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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, Atherosclerosis is an inflammatory process involving vascular wall cells, monocytes,
GSVM, Kanpur, 2Department T‑lymphocytes, pro‑inflammatory cytokines, chemoattractant cytokines (chemokines), and growth
of Medicine, JNMCH, AMU, factors. The presence of inflammatory cells in the atherosclerotic lesion and elevated levels of
Aligarh, Uttar Pradesh, India 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.
Received: November, 2016.
Accepted: January, 2017. Keywords: Acute coronary syndrome, interleukin‑6, tumor necrosis factor‑α
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.
44 © 2017 Journal of Clinical and Preventive Cardiology | Published by Wolters Kluwer - Medknow
[Downloaded free from http://www.jcpconline.org on Friday, August 3, 2018, IP: 106.76.152.33]
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.
Razi, et al.: Association of inflammatory cytokines/biomarkers with acute coronary syndrome and its correlation with severity and hospital outcome
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
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 significantly elevated in patients with ACS, supporting the
the risk of AMI and death but not angina.[11,20] The risk of MI view that inflammatory cytokines are associated with ACS.
increased to 38% with each quartile increment of baseline IL‑6 Further, there is a direct correlation between the levels of IL‑6
levels. This study signifies that mortality was increased with and TNF‑α and severity of ACS, including the in‑hospital
increased levels of IL‑6. mortality.
In the present study, the mean value of cTrop‑I in USA, Financial support and sponsorship
NSTEMI, and STEMI was 0.1000 ± 0.000 pg/ml, Nil.
4.6700 ± 2.8465 pg/ml, and 8.1847 ± 4.3889 pg/ml, respectively.
Its value was maximum in STEMI and minimum in USA Conflicts of interest
patients. There are no conflicts of interest.
In the present study, the mean value of cTrop‑I in the patients
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