ARTICLE
Auteur(s) : Kenji Ueshima1, Masashi
Shibata2, Tomomi Suzuki2, Shigeatsu
Endo2, Katsuhiko Hiramori1
1 The Second Department of Internal Medicine,
Iwate Medical University;
2 The Critical Care and Emergency Center, Iwate Medical
University, Morioka, Japan
Address for correspondence: Kenji Ueshima, MD, Second Department of
Internal Medicine, 19-1 Uchimaru Morioka Iwate
020-8505 Japan. Fax: + 81-19-624-8374;
Tel: + 81-19-651-5111 (ext) 7401
e-mail: k—ueshima@imu.ncvc.go.jp
Introduction
As previously described [1], there is a relationship between
ionized magnesium (Mg2+) levels in blood and severity of
coronary heart disease. If the blood Mg2+ level is
lower, the disease severity is more serious. It is well known that
the prognosis of patients with acute myocardial infarction (AMI),
particularly associated with congestive heart failure, is poor,
although coronary reperfusion therapy improves the prognosis
[2].
Otherwise, MMPs (matrix metalloproteinase) are responsive to
cytokines, growth factors and various hormones. The action of
matrix metalloproteinase-1 (MMP-1) in extracellular matrix
degeneration can be regulated at many stages; gene activation and
transcription, messenger ribonucleic acid stabilization,
translation and secretion of latent proenzymes, binding of
proenzymes to cell membranes and extracellular matrix components,
proenzyme activation, inactivation by endogenous inhibitors and
degradation or removal of the active or inactive enzyme species. At
the transcription level, many MMPs appear to be regulated by
similar mechanisms.
The pathophysiology of reperfusion injury may be multifactorial.
The leading theories are intracellular calcium overload and the
generation of oxygen-derived free radicals and cytokines [3, 4].
These processes may be interrelated, since a decrease in cytosolic
magnesium levels and an increase in cytosolic calcium levels
contribute to the release of myocardial catecholamines and
cytokines. Elevated cytosolic free calcium levels can weakly
activate proteases that compromise the plasma membrane integrity,
allowing an intracellular calcium overload and irreversible damage
to the mitochondria and extracellular matrix. The features of
reperfusion injury include the death of cells that were still
viable at the onset of reperfusion, the no-reflow phenomenon and
loss of vasodilatory reserve, myocardial stunning [5],
arrthythmias, aggravated chest pain and exacerbation of ST
elevation [6].
Mg has several effects which may be beneficial to patients with
AMI. It has been shown to (a) reduce the intracellular calcium
overload [7, 8] considered to be a central mechanism in ischemic
myocardial damage [9], (b) dilate coronary arteries with reduced
total peripheral resistance [10-12], and (c) inhibit platelet
function, possibly by an effect on prostacyclin secretion [13, 14].
Mg has also been shown to attenuate catecholamine release following
myocardial infarction [15, 16] and reduce the size of
catecholamine-induced myocardial necrosis [17].
The first aim of this study was to clarify the relationship
between the severity of AMI and interleukin-6 (IL-6) or MMP-1. The
second aim was to evaluate the effects of the Mg administration
during coronary reperfusion therapy on reperfusion injury caused by
IL-6 and MMP-1.
Methods
Subjects: Consecutive 34 patients (30 men and
4 women, mean age 60 ± 11 years) with AMI
treated with successful coronary reperfusion therapy were enrolled
in the first study. Diagnosis of AMI was determined from symptoms,
electrocardiographic evidence, and increase of creatinekinase
levels greater than twice the normal. If TIMI 3 flow was
obtained, reperfusion therapy was estimated as success. Plasma
IL-6 and MMP-1 concentrations were measured every
6 hours during the first 24 hours following admission.
The IL-6 and MMP-1 concentrations were quantified by enzyme-linked
immunosorbent assays, using an IL-6 kit (TFB, Tokyo, Japan), and an
MMP-1 kit (Amersham, Buckinghamshire, UK) respectively. The lowest
detectable concentration was 10 pg/ml for IL-6 and
1.7 ng/ml for MMP-1. The standard hemodyamic variables such as
pulmonary capillary wedge pressure and cardiac index were measured
with thermodilution methods just after the reperfusion therapy.
Left ventricular ejection fraction was measured with left
ventriculography, which was performed before discharge (mean period
from admission: 22 ± 4 days)
36 patients consecutive (33 men and 3 women, mean
age 60 ± 13 years) admitted to the coronary care
unit within 6 hours after the onset of AMI were enrolled in
the second study. They underwent coronary reperfusion therapy,
which included administration of tissue plasminogen activator or
direct percutaneous transluminal coronary angioplasty (PTCA). This
study was designed as an open-labeled randomized controlled trial
without placebo and was approved by the Iwate Medical University
Ethics Committee. The patients were randomized to a magnesium group
or a control group. In the magnesium group (n = 18, mean
age 64 ± 10 years), magnesium sulfate
(MgSO4) was infused intravenously (0.27 mmol/kg,
during a 20-30 minute period) and continuously before and
during the reperfusion therapy. In the control group
(n = 18, mean age 57 ± 10 years),
MgSO4 was not administered. All patients were
heparinized throughout the study and received intravenous
nitroglycerin for the first 48 hours and 81 mg oral
aspirin on the day of the admission. Informed consent was obtained
from the patients or their families prior to enrollment in the
study. The blood levels of Mg2+ were measured with an
ion-selective electrode (NOVA 8 Analyzer, Nova Biomedical
Inc., Waltham, MA) immediately after blood sampling. The
MMP-1 and IL-6 concentrations were also measured every
6 hours during the first 24 hours after admission. The
reperfusion injuries observed immediately after coronary
reperfusion included aggravated chest pain and recurrent
arrhythmias such as ventricular tachycardia, ventricular
fibrillation, accelerated idioventricular rhythm and complete
atrial ventricular block and exacerbation of ST elevation in a
12-lead electrocardiogram. A 12-lead electrocardiogram was recorded
every 5 minutes or when patients claimed some complaints from
the beginning of reperfusion therapy until leaving our
catheterization laboratory.
Statistical analysis: The results are expressed as
mean ± SD. A repeated-measures ANOVA was performed to
evaluate statistical significance. We used the unpaired Wilcoxon
test for differences and Pearson's formula for correlation. A value
of p < 0.05 was considered significant.
Results
There was a positive correlation between the peak plasma MMP-1
values and the peak plasma creatine kinase (CK) values in all
patients (r = 0.43, p = 0.04) and a negative
correlation between the peak plasma MMP-1 values and left
ventricular ejection fraction measured by left ventriculography
during hospital stay (r = – 0.52,
p = 0.005) (Figure 1). Moreover, there was
a positive correlation between the peak plasma MMP-1 values and the
pulmonary capillary wedge pressure (r = 0.70,
p < 0.0001) and a negative correlation between the
peak plasma MMP-1 values and the cardiac index (a mean period from
admission: 22 ± 4 days, r = – 0.55,
p = 0.0007) (Figure 2).
The patients with higher MMP-1 level (≥ 20 ng/ml) were
likely to have the higher pulmonary capillary wedge pressure and
the lower cardiac index (Figure 3). In addition, there
was a positive correlation between the peak plasma IL-6 values and
the peak plasma MMP-1 values in all patients (r = 0.60,
p = 0.0002) (Figure 4).
To evaluate the influence of disease severity on the plasma
concentration of IL-6 and the MMP-1, patients in the first study
were clinically classified into 2 groups according to whether
they had congestive heart failure (CHF) or not (C group or NC
group). There were 9 cases with CHF (Killip 2, 3) and
25 cases without CHF (Killip 1). The peak blood IL-6 and MMP-1
level increased in acute phase of AMI, particularly in patients
with CHF (C group vs NC group; 130.2 ± 22.1 vs
50.6 ± 12.1 pg/mL and 37.0 ± 7.8 vs
18.3 ± 8.1 ng/mL, both p < 0.01). Time
courses of the plasma IL-6 and MMP-1 values in both
groups were shown in Figure
5. In terms of plasma IL-6, the values in the patients with CHF
were higher than those in the patients without CHF 12 and
24 hours after admission (92.2 ± 11.2 vs
39.3 ± 10.5 and 89.0 ± 11.4 vs
22.6 ± 10.1 pg/ml, p < 0.05,
respectively). The plasma MMP-1 values were higher in patients with
CHF than in those without it 6, 18 and 24 hours after
admission (25.2±7.8 vs 14.4 ± 6.6,
24.3 ± 7.7 vs 14.6 ± 5.9, and
26.6 ± 8.0 vs 13.7 ± 6.4 ng/ml,
p < 0.05, respectively).
Table I shows demographic and clinical
variables for each group in the second study. The two groups were
well matched demographically. The blood Mg2+ level rose
from 0.39 ± 0.08 to 1.04 ± 0.10 mmol/l at
1 hour in the magnesium group and returned to the baseline
value by 6 hours after the reperfusion therapy. No patients
developed significant hypotension or conduction disturbance.
Table 1. Characteristics of the
patients in the second study. The magnesium group was given
MgSO4 and the control group was not.
|
Control |
Magnesium |
|
| Number |
18 |
18 |
NS |
| Age (year) |
58 (10) |
63 (10) |
NS |
| Male/Female |
16/2 |
17/1 |
NS |
| Infarcted area |
|
|
NS |
| (anti/inf/non-Q) |
10/7/1 |
14/3/1 |
NS |
| Prior MI |
3 |
2 |
NS |
| ICT/PTCA |
10/8 |
9/9 |
NS |
| Peak CK (IU/L) |
5728
(2709) |
4287
(3108) |
NS |
| 1 Month Mortality |
0 |
0 |
NS |
UCT: intracoronary thrombolysis; PTCA: percutaneous transluminal
coronary angioplasty; CK: creatine kinase; NS not significant; ():
SD
The appearance of reperfusion arrhythmias was significantly
lower in the magnesium group than the control group (17 vs.
78%, p < 0.001) (Figure 6, left panel). In
addition, there was a trend for the degree of transient
exacerbation of ST re-elevation in the magnesium group to be lower
than that in the control group (2.5 ± 2.3 vs.
4.7 ± 3.8 mm, p = 0.07). No significant
difference was observed in the incidence of chest pain aggravation
between the 2 groups (67 vs. 73%, n.s.). The peak
IL-6 value in the magnesium group was significantly lower than
that in the control group (38.9 ± 25.0 vs.
92.3 ± 76.5 pg/ml, p = 0.02) (Figure 6, right panel), while
the peak MMP-1 value in the magnesium group was likely to be lower
than that in the control group (16.2 ± 4.8 vs.
19.7 ± 9.0 ng/ml, p = 0.09). The plasma IL-6
and MMP-1 values were lower in the magnesium group than in the
control group (Figure
7). The plasma IL-6 values were lower in the magnesium group
than in the control group 12, 18 and 24 hours after admission
(31.6 ± 23.2 vs 72.3 ± 67.3,
33.0 ± 27.4 vs 58.6 ± 63.3, and
19.6 ± 12.2 vs 62.7 ± 62.8 pg/ml,
p < 0.05. respectively). The plasma MMP-1 values were
lower in the magnesium group than in the control group 18 and
24 hours after admission (12.2 ± 6.1 vs
16.4 ± 6.6 and 10.6 ± 4.2 vs 15.7 ±
6.4 ng/ml, p < 0.05, respectively).
Discussion
Several reports have been published on the relationship between
coronary heart disease and cytokines [18-21]. IL-6 is a major
cytokine in unstable angina pectoris and AMI, both locally and
systemically. Miyao et al. [22] quantified IL-6 in the AMI
patients. He found that the time course of IL-6 paralleled that of
C-reactive protein, and that the peak IL-6 level was positively
correlated with that of C-reactive protein. The present findings
suggested that leukocytes, endothelial cells and cardiac myocytes
might produce and release plasma IL-6 in the AMI patients who
received reperfusion therapy. These findings indicated that AMI
patients with an unfavorable course had high cytokine levels.
Extracellular matrix is the supporting cytoarchitecture and
triggers multiple physiological activities. Several basement
membrane components interact with extracellular matrix and MMP-1 of
the extracellular matrix. MMP-1 is produced by inflammatory
cells such as leukocytes, fibroblasts and endothelial cells and is
released due to the action of several cytokines [23]. These results
in the first study indicate that MMP-1 and IL-6 are produced in the
acute stages of AMI, and that they do not only serve as chemical
mediators of granulocyte migration, host defense and tissue repair,
but also could pay a role in multiple organ injury.
Effects of Mg administration on the prognosis of patients with
AMI is contraversial. The mortality within 1 month after the
onset of AMI was significantly reduced by Mg administration in the
LIMIT-2 [24], whereas ISIS-4 [25] and MAGIC [26] failed
to corroborate that. In the present study, we focused the time
course and several parameters after reperfusion therapy for AMI
patients, and observed a significant lower blood Mg2+
level in AMI patients and a significant reduction in the
MMP-1 and IL-6 release in the Mg group. Intracellular
calcium overload is considered to be a central mechanism in
ischemic myocardial death [9]. Mg inhibits intra-cellular calcium
influx, in addition, reduces mitochondrial calcium overload and
conserves intracellular adenosin triphosphate (ATP) as ionized
Mg-ATP. Increased extracellular Mg has shown a protective effect
during myocardial ischemia [27]. Mg inhibits the contractility of
coronary arteries, increases coronary blood flow and decreases
coronary vascular resistance without increasing myocardial oxygen
consumption [11].
Reperfusion therapy is beneficial in terms of myocardial
salvage. However, reperfusion therapy may come at a cost because of
reperfusion injury [28]. The pathogenesis of reperfusion injury is
probably multifactorial, and leading theories include intracellular
calcium overload, and the generation of oxygen-derived free
radicals and activated cytokines [2-4]. These present findings also
indicate that Mg inhibited intracellular calcium overload, and that
it may reduce activation of MMP-1 and IL-6 in patients
with AMI as a reperfusion therapy. We also observed that the Mg
therapy inhibited reperfusion arrhythmias and exacerbation of ST
segment elevation. Our results may suggest that Mg supplementation
associated with reperfusion therapy for patients with AMI may
reduce reperfusion injuries and play a beneficial role in the acute
phase of AMI.
Conclusions
In this study, the plasma IL-6 and MMP-1 values were
increased in patients in the acute phase of myocardial infarction,
and the severity of AMI is reflected by the plasma IL-6 and
MMP-1 values. In addition, increased blood Mg2+
inhibited arrhythmic recurrence after coronary reperfusion, and
also inhibited the release of MMP-1 and IL-6. It is possible
that increased IL-6 induced the production of MMP-1 and
that the MMP-1 then induced tissue organ injury. Pre-treatment
with Mg may protect patients with an AMI from reperfusion
injuries.
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