streak
Address for correspondence:
Dr. Nasar Abdali, MD,
D 16, Medical College Campus, GSVM, Kanpur ‑ 208 002,
Uttar Pradesh, India.
E‑mail: editor.hadi@gmail.com
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak,
and build upon the work non‑commercially, as long as the author is credited and the new
creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com

How to cite this article: Razi MM, Abdali N, Asif SM, Azharuddin M.
Association of inflammatory cytokines/biomarkers with acute coronary
DOI: 10.4103/2250-3528.203532 syndrome and its correlation with severity and hospital outcome. J Clin
Prev Cardiol 2017;6:44-9.

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Razi, et al.: Association of inflammatory cytokines/biomarkers with acute coronary syndrome and its correlation with severity and hospital outcome

formation, and finally stable or unstable fibrous plaque. Table 1: List of major cytokines, their receptors, and
This cascade of events is mediated by pro‑inflammatory
cytokine‑related inflammatory mediators implicated in
cytokines, chemoattractant cytokines (chemokines), growth
the pathophysiology of acute coronary syndrome and
factors, and adhesion molecules produced by activated
related heart failure[6,7]
inflammatory, vascular smooth muscle, and endothelial
C‑reactive protein
cells. Pro‑inflammatory risk factors cause local  (vascular)
Pro‑inflammatory cytokines and their soluble receptors
or systemic  (extravascular) inflammation which triggers the
production of primary pro‑inflammatory cytokines such as TNF‑α
interleukin‑1a (IL‑1) and tumor necrosis factor‑alpha (TNF‑α). sTNFR‑I and sTNFR‑II
Measurement of these cytokines in serum can provide IL‑1
information about the inflammatory status of an individual. IL‑1ra
IL‑2
Markers of inflammation and pro‑inflammatory cytokines sIL‑2R
such as C‑reactive protein (CRP), TNF‑alpha, and monocyte
IL‑6
chemoattractant protein‑1 are under evaluation as a marker of
sIL‑6R
monocytes/macrophages activation, soluble IL‑2 receptor as a
IL‑18
marker of T‑lymphocyte activation, and tryptase as a marker of
Anti‑inflammatory cytokine
mast cell activation.
IL‑10
Primary pro‑inflammatory cytokines and oxidatively modified Chemotactic cytokines
LDL activating the endothelium also leads to the expression IL‑8
of adhesion molecules that are crucial to the recruitment of MCP‑1
inflammatory cells from bloodstream into the vessel wall. MIP‑1α
These adhesion molecules may be released in soluble form Nitric oxide
into the bloodstream and can serve as markers of vascular Soluble adhesion molecules
inflammation. sICAM‑1
Nucleated cells express heat shock proteins (Hsp), in response sVCAM‑1
to environmental stress. Increased expression of Hsp has been Selectins
detected in the cells of atherosclerotic lesions, and elevated P‑selectin
antibodies against heat shock proteins (Anti‑Hsp‑Ab) levels E‑selectin
have been shown to be associated with human atherosclerosis. Integrins
In addition, primary pro‑inflammatory cytokines stimulate the LFA‑1
production of chemoattractant cytokines (chemokines) which TNF‑α=Tumor necrosis factor‑α, sTNFR‑I=Soluble TNF receptors
may play a major role in atherogenesis and can be used as I, sTNFR‑II=Soluble TNF receptors II, IL‑1=Interleukin‑1,
markers of inflammation. Moreover, primary pro‑inflammatory IL‑1ra=IL‑1 receptor antagonist, IL‑2=Interleukin‑2,
cytokines stimulate the production of IL‑6, a secondary sIL‑2R=Soluble IL‑2 receptor, IL‑6=Interleukin‑6, sIL‑6R=Soluble
IL‑6 receptors, IL‑18=Interleukin‑18, IL‑10=Interleukin‑10,
pro‑inflammatory cytokine, which in turn stimulates the
IL‑8=Interleukin‑8, MCP‑1=Macrophage chemoattractant
production of acute phase proteins by the liver. Examples
protein‑1, MIP‑1α=Macrophage inflammatory protein‑1α,
of these proteins include CRP, serum amyloid A (SAA),
sICAM‑1=Soluble intercellular adhesion molecule‑1,
and fibrinogen. These proteins can be used as markers of sVCAM‑1=Soluble vascular cell adhesion molecule‑1,
inflammation. P‑selectin=Platelet‑selectin, E‑selectin=Endothelial‑selectin,
CRP is an acute phase protein which increases in LFA‑1=Lymphocyte function associated antigen‑1
various inflammatory and infective states. Increased CRP
concentrations may indicate widespread inflammation and LPS Institute of Cardiology and J. N. Medical College Hospital
instability of atherosclerotic plaques in coronary arteries.[5] were taken for prospective study from the year January 2014
Table 1 enumerates list of major cytokines, their receptors, to January 2015. Informed consent was taken from all study
and cytokine-related inflammatory mediators implicated in the participants, and the study protocol was approved by the board
pathophysiology of acute coronary syndrome and related heart of studies of medicine department and the Local Institutional
failure.[6,7] Review Committee.
Thus, the present study was undertaken with the aim to
The diagnosis of ACS was made if two or more of the
evaluate the association between inflammatory cytokines and
following criteria were fulfilled.[8]
acute coronary syndrome (ACS) and to correlate them with
severity of the disease and hospital outcomes. • Central chest pain lasting longer than 30 min
• Typical changes in cardiac Troponin I (cTrop‑I)
Materials and Methods • Typical electrocardiogram changes including ST‑T
A total of sixty participants, including twenty controls and changes with or without pathological Q waves in at
forty patients of ACS, admitted to the Coronary Care Unit of least two contiguous leads.

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Razi, et al.: Association of inflammatory cytokines/biomarkers with acute coronary syndrome and its correlation with severity and hospital outcome

Exclusion criteria Table 2: Baseline demographics of the study subjects

• Patients with a history of recent surgery or trauma Control Cases P
within the preceding 2 months (n=20) (n=40)
• Renal insufficiency (creatinine >1.5 mg/dl) Age (years) 55.15±8.94 54.73±9.5 0.60
• Malignancy Sex
• Febrile disorders  (infections) and patients with body Male 13 28 0.70
temperature >37.5°C Female 7 12 0.63
• Acute or chronic inflammatory diseases Risk factors
• Patients with a history of recent infections Smoking 4 13 0.34
• Patients with known or suspected thrombotic disorders. Diabetes mellitus 5 10 1.0
Hypertension 3 10 0.5
The concentration of TNF‑α (pg/ml) in serum of patients Obesity 3 11 0.3
and healthy controls was determined by use of a commercial
Family history of premature 0 14 0.001
ELISA Kit (R and D Systems). CAD
IL 6 concentrations in patients and healthy controls were CAD=Coronary artery disease
determined by use of a commercial ELISA Kit (R and D
Systems), which employed the quantitative sandwich enzyme
Table 3: Clinical diagnosis at presentation
immunoassay technique.
Sex Control ACS group (n=40)
All statistical data were analyzed using SPSS software (n=20) USA (n=13) NSTEMI STEMI
version 19 Statistical package for windows (IBM Corp. Released (n=10) (n=17)
2010, Armonk, NY). Continuous variables were expressed as Number of Number of Number of Number of
mean ± standard deviation (Gaussian distribution) or range and subjects (%) subjects (%) subjects (%) subjects (%)
qualitative data were expressed as percentage. Depending on Male 13 (65) 10 (76.92) 6 (60) 12 (70.59)
normality distribution, unpaired t‑test for independent samples Female 7 (35) 3 (23.08) 4 (40) 5 (29.41)
was used for comparing continuous variables between two ACS=Acute coronary syndromes, USA=Unstable angina,
groups. Categorical variables were analyzed using Chi‑square STEMI=ST elevation myocardial infarction, NSTEMI=Non‑ST
test. ANOVA was used enabling post hoc comparisons using elevation myocardial infarction
Bonferroni method, for obtaining P values for comparison
between individual groups. All P values were two tailed, and
Table 4: Presenting symptoms in patients with acute
P < 0.05 was considered statistically significant. All confidence
coronary syndrome
intervals were calculated at 95% level.
Symptoms Number of subjects (%)
Ischemic pain 25 (62.50)
Results
Chest pain 21 (84.00)
A total of forty cases and twenty controls with statistically Epigastric pain 4 (16.00)
nonsignificant difference regarding age and sex were enrolled Shortness of breath 16 (40.00)
in the study. Cases enrolled had more risk factors for ACS as Vomiting 13 (32.50)
compared to control [Table 2]. Most of the patients enrolled Palpitation 11 (27.50)
as cases had ST‑elevation myocardial infarction (STEMI),
Diaphoresis 6 (15.00)
followed by unstable angina (USA) and non‑ST‑elevation
Dizziness/syncope 2 (5.00)
myocardial infarction (NSTEMI) with chest pain being the
most common presenting complaint [Tables 3 and 4]. Serum
level of Cardiac biomarkers such as IL‑6, TNF‑α, and cTrop‑I Table 5: Inflammatory markers/markers of myocardial
was statistically more significant in cases than in controls injury in controls and in acute coronary syndrome
with STEMI showing the highest level followed by NSTEMI patients
and USA [Tables 5 and 6]. Level of these cardiac biomarkers
Inflammatory/ Control group ACS group t P
also correlated well with Killip class [Table 7]. Furthermore, bio‑marker (n=20) (n=40)
level of these biomarkers has statistically significant impact on IL‑6 (pg/mL) 05.05±02.01 96.35±36.81 15.64 <0.001
patient’s hospital outcomes [Table 8]. 03.87±01.93 278.12±84.02 20.63 <0.001
TNF‑α (pg/mL)
cTrop‑I (ng/mL) ‑ 04.67±04.70 ‑ ‑
Discussion
ACS=Acute coronary syndrome, IL‑6=Interleukin 6,
Cells of the immune system are widely present in the TNF‑α=Tumor necrosis factor α, cTrop‑I=Cardiac troponin I
atherosclerotic plaque and that the disease seems to be driven
by inflammatory mechanisms. Moreover, total leukocyte inflammatory mediators such as[10] IL‑6, fibrinogen, TNF‑α, and
count[9,10] and levels of systemic inflammatory mediators such CRP are acute phase proteins that respond to injury. Synthesis
as IL‑6,[11,12] fibrinogen,[13] TNF‑α,[14] SAA, and CRP have of these factors takes place mainly in the liver, but recently
been shown to predict the onset of cardiovascular disease. The adipose tissue has emerged as another source of cytokines.[15]

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Razi, et al.: Association of inflammatory cytokines/biomarkers with acute coronary syndrome and its correlation with severity and hospital outcome

Table 6: Inflammatory markers/markers of myocardial injury in patients with different forms of acute coronary
syndrome
Inflammatory/ ACS group P
bio‑marker USA NSTEMI STEMI
USA versus USA versus NSTEMI versus
NSTEMI STEMI STEMI
IL‑6 (pg/mL) 54.37±13.46 101.22±06.67 125.60±28.05 <0.001 <0.001 <0.01
TNF‑α (pg/mL) 177.73±51.31 310.21±10.81 336.04±52.68 <0.001 <0.001 NS
cTrop‑I (ng/mL) 00.10±0.00 04.67±02.84 08.18±04.38 <0.01 <0.01 <0.05
All values are mean±SD. ACS=Acute coronary syndrome, IL‑6=Interleukin 6, TNF‑α=Tumor necrosis factor α, cTrop‑I=Cardiac troponin I,
USA=Unstable angina, STEMI=ST elevation myocardial infarction, NSTEMI=Non‑ST elevation myocardial infarction, SD=Standard deviation,
NS=Not significant

Table 7: Inflammatory markers/markers of myocardial injury in acute coronary syndrome patients as per the Killip
class at presentation
Inflammatory/ KC‑I KC‑II KC‑III KC‑IV Differences (P)
biomarkers KC‑I KC‑I KC‑I KC‑II KC‑II KC‑III
versus versus versus versus versus versus
KC‑II KC‑III KC‑IV KC‑III KC‑IV KC‑IV
IL‑6 (pg/mL) 86.73±32.72 79.82±35.03 113.00±35.03 129.67±24.31 NS NS <0.05 NS <0.05 NS
TNF‑α (pg/mL) 252.36±73.72 241.60±88.95 318.03±52.49 357.57±44.10 NS NS <0.05 NS <0.05 NS
cTrop‑I (ng/mL) 3.30±04.07 2.98±04.21 5.86±04.26 9.10±04.36 NS NS <0.05 NS <0.05 NS
All values are mean±SD. IL‑6=Interleukin 6, KC=Killip class, TNF‑α=Tumor necrosis factor α, cTrop‑I=Cardiac troponin I, NS=Not
significant, SD=Standard deviation

Table 8: Inflammatory markers/markers of myocardial 54.36 ± 13.46 pg/ml, 101.22 ± 6.67 pg/ml, and 125.60 ± 28.05 pg/

injury in acute coronary syndrome patients according to
the clinical outcome
Inflammatory/ Dead (n=08) Survived t P
bio‑marker (n=32)
IL‑6 (pg/mL) 132.52±27.72 87.31±33.31 3.95 <0.01
TNF‑α (pg/mL) 364.07±41.20 256.63±78.20 5.35 <0.001
cTrop‑I (ng/mL) 8.88±04.82 3.62±04.10 2.83 <0.05
All values are mean±SD. IL‑6=Interleukin 6, TNF‑α=Tumor
necrosis factor α, cTrop‑I=Cardiac troponin I, SD=Standard
deviation
In the present study, increased level of TNF‑α and IL‑6 was
seen in different ACS groups which also correlated well with
severity of disease. It was seen that its value in different ACS
group was maximum in STEMI and minimum in USA and that
STEMI had worst prognosis. Maury and Teppo, 1989, have
reported that increased levels of TNF‑α have been observed
after acute myocardial infarction (AMI).[16]
In the present study, the mean value of TNF‑α in patients who
died was 364.07 ± 41.20 pg/ml and in those who survived was
256.63 ± 78.20 pg/ml, and this difference in the two group
was statistically significant (t = 5.35; P < 0.01). Mortality
of the patients was directly related to the increased level of
TNF‑α. Similar observation was reported by Ridker et  al.,
1997, a follow‑up study of 17‑months, which showed that the
increased levels of TNF‑α were associated with increased risk
of recurrent coronary events and increased mortality.[17]
In the present study, the mean value of IL‑6 in control group,
USA, NSTEMI, and STEMI was 5.0560 ± 2.01 pg/ml,
ml, respectively. Its value among ACS group was maximum
in STEMI and minimum in USA. As compared to control, the
rise in the value of IL‑6 was maximum in STEMI followed by
NSTEMI and then USA.
As it was seen in the previous study of Biasucci et  al., 1996,
and Ikonomidis et  al., 1999, the patients with stable angina
had higher IL‑6 concentration than healthy controls and
patients with USA had higher IL‑6 concentration than patients
with stable angina.[18,19]
In the present study, the mean value of IL‑6 in the patients
who died was 132.52 ± 27.72 pg/ml and in those who survived
was 87.31 ± 33.31 pg/ml. This difference was statistically
significant (t = 3.95; P < 0.01) and is in conformation with the
previous observation of Biasucci et  al.[18] They had reported
that the patients with USA and with complicated in‑hospital
course (urgent need for revascularization) had higher IL‑6
concentration both on hospital admission and during the 48 h
follow‑up compared with those patients with USA and without
cardiovascular events during their hospital stay.
In the present study, raised IL‑6 at the time of admission was an
indicator of adverse in‑hospital cardiovascular events. Biasucci
et  al. have also reported that elevation of IL‑6 within the first
2 days of an episode of ACS was associated with adverse
in‑hospital outcomes.[18] Thus, IL‑6 during the first 48  h of an
ACS is a good predictor of a major adverse cardiovascular
event (MACE) during the 1st month and the 1st year after the
initial coronary event. Ridker et al., 2000, and Luc et al., 2000,
also showed that patients with persistently elevated IL‑6 levels
are associated with a worse in‑hospital outcome following

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Razi, et al.: Association of inflammatory cytokines/biomarkers with acute coronary syndrome and its correlation with severity and hospital outcome
admission with USA. Further, elevated levels of IL‑6 predict
the risk of AMI and death but not angina.[11,20] The risk of MI
increased to 38% with each quartile increment of baseline IL‑6
levels. This study signifies that mortality was increased with
increased levels of IL‑6.
In the present study, the mean value of cTrop‑I in USA,
NSTEMI, and STEMI was 0.1000 ± 0.000 pg/ml,
4.6700 ± 2.8465 pg/ml, and 8.1847 ± 4.3889 pg/ml, respectively.
Its value was maximum in STEMI and minimum in USA
patients.
In the present study, the mean value of cTrop‑I in the patients
who died was 8.88 ± 4.82 ng/ml and those that survived
was 3.62 ± 4.10 ng/ml, and this difference was statistically
significant  (t = 2.83; P < 0.05). The increased value of
cTrop‑I was associated with increased risk of mortality. Our
study further strengthens the study by Antman et  al., 1996, in
which they hypothesized that cTrop‑I provides for the early
identification of patients at an increased risk of death.[21] The
measured value of cTrop‑I at concentration of 0.4 mg/L was
associated with significantly higher mortality at 42  days than
lower concentrations among patients with USA or non‑Q‑wave
infarction. This was an independent predictor of short‑term
mortality after adjustment for age and the presence of
ST‑segment depression. Several other clinical outcome‑based
studies have demonstrated that patients with acute cardiac
ischemia in whom CK‑MB, cTnI, and/or cTnT was increased,
are at increased risk for adverse events including MI or cardiac
death.[22,23] A similar result was also seen in the study of Lindahl
et al., 1996, and FRagmin during InStability in Coronary artery
disease trial, where the authors measured the incidence of
cardiac death at 1 year and found that the risk ranged from 0%
to 16% among patients who had elevated troponin and CRP
levels.[24] The elevated levels of troponin STEMI patients were
found to be associated with increased risk of short‑term and
long‑term MACE and death.
Limitations of the study
Our study had some limitations which merit attention. IL‑6
and TNF‑α are nonspecific inflammatory markers and do not
necessarily indicate an association with CAD. However, in our
patients, the levels of the markers were associated with severity
of clinical presentation as well as in‑hospital mortality. These
findings indicate that these markers indeed reflect heightened
inflammatory activity in response to an acute coronary event.
Second, the small size of the case and control group which
was also not matched with respect to various cardiovascular
risk factors needs to be kept in mind. However, a consistent
relationship between the levels of inflammatory markers and
the severity of coronary event suggests that the elevated levels
of the studied inflammatory markers in ACS patients were not
just because of greater prevalence of cardiovascular risk factors
but more likely reflected the ongoing atherosclerotic activity.
Conclusions
This study once again demonstrates that the circulating
levels of inflammatory markers such as IL‑6 and TNF‑α are
48 Journal of Clinical and Preventive Cardiology  ¦  Volume 6  ¦  Issue 2  ¦  April-June 2017
significantly elevated in patients with ACS, supporting the
view that inflammatory cytokines are associated with ACS.
Further, there is a direct correlation between the levels of IL‑6
and TNF‑α and severity of ACS, including the in‑hospital
mortality.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Journal of Clinical and Preventive Cardiology  ¦  Volume 6  ¦  Issue 2  ¦  April-June 2017 49