ARTICLE
Auteur(s) :, DP
Papadopoulos1,*, I Moyssakis1, TK
Makris1, M Poulakou2, G
Stavroulakis1, D Perrea2, VE
Votteas1
1Department of Cardiology, Laiko Hospital of Athens,
6-8 Glykonos street, 106-75 Athens, Greece
2Department of Experimental surgery and surgical
research, Athens Medical School, Greece
Left ventricular dysfunction and remodeling after myocardial
infarction (MI) are thought to be among the first steps to
progression to heart failure, the degree of remodeling predicting
morbidity and mortality [1-6].The combination of cellular and
extracellular events that occur during the post-MI period results
in changes in left ventricular geometry, and has been called
infarct expansion [3-6] Previous studies have demonstrated that a
structural determinant of infarct expansion is the extracellular
collagen matrix (ECCM) remodeling [1-6]. The matrix
metalloproteinases are a family of proteolytic enzymes, that
contribute to the left ventricular remodeling process [7,
8].Endogenous MMP activity is controlled by tissues inhibitors of
MMP (TIMP) [7, 8]. Another role of the TIMP that is independent of
modulating MMP actional states, is through their effects on cell
growth. TIMP-1 and TIMP-2 have been shown to stimulate a growth
response in fibroblast cell cultures in a concentration–dependent
manner [9]. Past clinical studies have demonstrated alterations in
MMP and TIMP after MI [10, 11]. Recent experimental data have
provided evidence for a cause-and-effect relationship between
MMP-induced- and the post-MI myocardial-remodeling process [7,
12-14].The purpose of this study was to examine whether a
differential expression of plasma concentration occurs between
matrix metalloproteinase-1 (MMP-1) and its natural tissue inhibitor
(TIMP-1) in patients with acute MI. This unequal expression of
plasma concentrations affects left ventricular chamber dimensions
and global contractile performance.
Materials and methods
Study population
The study population consisted of 24 patients (22 males, 2 females,
mean age 59±14 years) who had been admitted to our department of
Cardiology in Laiko Hospital, with a first attack of acute MI, and
12 healthy subjects as controls (8 males, 4 females, mean age
43±14), who were studied in order to estimate normal levels of
collagenolytic enzymes. The control subjects had no past history or
any evidence of cardiovascular disease, hypertension or diabetes
mellitus. The present study did not include any patients or control
subjects with a history of neoplastic, hepatic, or infectious
disease, severe renal failure, serum creatinine > 2.5mg/dL or
any surgical procedure in the preceding 6 months. The local
scientific ethics committee approved the study and each participant
gave their informed written consent.
The diagnosis of acute MI was confirmed by typical, prolonged
chest pain, accompanied by serial changes on the standard, 12-lead
electrocardiogram (ECG), or significant (two-fold greater than the
normal range) increases in markers of myocardial damage creatine
kinase (CK) or its isoenzyme MB (CK-MB).
All patients were admitted less than 6h from the onset of chest
pain (mean 4.2h±0.6h). Depending upon the indications, patients
were thrombolyzed using alteplase, and were treated with
angiotensin-converting enzyme inhibitor (ACEI) (table 1)(
Table 1 ). All patients received a
combination of standard medication including nitrates,
beta-adrenergic blockers, calcium antagonists, and low molecular
weight heparin and antiplatelet drugs such as aspirin or
clopidogrel.
Two out of the 24 patients died on the 4th
post-infarction day, one from acute pulmonary edema due to rupture
of the chordae tendinae followed by acute mitral regurgitation and
death, and the other as a result of extension of the acute MI from
the inferior towards the lateral and anterior wall, followed by
cardiogenic shock and ventricular fibrillation. These two patients
are not included in the study. In sixteen patients, the infarct
location was the anterior wall, and in eight, the inferior
wall.
Patients were assigned to two groups according to the normal
lower limits of LVEF = 45%, and the mean value (47.5mm) of EDD
measured at papillary muscle level by two-dimensional
echocardiography. Ten patients with an ejection fraction of <
45%, heart failure symptoms (third heart sound (S3) and
basal rales on auscultation, mild congestion on chest X-ray) during
the hospitalization in the coronary care unit, and left ventricular
end-diastolic diameter (LVEDD) > 47.5 mm were included in
group A. This group was compared to the remaining 12 patients with
an LVEF > 45%, without heart failure symptoms, and LVEDD <
47.5 mm (group B).
Table 1 Baseline characteristics
|
Group A
|
Group B
|
Control group
|
|
Patient number
|
10
|
12
|
12
|
|
Age (years):
|
|
Mean ± SD
|
55 ± 13
|
57 ± 11
|
43 ± 14
|
|
Range
|
37-70
|
41-77
|
31-77
|
|
Sex:
|
|
Male/Female
|
10/0
|
10/2
|
8/4
|
|
Infarct location:
|
|
Anterior/Inferior
|
9/1
|
6/6
|
|
|
Extent of coronary artery disease:
|
|
0 vessel disease
|
0
|
0
|
|
|
1 vessel disease
|
1 pt
|
7 pts
|
|
|
2 vessel disease
|
5 pts
|
4 pts
|
|
|
3 vessel disease
|
3 pts
|
-
|
|
|
No catheterization
|
1 pt
|
1pt
|
|
|
Total Cholesterol:
|
|
|
|
|
> 200 mg%
|
6 pts
|
10 pts
|
|
|
< 200 mg%
|
4 pts
|
2 pts
|
|
|
Thrombolysis:
|
|
Yes
|
9 pts
|
5 pts
|
|
|
No
|
1 pt
|
7 pts
|
|
|
Angiotensin converting enzyme inhibitor
|
|
Yes
|
8 pts
|
5 pts
|
|
|
No
|
2 pts
|
7 pts
|
|
Hemodynamic and echocardiographic evaluation
On 6th post-MI day, twenty out of the 22 patients (two
patients refused) underwent coronary arteriography to estimate the
extent of coronary artery disease and single-plane ventriculography
in the right anterior oblique (RAO) view in order to estimate
ejection fraction [15] and regional wall movement abnormalities in
the anteriobasal, and posteriobasal segments [16]. We evaluated
LVEDD, on the 6th and 30th days [17, 18],
using a Hewlett Packard Sonos 1000 ultrasound system with a
2.5 MHz transducer.
Serum plasma concentrations of MMP-1, TIMP-1 and MMP-1/TIMP-1
complex
Blood samples were collected on admission (0 hours), at 3h, 6h, 9h,
12h, 18h, 24h, 36h and 48 hours and on the 3th,
4th, 5th, 7th,
15 th and 30 th day after the acute
MI. They were centrifuged for 10 minutes at 3000 rpm and stored at
-20o to 30oC until the assay (within 6
months).
Plasma concentrations of MMP-1, TIMP-1, and MMP-1/TIMP-1 complex
antigen levels were measured using the relevant ELISA kits provided
by Amersham International plc, Buckingham, UK. The matrix
metalloproteinase-1 human ELISA system code 2610 [19] measured
total human MMP-1, both free and that complexed with TIMP-1.The
lower limit of detection was 0.5 ng/mL and the coefficients of
variation of the intra-assay/ inter-assay were 6.7% and 12.4%
respectively. The immuno-assay system for TIMP-1, code 2611 [20],
recognize total human TIMP-1, free TIMP-1 and that complexed with
MMP-1. The lower detection limit and the intra-assay/inter-assay
variation coefficients were 45 ng/mL, 10.5% and 13.7% respectively.
Also, the immuno-assay systems for MMP-1/TIMP-1 complex, code 2612
[21], recognize activated MMP-1 that had subsequently been
complexed with the specific inhibitor TIMP-1. It did not recognize
free, active MMP-1, TIMP-1, or Pro MMP-1 or MMP-1/TIMP-1 complex
from other species. The lower detection limit was 1.5 ng/mL, and
the intra-assay/inter-assay variation coefficients were 8.2% and
12.7% respectively. The immuno-assay is based on a two-side ELISA
sandwich format. Concentrations in ng/mL were determined by
interpolation from a standard curve for each collagenolytic
enzyme.
Blood samples for assay of CK and its isoenzyme MB were obtained
at the same time points, and measured using Medicon, Olympus and
Bayer ELISA Kits respectively.
Statistical analysis
We employed analysis of variance (ANOVA repeated measurements) to
assess time-dependent alterations in serum MMP-1, TIMP-1, and
MMP-1/TIMP-1 complex concentrations. If the analysis indicated a
statistically significant change, between subjects and within
subjects, then the difference between the mean values was compared
by paired and unpaired Student’s t-test and the Mann-Whitney test
for the same period of time. Blood values are given as mean ± SD. p
< 0.05 was considered statistically significant.
Results
The clinical and demographic characteristics of both groups of
patients are presented in table 1. There were no significant
differences as regards age and sex. However, clear baseline
differences existed in blood plasma cholesterol levels, extent of
coronary artery disease, site and size of infarct, number of
patients having been thrombolysed (n = 14) and treated with ACEI (n
= 13).
Time course of MMP-1, TIMP-1, MMP-1/TIMP-1 complex plasma
concentration changes
MMP-1
( Figure 1
) shows the time-dependent changes in plasma concentrations of
MMP-1 in both groups of acute MI patients. Group A expressed higher
levels of MMP-1 plasma concentrations, average percentage increase
(21%) for the total study period, while the mean±SD value was
1.3±0.2 ng/mL in group A versus 1±0.1 ng/mL in group B.
Furthermore, at certain time points (6h, 18h, 24h, 48h), the mean
values of the differences between the groups, were statistically
significant (p < 0.006).
TIMP-1
( Figure 2 )
outlines the time-dependent changes in TIMP-1 plasma
concentrations. Note that both curves for TIMP-1 plasma
concentrations are characterized by fluctuations of mean values
throughout the study period, while the mean average plasma
concentrations were 704±213 ng/mL in group A versus 691±165 ng/mL
in group B, and the percentage difference between them was 6%.
MMP-1/TIMP-1 complex
( Figure 3 )
demonstrates the time-dependent changes in MMP-1/TIMP-1 complex
plasma concentrations for each time point in both groups of acute
MI patients. Note that the MMP-1/TIMP-1 complex, reflecting
activated MMP-1 and expressed as TIMP–1 component, shows a lower
average expression in group A compared to group B (-38%) over the
total study period, while the mean ± SD values were 2.7±0.6 ng/mL
versus 3.7±0.5 ng/mL in both groups, respectively. Furthermore, at
48h and on the 4th day, the mean values for the
differences between groups were statistically significant, with p
< 0.031 and p < 0.0052 respectively.
Healthy subjects
Mean ± SD plasma values for these subjects were, MMP-1 1.2±0.2
ng/mL, TIMP-1 222±69 ng/mL and MMP-1/TIMP-1 complex 1.3±0.3 ng/mL.
Statistical analysis between the mean values for MMP-1, TIMP-1,
MMP-1/TIMP-1 complex, and the corresponding mean values for normal
healthy subjects showed no statistical significance for MMP-1,
while TIMP-1 and MMP-1/TIMP-1 were statistically significant with p
< 0.048 and p < 0.049 respectively at most time points.
Left ventricular ejection fraction
Characteristics are the mean values for ejection fraction ( (figure 4) )
between the two groups of acute MI patients. Group A had an
ejection fraction of 35.8±8.8%, whereas group B had an ejection
fraction of 51.2±1.8%. This -43% percentage reduction in the
ejection fraction in group A compared to group B was statistically
significant (p < 0. 00014).
Left ventricular dimensions
Echocardiographic study on the 6th day, showed a mean
value for LVEDD of 52.2±6.9 mm in group A, whereas group B
patients demonstrated a mean value for LVEDD of 42.9±3.2 mm (
(figure 5)
). This 17% difference between the two groups was statistically
significant (p < 0.001319). Moreover, echocardiographic study on
the 30th day, showed a value for LVEDD of 53.2±7.4mm for
group A versus 43.3 ± 2.4mm for group B. This 18% difference was
also statistically significant (p < 0.0009).
Creatine kinase
Additionally, ( figure
6 ) demonstrates the mean values for the changes in CK
(IU/mL), as a function of time, in both groups of acute MI
patients. Note the significance of changes between time points 6h
to the 5th day (p < 0.024). Also, a good correlation
was found between plasma concentrations of CK and MMP-1 at 18h (r =
0.422, p = 0.041) (( figure 7 )a), and on
the 4th day (r = 0.67 p < 0.046) (( figure 7 )b), and of
TIMP-1 on the 4th day (r = 0.67 p < 0.047) (( figure 8 )).
Discussion
The findings of our study demonstrated two patterns of
collagenolytic enzyme activity (collagenolysis) in acute MI
patients.
Pattern I collagenolysis of group A was characterized by higher
expression of MMP-1, by different expressions of TIMP-1, and by
lower expression of the MMP-1/TIMP-1 complex. In contrast, pattern
II collagenolysis of group B was represented by lower expression of
MMP-1, by equivalent expression of TIMP-1, and by higher expression
of the MMP-1/TIMP-1 complex.
These quantitative differences in expression of collagenolytic
enzyme plasma concentrations, between the two groups of acute MI
patients, were accompanied by two kinds of post-MI left ventricular
function. More specifically, pattern I collagenolysis, seen in
group A, was followed by left ventricular dysfunction and a greater
left ventricular chamber dimensions, whereas pattern II
collagenolysis seen in group B, was associated with normal left
ventricular function and smallerleft ventricular chamber
dimensions. Additionally, at certain time points the mean values
for the differences in MMP-1 and MMP-1/TIMP-1 complex plasma
concentrations, between group A and group B, were statistically
significant.
Furthermore, the mean values for the differences in ejection
fraction and LVEDD, between both groups, were statistically
significant. These changes might be attributable, at least in part,
to the differential expression levels of collagenolytic enzymes, as
well as to other parameters of left ventricular dysfunction such as
location and size of infarction.
Relevant to our findings are recent reports indicating that
MMP-1 plays a role in post-MI left ventricular remodeling. Hirohara
et al. showed a time-dependent change in serum MMP-1 levels after
acute MI that may contribute to post-MI ventricular remodeling by
promoting the degradation of the extracellular matrix [10].
Additionally, Soejima et al. [22] have reported a negative
correlation, between MMP-1 plasma levels at 7 day and 2 weeks, and
left ventricular ejection fraction. Furthermore, Hojo et al. [23]
showed a significant correlation between maximum peripheral blood
mononuclear cell MMP-1 levels and maximum plasma C-reactive protein
levels, and left ventricular end diastolic volume index. So our
results are generally in agreement with their findings, except for
the fact that we could not find any correlation, between changes in
MMP-1, TIMP-1, and MMP-1/TIMP-1 complex plasma concentrations and
changes in LVEF. The only correlation was between plasma
concentrations of MMP-1 at 18h and day 4 and TIMP-1 at day 4, and
plasma concentrations of CK. The correlation between MMP-1, TIMP-1
and MMP-1/TIMP-1 complex and the clinical parameters LVDD, and EF
was estimated by performing multivariate analysis. No significant
correlation was observed.
Also, one other important finding emerging from our
echocardiographic study was the fact that left ventricular chamber
dimension changes occurred early, on the 1st or
2nd day post-MI. Furthermore, the very early initiation
of ACEI in acute MI patients, minimized post-infarction left
ventricular dilatation, through a reduction in metalloproteinase
enzyme plasma concentrations. This mode of action of ACEI may be
considered as an alternative mechanism responsible for their
beneficial effects on left ventricular expansion in the chronic
phase [24].
It is well known, that cardiac myocytes and the fibrillar
extracellular collagen matrix (ECCM) play a critical role in
determining cardiac performance [25, 26]. In particular, ECCM
provides structural support and integrity to the myocardium [27],
and facilitates the conversion of myocyte contraction into pump
function. The integrity of the original ECCM is thought to play an
important role in determining the extent of dysfunction after
myocardial infarction [28], whereas, parallel to myocyte cell death
is damage of the existing ECCM [29, 30].
Degradation of ECCM follows the activation of MMP that are
secreted, as zymogen [31]. Recent reports have documented the
time-dependent activation of MMP after ischemia or acute MI. MMP
activation can occur within minutes of ischemia, with significant
increases occurring as early as 15 minutes, and peaking 1 to 2 days
after MI [9, 32, 33]. Different mechanisms have been implicated in
MMP activation. It is believed that the early (< 48 hours)
MMP activation is associated with zymogen activation, whereas
subsequent (> 48 hours) increases are associated with newly
synthesized protein [32-35].
In our results, the curve for the time-dependent changes of MMP
activation ( (figure 1) ) showed an
early (< 24 hours) and a late
(5th-30th days) increase in mean values for
MMP-1 plasma concentrations. This early increase is due to
activation of latent, pro-MMP, to active MMP by the urokinase
plasminogen activator (uPA) plasmin system [36]. Also, the late
increase in MMP-1 activation may be due to the newly synthesized
protein resulting from macrophage infiltration of the infarcted
myocardial area [32, 33, 35].
Many studies have shown that remodeling of ECCM plays a major
role in left ventricular remodeling [37, 38]. Differential regional
remodeling of the ECCM contributes significantly to global left
ventricular structural dysfunction after acute MI [37, 38], and
plays a pivotal role in infarct expansion [37], infarcted dilation
[12, 37], and progressive global left ventricular dilatation [38,
39]. The function of MMP during the healing and remodeling process
of the left ventricle after acute MI has been clarified in studies
using broad range MMP inhibitors and genetically modified mice.
Rohde et al. [12] first demonstrated that in vivo MMP inhibition
attenuates early, left ventricular dilatation, four days after
experimental, acute MI in mice. Also Creemers et al. [40], have
studied the effects of a broad range MMP inhibitor on left
ventricular remodeling and infarct healing, one and two weeks after
acute MI in mice. In this study, infarcted mice allocated to
ilomast treatment, showed a significant decrease in left
ventricular dilatation after MI, as measured by
echocardiography.
Also, other studies have shown a fine balance between matrix
metallproteinases that degrade ECCM and endogenous tissue
inhibitors (TIMP) that inhibits MMP, [41] and maintains normal
remodeling and function, while an imbalance in their expression can
result in adverse remodeling [41-44]. The functional role of TIMP-1
in the control of left ventricular geometry and cardiac function
was recently studied in TIMP-1-deficient mice [45].
Echocardiography in these mice demonstrated an 18% increased in
left ventricular end diastolic volume, and a 38% increase in
cardiac mass at four months of age. Reduced myocardial collagen
content probably accounted for the increased left ventricular
dilatation. These results suggest that constitutive TIMP-1
expression contributes to the maintenance of normal left
ventricular myocardial structure [45]. Furthermore, several
transgenic models have been constructed that disrupt normal
myocardial MMP and TIMP levels [7, 45, 46]. Kim et al. [46]
demonstrated that cardiac-restricted, over expression of MMP-1
resulted in changes in the myocardial ECCM structure, which was
accompanied by alterations in left ventricular function. Finally,
in a rat MI model, MMP-1 mRNA levels increased soon after MI, but
this increase was not associated with a concomitant increase in
TIMP-mRNA levels [7].
The MMP-1/ TIMP-1 complex is formed in a stoichiometric, 1:1
molar ratio and forms an important endogenous system for regulating
MMP activity. Its plasma levels might express the power of
endogenous MMP inhibitory control of human myocardium TIMP-1 to
form a complex with several MMP [47]. In the present study, we
found a discrepancy between MMP-1 levels and MMP-1/TIMP-1 complex
levels, while TIMP-1 levels fluctuated. The lower MMP-1/ TIMP-1
levels found in group A compared to group B in acute MI patients
might be explained by the loss of TIMP-mediated inhibitory control
that has been reported recently in post-MI remodeling [7], in
dilated cardiomyopathy [48], and in an in vitro system of ischemia
and reperfusion [49].
Taken together, the above data suggest that the increased MMP
expression and activation, coupled with the loss of endogenous MMP
inhibitory control occurring early in the post-MI period can
potentially contribute to post-MI left ventricular remodeling and
dysfunction.
Study limitations
We could not compare plasma concentrations of collagenolytic
enzymes occurring in acute MI patients with comparable MI involving
the same wall, because of the small size of the study population.
A larger patient population and a longer period of observation
are required to clarify the exact role of the differential
expression of collagenolytic enzymes in the pathophysiology of
post-infarction cardiac remodeling, and to establish correlations,
between the patterns of collagenolysis and progressive cardiac
enlargement.
Conclusion
In acute MI patients, increased MMP-1, with no change in TIMP-1, is
associated with left ventricular dysfunction and dilatation,
suggesting that increased collagenolytic activity contributes to
loss of left ventricular function.
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