Background: The pathophysiology of acute  coronary syndromes (ACS) is now accepted as the rupture or erosion of an atherosclerotic plaque, which initially occurs at the shoulder of the plaque and is followed by intra-plaque thrombosis then spread to the vascular lumen and cause total partial vascular occlusion. MMP-9 is an extracellular matrix degrading enzyme that plays a crucial role in the breakdown of the fibrous cap of plaque and subsequent rupture in the pathogenesis of ACS. Cardiac troponins are currently the most sensitive and specific biochemical markers of myocytes necrosis.
Objective: To know the correlation between serum level MMP-9 and serum level of Troponin-I in patients with ACS Method: Study design was cross sectional. Data were collected by consecutive sampling from patients in ICCU ward of RSUP Dr. Sardjito General Hospital, Yogyakarta, from June 2008-August 2010. A questionnaire was used to collect information from patient. After admission, peripheral venous blood was drawn once and measured concentration of serum level of MMP-9 and Troponin-I before definitive thrombolysis. Data were expressed as means ± standard deviation (SD). Correlation between serum level of MMP-9 and serum level of Troponin-I were assessed using Spearman\u27s rank correlations test. A value of 

Ruchanihadi , Budi Yuli Setianto , Hariadi Hariawan

English

UGM Journals, OAI Repository

9O R I G I N A L  A R T I C L E
CORRELATIONS BETWEEN SERUM LEVEL OF MATRIX  
METALLOPROTEINASE-9 (MMP-9) AND SERUM LEVEL OF TROPONIN-I 
IN PATIENT WITH ACUTE CORONARY SYNDROME (ACS)
1. Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta
2. Subdivision of Cardio Vascular, Department of Internal Medicine, Dr. Sardjito Hospital, Yogyakarta
*Corresponding Author:hariadi_yk@yahoo.com
1 2 2*Ruchanihadi , Budi Yuli Setianto , Hariadi Hariawan
ABSTRACT
Background: The pathophysiology of acute 
coronary syndromes (ACS) is now accepted as the 
rupture or erosion of an atherosclerotic plaque, 
which initially occurs at the shoulder of the plaque 
and is followed by intra-plaque thrombosis then 
spread to the vascular lumen and cause total partial 
vascular occlusion. MMP-9 is an extracellular 
matrix degrading enzyme that plays a crucial role in 
the breakdown of the fibrous cap of plaque and 
subsequent rupture in the pathogenesis of ACS. 
Cardiac troponins are currently the most sensitive 
and specific biochemical markers of myocytes 
necrosis. 
Objective: To know the correlation between 
serum level MMP-9 and serum level of Troponin-I in 
patients with ACS
Method: Study design was cross sectional. 
Data were collected by consecutive sampling from 
patients in ICCU ward of RSUP Dr. Sardjito General 
Hospital, Yogyakarta, from June 2008-August 2010. 
A questionnaire was used to collect information 
from patient. After admission, peripheral venous 
blood was drawn once and measured concentration 
of serum level of MMP-9 and Troponin-I before 
definitive thrombolysis. Data were expressed as 
means ± standard deviation (SD). Correlation 
between serum level of MMP-9 and serum level of 
Troponin-I were assessed using Spearman's rank 
correlations test. A value of p<0.05 was considered 
statistically significant.
Result: There were 139 patients with ACS 
and comprising 63 patients with STEMI, 27 patients 
with NSTEMI, and 49 patients with UAP. Means±SD 
of Troponin-I from all of samples was 9.49±10.47 
ng/dL. Mean±SD of MMP-9 from all of samples was 
1296.06±729.97 ng/dL. There were significant 
correlations between MMP-9 and Troponin-I in 
patients with ACS (r=0.34, p=0.000).
Conclusion: There were significant 
correlations between MMP-9 and Troponin-I in ACS 
patients in ICCU ward, RSUP Dr. Sardjito General 
Hospital, Yogyakarta, from June 2008-August 2010.
Keywords: ACS, MMP-9, Troponin-I
INTRODUCTION
Pathophysiology of ACS is rupture or 
erosion of atherosclerotic plaque. First rupture 
occurred in the shoulder of plaque, which followed 
1by thrombosis in the plaque . Trombogenesis 
initiated by tissue factor released by monocytes, 
macrophages, endothelial cells, and smooth muscle 
cells, and other clotting factors will lead to a 
2thrombosis . Thrombosis within the plaque, will 
spread into the blood vessels by causing platelet 
aggregation that leads to a thrombus. Thrombus can 
1cause a total or a part occlusion blockage .
The main factor which is estimated to cause 
rupture of atherosclerotic plaques is inflammation 
and accelerated degradation of collagen and matrix 
components. Atherosclerotic has been accepted as a 
chronic inflammation disease. Previous studies 
showed that ACS occurs through several steps: 
triggered by proinflammatory cytokines such as 
interleukin-6 (IL-6) and chemoattractant which will 
attract leucocytes to the endothelium, and together 
with CD40-ligand (CD40L), will enable the 
atherosclerotic plaque macrophages. Macrophages 
will produce matrix metalloproteinase (MMPs), 
which will cause damage to the plaque extracellular 
3matrix, so that the plaque becomes unstable . This 
instability will cause plaque rupture, ischemia, 


12
Acta Interna - The Journal of Internal MedicineRuchanihadi, et al
A cut-off level of MMP-9 was 1,103 
ng/mL. At this level, sensitivity and specificity were 
73.5% and 59.2%. Based on this cut-off, subjects 
were divided into 2 groups, first is the group with 
MMP-9 higher than the cut-off,  77 subjects 
(55.4%) and group with MMP-9 lower than the cut-
off, 62 subjects (44.6%).
Standard level of cTn-I to diagnosed 
STEMI was 0.6 ng/mL, subject were divided into 2 
groups: the first group with higher level than 0.6 
ng/mL (90 subjects/64.7%), and the other group 
with  lower  level  than 0 .6  ng/mL (49 
subjects/35.3%).
Correlation between MMP-9 and cTn-I 
based on the cut-off respectively, were performed 
by Chi square. Chi square test results showed a 
significant relationship (p=0.000). Prevalence ratio 
was 1.98 (95% CI=1.45-2.70).
Discussion
Pathophysiology of ACS was sudden 
decrease of coronary blood flow after the thrombus 
occlusion, which results imbalance oxygen demand 
and supplies the heart muscle. In the most cases, 
infraction occurs when atherosclerotic plaque has 
fisur, rupture, or ulceration and started the 
coagulation cascade by exposure of tissue factor 
(TF) on endothelial cells are damaged, and cause 
fibrin formation. This process also stimulated 
aggregation platelets and thrombud formation, so-
called red thrombus/fibrin-rich red thrombus. 
Historically showed coronary plaque prone to 
rupture if that had a thin fibrous cap, and a rich lipid 
13core (lipid-rich-core) .
Histologically, atherosclerosis appears to 
be thickening tunica intima with an increased 
number of smooth muscle cells (VSMC) in the 
lining of blood vessels and extracellular matrix. The 
increased of these cells derived from components of 
hematopoietic stem cells, and than migrate and 
proliferate in the tunica intima. This was followed 
by accumulation of intracellular or extracellular 
lipid, or both, making fatty streak. Fatty streak also 
contains macrophages and a number of lymphosit T. 
At an advanced stage, VSMC, macrophages, and 
cytoplasmic remnants in tunica intima, caused 
calcification. This process plays a role in changes 
fatty streaks into atherosclerotic plaques, which 
occur due to plaque accumulation of lipid rich 
macrophages, smooth muscle cells, lipids. Fibrous 
cup occurs because grown fatty streak with 
accumulation of connective tissue and increase the 
number of smooth muscle cells are filled with 
14,2lipid .
MMP is an endoproteinase that contain 
zinc, with structures that are similar but have 
differences in the substrate. MMP capable 
15degradated matrix extracellular . MMP is classified 
into 4 groups: (1) Collagenases (MMP-1, MMP-8, 
MMP-13), able to degrade type I,II,III collagen, (2) 
gelatinase (MMP-2 and MMP-9), can degrade 
collagen type IV in basal membrane, (3) 
Stromelysin (MMP-3, MMP-10, MMP-11), can 
degrade extracellular matrix components in 
general, including proteoglycans, laminins, 
fibronectin, vitronectin, and some types of collagen, 
(4) Membrane-type MMP (MTI-MMPs) which can 
degrade extracellular matrix components and may 
15activate the other MMP . The sources of MMP-9 
were the vascular smooth muscle cell (VSMC), 
macrophages, T lymphocytes and fibroblast 
15adventitial .
Atherosclerotic plaque disruption that lead 
to thrombosis and coronary artery occlusion can 
occur in 2 forms, namely: 'frank rupture' and 
'superficial Erosion'. Rupture is defined as the 
outbreak of the fibrous cap and place of exposure to 
content that is prothrombotik. It identifies the local 
over-expression of MMP activity and matrix 
degradation in the shoulder of plaque, as a possible 
mechanism of the causes. Analysis of plaque 
atheroma in (unstable angina plaque) UAP and 
(stable angina plaque) SAP, showed an active 
synthesis of MMP-9 from macrophages and SMC. 
MMP-2 and MMP-9 increased in ACS patients, 
which raise the idea to develop non-invasive 
16method to detect fragility plaque .
There were increased levels of MMP-1, -2, 
-3, -7, -9, -11, -12, -13, -14, and -16 in human 
atherosclerotic plaques, especially in the shoulder-
rich plaque macrophages. Much more research that 
t r a i n e d  c o r r e l a t i o n  w i t h  t h e  p l a q u e  
disruption/rupture. MMP-11 was limited to 
advanced atherosclerotic plaque, rather than lipid-
rich-plaque core. There was no difference in levels 
of MMP-1, -2, and -3 at the condition of plaque 
instability, although evidence of plaque rupture, but 
there was an increase in the levels of MMP-9, two-
four times in plaque rupture. In other research, there 
was an increase of MMP-9 levels in patients with 
13
Correlations Between Serum Level of MMP-9Volume 1, Number 2, December 2011
UAP compared with SAP patients, and there was a 
clear link between increased levels of MMP-9 and 
17plaque instability .
Measurement of MMP-9 in the ACS was 
18first done by Kai et al. . This research was 
conducted on 33 ACS (which consisted of 22 
patients with acute myocardial infraction (AMI) 
and 11 patients with UAP), 17 patients with SAP 
and control patients. Plasma levels of MMP-9 in 
UAP group was 87±26 ng/mL, and significantly 
different than control (p<0.001), also significantly 
different to the SAP (34±11ng/mL, p<0.001) and 
different with AMI (49±28ng/mL, p<0.001). 
Plasma levels of MMP-9 in the AMI group was also 
significantly different than control (p<0.05), 
although there were 6 patients with increased of 
MMP-9 and 7 patients with similar levels of the 
19 control group and SAP. Fukuda et al. conducted on 
47 patients with AMI, 23 patients with UAP and 19 
patients with SAP. MMP-9 levels in AMI was 
significantly higher (328±209.6ng/mL, p=0.04) 
than the SAP group. Levels of MMP-9 in UAP was 
significantly higher (306.6±209.6 ng/mL, p=0.04) 
than SAP (199.0±156.8 ng/mL).
Increased levels of MMP-9 also showed in 
this study. The mean and standard deviation levels 
of MMP-9 in this study were 1296.06±729.97 
ng/mL, which clearly increased than the normal 
levels. MMP-9 levels increased and changed with 
6 time as long as duration of ACS. Kaden et al. study, 
the highest levels of MMP-9 obtained during 
hospitalization and then decreased and reached 
18normal after 1 week later. Kai et al.  study were 
showed the highest level of MMP-9 at 0-day in 
patients with UAP (when they come to the hospital) 
and about 3 times higher than normal controls and 2-
fold higher compared to patients with angina, which 
then decreases approaching control levels within 7 
days. However, some patients with UAP showed 
increased MMP-9 up to day-to-3, and then declined 
until day 7. In the group of AMI patients, the profile 
of increase in MMP-9 was also varied. In some 
patients with AMI, the early level 0-day, which 
showed similarity to the control group and angina, 
then increased to peak on day-3. But in others, a 
significant increase (2-fold compared to control) 
was happened from 0-day, and remained high on 
day-3.
This study had successfully demonstrated 
the correlation between MMP-9 and cTn-I in ACS 
patients, although weak relationship (r=0.34) but 
20remained significant (p<0.05) . This correlation 
21was consistent with Manginas et al. , who found a 
weak correlation (r=0:29). This result was different 
22than Tan et al. , that showed insignificant 
correlation between MMP-9 and cTn-1.
Plaque atheroma has been known to contain 
Vascular Smooth Muscle Cell (VSMC) which 
showed activity as hystocompatibility class II 
antigens, and different with the normal arterial 
tissue. This antigen will trigger chemotaxis of 
macrophages, which are very much in place of 
plaque rupture, triggering CD40sL, and stimulate 
the expression of collagenase and proteinase 
(stromeylysin). It has been proven that an increasing 
in expression of MMPs in the shoulder region of 
atherosclerotic plaque, but not in the arteries that are 
23not involved .
This study showed inflammatory markers 
(MMP-9) involved in the pathophysiology of ACS. 
Increased levels of MMP-9, resulted an increased 
collagen and extracellular matrix disruption that 
lead to atherosclerotic plaque instability and prone 
to plaque rupture. The impact of increased MMP-9, 
cared therapeutic implications controlled the levels 
of MMP-9 for the prevention ACS. 
Based on the cut-off levels of MMP-9, the 
prevalence ratio of elevated levels of cTn-1 more 
than 0.6ng/mL was 1.98 times. This elevation was 
found that will found in the ACS patients with serum 
levels of MMP-9 above the cut off (>1103ng/mL), 
compared with the below cut-off. Correlation in this 
study analyzed in 1 group of ACS and correlation in 
sub group of ACS was unknown. Furthermore, the 
cross sectional method used in this study could not 
show a direct causal relationship.
Conclusion
Correlation between serum levels of MMP-
9 and Troponin-I showed the role of MMP-9 in 
pathophysiology of ACS and higher levels of MMP-
9 prone higher prevalence of heart muscle damage.
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C O R R E L AT I O N S  B E T W E E N  S E R U M L E V E L O F  M AT R I X  METALLOPROTEINASE-9 (MMP-9) AND SERUM LEVEL OF TROPONIN-I IN PATIENT WITH ACUTE CORONARY SYNDROME (ACS)

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C O R R E L AT I O N S B E T W E E N S E R U M L E V E L O F M AT R I X METALLOPROTEINASE-9 (MMP-9) AND SERUM LEVEL OF TROPONIN-I IN PATIENT WITH ACUTE CORONARY SYNDROME (ACS)

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