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(Circulation. 1995;92:748-755.)
© 1995 American Heart Association, Inc.
Articles |
Cardiac Release of Cytokines and Inflammatory Responses in Acute Myocardial Infarction
Presented in part at the 67th Annual Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.
From the Medizinische Klinik der Technischen Universität and the Abteilung Klinische Chemie und Klinische Biochemie an der Chirurgischen Innenstadtklinik der Ludwig-Maximilians-Universität (M.J.), München, Germany.
Correspondence to Priv-Doz Dr Franz-Josef Neumann, Medizinische Klinik der Technischen Universität, Ismaninger Str 22, 81675 München, Germany. E-mail neumann@med1.med.tu-muenchen.de.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the ß2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury.
Methods and Results In 12 patients with acute anterior MI, blood
samples were obtained from the coronary sinus and from the
aorta immediately before and after recanalization
of the coronary occlusion by balloon angioplasty. Twelve
patients undergoing elective balloon angioplasty served as control
subjects. Plasma concentrations of interleukin (IL)-1ß, IL-6, IL-8,
tumor necrosis factor-
, and thrombomodulin were determined by
immunoassay, and surface expression of CD11b and CD62L was assessed by
flow cytometry. Differences in coronary sinus and
arterial blood were found in IL-6 before (median, 6.3 ng/L,
P=.01) and after (13.4 ng/L, P=.002)
recanalization and in IL-8 after
recanalization (10.7 ng/L, P=.02). The
cardiac release of both cytokines significantly
(P
.03) increased with reperfusion. Cytokine
release after reperfusion was associated with significant transcardiac
gradients in surface expression on neutrophils of CD11b (10.1 mean
channel of fluorescence intensity [mean fl], P=.01)
and
CD62L (-8.7 mean fl, P=.007) and with a thrombomodulin
release (4.5 µg/L, P=.004). Transcardiac gradients in
IL-1ß and tumor necrosis factor- were not found. None of the
changes found in MI were detectable in the control group.
Conclusions As evidence of cardiac inflammatory responses in reperfused acute MI, the study demonstrates cardiac neutrophil activation with signs of endothelial injury and a release of the proinflammatory cytokines IL-8 and IL-6. These findings may assist in the design of pharmacological interventions aimed at reducing microvascular reperfusion injury.
Key Words: myocardial infarction • endothelium • leukocytes • reperfusion • cytokines
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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In acute myocardial infarction (MI), the clinical benefit from timely recanalization of the infarct-related coronary artery depends critically on the blood flow achieved.1 If coronary blood flow after recanalization continues to be compromised, such intervention does not afford a substantial reduction in mortality or preservation of left ventricular function.1 Residual stenoses are the most obvious cause for depressed coronary blood flow after recanalization of the infarct-related artery. In addition, reperfusion in acute MI is limited by postischemic microvascular incompetence,2 3 4 which cannot be managed by standard interventional procedures.
In experimental models of MI, inflammatory responses are the primary cause of the microvascular incompetence in ischemia and reperfusion.5 6 7 8 9 10 In such models, some therapeutic strategies designed to reduce the inflammatory interactions of leukocytes and endothelial cells have resulted in beneficial effects.7 8 9 11 12 13 In patients, direct evidence of inflammatory cell activation within the infarcted area is still missing. Moreover, the mediators that regulate the postischemic inflammatory responses locally have not been identified. A better understanding of the detrimental inflammatory consequences of human MI may allow a rational approach to the treatment of microvascular incompetence after successful recanalization of the infarct-related coronary artery.6
We therefore investigated cardiac inflammatory responses in patients with acute MI undergoing immediate balloon percutaneous transluminal coronary angioplasty (PTCA). Specifically, we examined cardiac release of cytokines, transcardiac changes in the surface expression on neutrophils of the ß2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and cardiac release of thrombomodulin as a marker of endothelial injury. The findings obtained in acute MI were compared with those in elective PTCA.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
The study group comprised 12 patients presenting with acute anterior MI within 3 to 9 hours after the onset of pain. The diagnosis of acute MI was based on a history of prolonged ischemic chest pain and characteristic ECG changes. In all study patients, immediate coronary angiography revealed an occluded left anterior descending coronary artery (LAD) that was judged suitable for recanalization by PTCA (Table 1
).
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The control group included 12 patients undergoing elective PTCA for an LAD stenosis within 19 to 44 days after successful thrombolysis for acute anterior MI. Indication for PTCA was based on a history of postinfarction angina and/or a positive exercise stress test in the presence of a significant (>70%) residual LAD stenosis.
Patients with interfering noncardiac diseases such as
inflammatory
disorders, malignancy, or infection were not eligible for either the
study or the control group. The regular medication of the patients was
not altered for the study; none of the patients was on any
antiinflammatory agent except aspirin 100 mg/d. Table 2
lists the baseline characteristics of the study and control patients.
The study was approved by the institutional ethics committee for human
subjects. Written informed consent was obtained from all patients.
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Study Protocol
Before the study, all patients with acute MI
were given
intravenous bolus injections of 5000 IU heparin, 1 g
aspirin, one to three injections of 5 mg metoprolol, and one to two
injections of 5 mg morphine, depending on individual response.
Furthermore, patients were kept on intravenous infusions of
nitroglycerin 0.24 to 2.4 mg/h, adjusted to obtain a
systolic pressure between 100 and 120 mm Hg. Before coronary
angiography, an additional dose of 10 000 IU heparin was given
intra-arterially. Coronary angiography was
performed by the transfemoral approach. While one operator placed the
guiding catheter, a second operator cannulated the coronary
sinus with a 7F multipurpose catheter using the brachial approach. If
the coronary anatomy was judged suitable for mechanical
recanalization, the operators immediately proceeded
to PTCA using fixed wire balloon catheters (ACE, Scimed Life
Systems).
Three sets of blood samples were obtained simultaneously
from the coronary sinus and the guiding catheter. The first set
of blood samples was taken after the guide wire of the balloon catheter
was placed at the proximal end of the occlusion; the second one was
taken immediately after the first balloon inflation. In 9 patients
(Table 1
), the first balloon inflation resulted in restoration
of blood
flow (Thrombolysis in Myocardial Infarction [TIMI] grade
2 or 3). In these patients, a third set of blood samples was obtained
after a period of 5 minutes, during which the angiographic result was
optimized by one to three additional balloon inflations. In 3 patients,
blood flow (TIMI grade 2 or 3) was restored by the second balloon
inflation (Table 1). In these patients, the third set of blood
samples
was drawn after the second balloon inflation.
In control patients, PTCA was also performed with the femoral approach, and the coronary sinus was cannulated through an antecubital vein. Identical to the study patients, control patients received an intravenous dose of 1 g aspirin and 15 000 IU heparin intra-arterially immediately after femoral arterial access was obtained. Again, three sets of blood samples were obtained simultaneously from the guiding catheter and the coronary sinus: the first after the guide wire for the balloon catheter was positioned; the second, immediately after the first balloon inflation, which lasted 90 seconds; and the third, after another 5-minute period, with one to two additional balloon inflations.
In both the control and study groups, all blood samples were drawn over a 1-minute period. The blood samples were put on ice and processed immediately, as indicated below.
Flow Cytometry
For flow cytometry, blood samples were
anticoagulated with 1:5
(vol/vol) CPDA (sodium citrate, phosphate buffer, dextrose, adenine; Fa
Greiner). Staining was performed in whole blood14 with
fluorescein-isothiocyanate (FITC)–conjugated anti-CD11b (clone, Bear1,
Immunotech) and anti-CD62L (clone, REG56, Immunotech) monoclonal
antibodies (MAb). Whole blood (25 µL) and an equal volume of PBS were
incubated with saturating concentrations of FITC-conjugated MAbs for 30
minutes at room temperature. Erythrocytes were lysed and leukocytes
were fixed with commercially available solutions (lysing solution and
fixing reagent, Coulter Electronics). Then, the cells were washed three
times and stored in 1% paraformaldehyde at 4°C until
flow cytometric analysis was performed within 24 hours after
sampling. MAb binding was assessed by flow cytometry with a FACScan
(Becton-Dickinson) equipped with a 488-nm argon laser at 500 mW.
Reproducibility was ensured by calibration with a mixture of
fluorescent monosized beads (CaliBRITE, Becton-Dickinson). To
analyze neutrophils, a gate was set in the forward angle versus
right angle scatter. Fluorescence intensity of 10 000 events was
recorded as mean channel number over a logarithmic scale of 1 to
1026 channels. Data were stored in list mode files and processed on a
Hewlett Packard computer programmed with CONSORT30
software. Results are expressed as mean channel of fluorescence
intensity (mean fl).
Immunoassays
For immunoassay, plasma samples were stored at
-120°C until
final processing. Concentrations of interleukin (IL)-1ß, IL-6, IL-8,
and tumor necrosis factor- (TNF-) were determined by
sandwich-type immunoassay (TNF and IL-6, IEMA, Immunotech; IL-1ß and
IL-8, Quantikine, R&D systems) with plasma samples from EDTA (1g/L)
anticoagulated blood specimens containing 5x108 IE/L
aprotinin. The detection limits were 3.9 ng/L for IL-ß, 2.0 ng/L for
IL-6, 3 ng/L for IL-8, and 10 ng/L for TNF-; the respective
intra-assay variabilities for the lower assay range were 11%, 7%,
4%, and 10%. The immunoreactivity of thrombomodulin
(Diagnostica STAGO) was determined in plasma samples from
citrated (3.8% vol/vol) blood specimens. The detection limit of this
assay was 8 µg/L, and the intra-assay variability for the lower assay
range was 3% to 5%.
Other Methods
Cell counts were performed with a Sysmex
Counter, model F800
(Digitana). An experienced technician examined blood smears. Total
neutrophil counts were obtained by multiplying the white cell count by
the respective differential cell count. Serum concentrations of
creatine kinase (CK) were determined enzymatically in the routine
laboratory of clinical chemistry.
Statistical Analysis
The Kolmogorov-Smirnov test showed that
the data were not
normally distributed. Thus, results are reported as median
(interquartile range) unless otherwise indicated. Differences between
more than two matched samples were tested by Friedman's test, followed
by Wilcoxon's matched-pairs signed-ranks test, and differences between
the study and the control groups were tested by the
Mann-Whitney-Wilcoxon rank-sum or Fisher's exact test, as appropriate.
A value of P<.05 in the two-tailed test was regarded as
significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline Characteristics
In the study group, the delay between onset of symptoms and the start of intervention ranged from 3 to 9 hours, and median peak plasma concentration of CK was 2935 U/L (interquartile range, 1781 to 3670 U/L) (Table 1
). Three patients had incomplete spontaneous
recanalization of the LAD (TIMI grade 1 flow)
before the mechanical recanalization, and 3 had a
faint collateral blood supply to the distal LAD (Table 1). At
all sampling times, significant
(P<.01) coronary sinus and arterial
blood differences in CK concentration were found, amounting to 40, 209,
and 200 U/L (interquartile ranges, 20 to 90; 106 to 774; and 156 to
1531 U/L) before, immediately after, and 5 minutes after
recanalization, respectively.
The study and control groups did not
differ with respect to age, sex
distribution, location of LAD stenosis, balloon sizes, or
maximal inflation pressures used (Table 2).
Cytokines
In patients with acute MI both before and after
recanalization of the LAD, we found significantly
elevated concentrations of IL-6 in the coronary sinus blood
compared with the arterial blood (Fig 1).
Coronary sinus and arterial blood differences in
IL-6 immediately and 5 minutes after recanalization
(13.4 ng/L [interquartile range, 6.5 to 54.8 ng/L],
P=.002; and 8.6 ng/L [interquartile range, 5.5 to 36.9
ng/L], P=.005, respectively) were significantly higher
than
those before recanalization (6.3 ng/L
[interquartile range, 0.4 to 22.0 ng/L], P=.01) (Fig
1).
IL-8 concentrations in the coronary sinus blood immediately
after recanalization of the LAD were higher than in
the concomitant arterial blood sample by a median of 10.7
ng/L (interquartile range, 5.2 to 23.0 ng/L, P=.02), while
there were no significant transcardiac gradients in IL-8 before
recanalization (Fig 2).
Coronary sinus and arterial blood differences in
the concentrations of IL-8 significantly increased with reperfusion and
remained elevated during the observation period (Fig 2).
Arterial concentrations of IL-6 and of IL-8 did not change
significantly (Table 3). Concentrations of TNF- and
IL-1ß did not show any significant arterial and
coronary sinus blood differences, nor were they affected by
reperfusion (not shown).
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In the control group, significant changes in
the concentrations of IL-6
and IL-8 were not found (Table 4).
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Adhesion Molecules on Neutrophils
Before recanalization of
the occluded LAD in
acute MI, we did not find significant coronary sinus and
arterial blood differences in the surface expression on
neutrophils of CD11b and CD62L (Figs 3 and 4).
Immediately after
recanalization, however, surface expression on
neutrophils of CD11b (Fig 3) in the coronary sinus blood was
higher by a median of 10.1 mean fl (interquartile range, 4.4 to 21.6
mean fl, P =.01) and that of L-selectin (Fig 4)
was lower by
a median of 8.7 mean fl (interquartile range, 2.7 to 21.3 mean fl,
P=.007) than the corresponding surface expressions in the
arterial blood. After 5 minutes of reperfusion, the
coronary sinus and arterial blood differences in
the surface expression on neutrophils of CD11b and L-selectin were less
pronounced than immediately after
recanalization and did not reach statistical
significance (Figs 3 and 4). Significant
systemic changes in the
surface expression on neutrophils of CD11b or L-selectin were not
detected in the study group (Table 3). In the control group,
surface
expression on neutrophils of CD11b and L-selectin essentially remained
unaffected by the intervention (Table 4).
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In the study
group, neutrophil counts did not show significant
coronary sinus and arterial blood differences
before (-0.10 nL-1 [interquartile range,
-0.39 to 0.55
nL-1]), immediately after (-0.32
nL-1
[interquartile range, -0.19 to 0.57 nL-1]),
or 5
minutes after (-0.20 nL-1 [interquartile range,
-0.34
to 0.64 nL-1]) recanalization of the
occluded LAD (P=.91 for the comparison of all samples).
Similarly, we did not find significant changes in neutrophil
counts in the control group (Table 4).
Thrombomodulin
Immediately after recanalization of the
occluded LAD in acute MI, we detected significant coronary
sinus and arterial blood differences in the
immunoreactivity of thrombomodulin (4.5 µg/L [interquartile range,
3.0 to 9.0 µg/L], P=.004) that were not present
before recanalization (Fig 5).
Coronary sinus and arterial blood differences in
the immunoreactivity of thrombomodulin tended to decrease during the
5-minute reperfusion period. Significant cardiac release of
thrombomodulin was not found in the control group (Table 4).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This report summarizes the first clinical study that reveals cardiac inflammatory responses in reperfused acute MI. The main findings are (1) a cardiac release of IL-6 and IL-8, (2) a cardiac neutrophil activation evidenced by increased surface expression of the ß2-integrin Mac-1 (CD11b/CD18) and shedding of L-selectin (CD62L), and (3) endothelial injury manifested by cardiac liberation of thrombomodulin.
These inflammatory changes became apparent as soon as the infarct-related LAD occlusion was recanalized by PTCA. Nevertheless, they could not be attributed to the interventional procedure itself, as proved by the findings in the control group. Performed electively in the absence of ongoing myocardial ischemia, a nearly identical interventional procedure as that in the study patients was not associated with any of the inflammatory changes found in acute MI. The cardiac inflammatory responses in acute MI arise largely, if not exclusively, from the reperfused area. Most of the changes can be demonstrated only after reperfusion has been established. Moreover, despite the increase in coronary sinus blood flow, all the transcardiac changes reflecting inflammatory responses increase substantially after recanalization of the LAD.
Cytokine Release
This study demonstrates for the first time
cardiac release of IL-6
and IL-8 in acute MI that extends into the first 5 minutes of
reperfusion. The transcardiac differences in IL-6 concentrations showed
a remarkable increase with reperfusion. A sizable cardiac release of
IL-6, however, occurs before recanalization of the
LAD. As suggested by the results of the CK measurements, the cardiac
release of IL-6 before recanalization may be
attributed to residual perfusion of the infarcted area even in patients
without visible antegrade or collateral flow.
Although we do not provide direct evidence, we speculate that the vascular endothelium may be the predominant source of the cardiac release of IL-6 and IL-8.15 Endothelial cells have been shown to produce IL-6 on stimulation with a variety of inflammatory mediators.15 Moreover, cultured endothelial cells release IL-8 under hypoxic conditions.16 The ischemia itself may therefore be an adequate stimulus for IL-8 release.
TNF- and
IL-1ß are predominantly leukocyte-derived
cytokines. Endothelial cells have not been
shown to produce TNF-15 and are only a minor source of
IL-1ß.17 Hypoxia increases the production of
TNF- and IL-1ß by human mononuclear cells.18
Nevertheless, we did not find significant transcardiac gradients in
TNF- or IL-1ß in acute MI. The number of leukocytes entrapped in
the coronary circulation before reperfusion may be too small to
generate detectable transcardiac cytokine gradients. Inflowing
leukocytes, however, cannot serve as a source for cytokines in
the instantaneous reperfusion period because liberation of
cytokines from leukocytes requires several hours after
appropriate stimulation.19 The lack of detectable
transcardiac gradients in TNF- and IL-1ß, however, does not
exclude a paracrine release by resident leukocytes and
macrophages, which may stimulate the
endothelial production of IL-6 and
IL-8.15 20
Neutrophil Activation and Endothelial
Injury
When activated by chemoattractants, neutrophils translocate the
ß2-integrin Mac-1 (CD11b/CD18) from cellular stores to
the plasma membrane and shed L-selectin (CD62L).21 22
IL-8
is one of the most potent chemoattractants,21 23
while an
effect of IL-6 on surface receptor expression by neutrophils has not
been shown so far. It is known, however, that IL-6 exerts a priming
effect.24 IL-6 may therefore potentiate the action
of IL-8 on neutrophils. Accordingly, we hypothesized that the local
inflammatory actions of IL-6 and IL-8 may induce changes in surface
receptor expression on neutrophils. Consistent with this
concept, we found an increased surface expression on neutrophils of
Mac-1 and a loss of surface L-selectin after passage through the
coronary circulation following
recanalization of the infarct-related artery. This
shows that the reperfused coronary circulation in acute MI
represents a proinflammatory environment.
Activated leukocytes may damage the vascular endothelium. Thrombomodulin is an established marker for endothelial injury, as proved in various clinical settings,25 26 and cultured endothelial cells have been shown to release thrombomodulin when exposed to activated neutrophils.26 We, therefore, hypothesized that, if functionally relevant, the cardiac neutrophil activation in acute MI was associated with a release of thrombomodulin. In keeping with this assumption, we found significant transcardiac gradients in thrombomodulin during reperfusion. Proteolytic enzymes released by activated leukocytes and oxygen free radicals generated by activated leukocytes and other sources are the most likely cause for the endothelial injury underlying the observed cardiac thrombomodulin release.27
Comparison With Previous Studies
The finding of a cardiac
leukocyte activation and release of IL-6
in the present study is supported by two previous studies on MI in
the dog model.28 29 Moreover, by demonstrating
cardiac
release of IL-8, the present study extends our knowledge from
animal experiments about the mediators that are involved in the cardiac
inflammatory responses in acute
MI.28 30 31
Clinical studies showing local inflammatory responses in acute MI, however, have been missing so far. Nevertheless, a number of systemic changes suggestive of neutrophil activation have been described.32 33 34 Recently, we demonstrated neutrophil activation and increased chemoattractant activity in pulmonary artery blood immediately after reperfusion through PTCA.35 With the present study, these changes and the formerly described systemic changes can be interpreted as a consequence of the inflammatory responses in the reperfused heart.
Study Limitations
The transcardiac gradients determined in
the present study
reliably reflect cardiac release. Their magnitude, however, depends on
a number of variables that could not be determined. These include
the extension of the reperfused area, myocardial blood flow through
this area, and admixture of blood from the noninfarcted
myocardium. The eventual infarct size does not even
reliably reflect the area at risk. Therefore, we did not try to
correlate the transcardiac gradients in cytokines,
thrombomodulin, and surface expression of adhesion molecules with
enzymatic estimates of infarct size.
The equilibrium between circulating and marginating neutrophils is critical to the observed changes in neutrophil function. In acute MI, circulating neutrophils may be entrapped or marginating neutrophils may be liberated. Nevertheless, we did not find significant coronary sinus and arterial blood differences in neutrophil counts. Even though this does not exclude subtle shifts between marginating and circulating neutrophils,32 it demonstrates that the changes in neutrophil function detected in the present study cannot be attributed to a release of activated neutrophils from the marginating pool. Shedding of L-selectin is one of the earliest events in neutrophil activation by chemoattractants.21 Because L-selectin is essential to the initial attachment of neutrophils to the endothelium under flow conditions,36 we detected a substantial number of activated neutrophils remaining within the circulation.
Among
potential inflammatory mediators in acute MI, this study
investigated only the cytokines IL-1ß, IL-6, IL-8, and
TNF-. A number of additional mediators, however, may contribute to
cardiac inflammatory responses in acute MI. These may include
chemotactic complement fractions, leukotriene B4,
and platelet activating
factor.6 28 30 31
Pathophysiological Implications
Inflammatory responses in
acute MI have both local and systemic
impacts. The surface expression of Mac-1 on neutrophils was increased
after passage through the infarcted and reperfused heart. Mac-1 is the
major ligand for intercellular adhesion molecule–1 (ICAM-1) and plays
a central role in leukocyte adhesion to endothelial
cells.12 On the other hand, shedding of L-selectin by
neutrophils, which also occurs in the reperfused heart, is a
prerequisite for the transmigration of leukocytes through the
endothelial barrier.36
Apart from its effects on chemotaxis and surface receptor expression on leukocytes, IL-8 is a potent stimulus of release of granule enzymes and oxidative burst in neutrophils.21 23 Experimental evidence about the role of IL-8 in the interaction of neutrophils and endothelial cells has been conflicting. While some studies show an inhibitory effect,37 38 39 others demonstrate that endothelial-derived IL-8 is necessary for the migration of neutrophils through inflamed endothelium.40 41 42 Recently, it was shown that blocking IL-8 antibodies reduce the leukocyte accumulation and vascular injury after immune complex lung and skin injury in rats43 and prevent lung reperfusion injury in rabbits.44
At the local level, IL-6 may prime24 and stimulate45 the oxidative burst in neutrophils, stimulate endothelial surface expression of ICAM-1,46 and increase endothelial permeability.47 Moreover, studies in canine MI suggest that IL-6 is an essential mediator of the interaction of neutrophils with myocytes.29 In addition, locally released IL-6 may exert important systemic effects when ongoing cardiac liberation causes an increase in arterial IL-6 concentrations. IL-6 is one of the primary mediators of the systemic inflammatory response syndrome.48 It induces hepatic production of a number of procoagulatory acute-phase reactants,48 including fibrinogen, which is consistently elevated following MI. Besides, IL-6 may contribute to the infarct-related leukocytosis.49
Clinical Perspectives
Cardiac inflammatory responses appear
to play a pivotal role in
scar formation after acute MI.50 However, if timely
reperfusion has been achieved, the microvascular injury caused by these
inflammatory responses is not desirable.27 Moreover, the
systemic inflammatory response syndrome may increase the short-term
risk of recurrent cardiac ischemia.51 This is
suggested by a recent study that related the risk of major cardiac
events in unstable angina to the serum concentration of C-reactive
protein.51 In addition, systemic elevations of the white
blood cell count and plasma fibrinogen concentration have been
identified as cardiovascular risk
factors.52 The identification of IL-6 and IL-8 as
inflammatory mediators in acute MI may therefore yield a rationale for
pharmacological anticytokine interventions after successful
reperfusion. An anticytokine therapeutic strategy may improve
myocardial salvage and decrease the risk of infarct extension and its
recurrence.
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Acknowledgments |
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The study was supported by a grant from the Deutsche Forschungsgemeinschaft (Ne 540/1-1), Bonn-Bad Godesberg, Germany. We thank K. Gloth for her invaluable technical assistance and Dr R. Busch for statistical advice.
Received January 12, 1995; accepted February 2, 1995.
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F.-J. Neumann Optimization of microvascular reperfusion in acute myocardial infarction Eur. Heart J. Suppl., May 1, 2001; 3(suppl_A): A21 - A25. [Abstract] [PDF]
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R. K. Kharbanda, M. Peters, B. Walton, M. Kattenhorn, M. Mullen, N. Klein, P. Vallance, J. Deanfield, and R. MacAllister Ischemic Preconditioning Prevents Endothelial Injury and Systemic Neutrophil Activation During Ischemia-Reperfusion in Humans In Vivo Circulation, March 27, 2001; 103(12): 1624 - 1630. [Abstract] [Full Text] [PDF]
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B. Tantini, F. Flamigni, C. Pignatti, C. Stefanelli, M. Fattori, A. Facchini, E. Giordano, C. Clo, and C. M. Caldarera Polyamines, NO and cGMP mediate stimulation of DNA synthesis by tumor necrosis factor and lipopolysaccharide in chick embryo cardiomyocytes Cardiovasc Res, February 1, 2001; 49(2): 408 - 416. [Abstract] [Full Text] [PDF]
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A GASPARDONE, M PERINO, A S GHINI, F TOMAI, F VERSACI, I PROIETTI, and F CREA Exercise induced myocardial ischaemia does not cause increase in C-reactive protein concentration Heart, December 1, 2000; 84(6): 668a - 669. [Full Text]
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P. Zoldhelyi, P. J. Beck, R. J. Bjercke, J. C. Ober, X. Hu, J. M. McNatt, S. Akhtar, M. Ahmed, F. J. Clubb Jr., Z.-Q. Chen, et al. Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3065 - H3075. [Abstract] [Full Text] [PDF]
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H. V. Barron, C. P. Cannon, S. A. Murphy, E. Braunwald, and C. M. Gibson Association Between White Blood Cell Count, Epicardial Blood Flow, Myocardial Perfusion, and Clinical Outcomes in the Setting of Acute Myocardial Infarction : A Thrombolysis In Myocardial Infarction 10 Substudy Circulation, November 7, 2000; 102(19): 2329 - 2334. [Abstract] [Full Text] [PDF]
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 B. Bozkurt Activation of cytokines as a mechanism of disease progression in heart failure Ann Rheum Dis, November 1, 2000; 59(90001): i90 - 93. [Full Text] [PDF]
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M. S. Eisenberg, H. J. Chen, M. K. Warshofsky, R. R. Sciacca, H. S. Wasserman, A. Schwartz, and L. E. Rabbani Elevated Levels of Plasma C-Reactive Protein Are Associated With Decreased Graft Survival in Cardiac Transplant Recipients Circulation, October 24, 2000; 102(17): 2100 - 2104. [Abstract] [Full Text] [PDF]
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 R. J. de Winter, J. Fischer, R. Bholasingh, J. P. van Straalen, T. de Jong, J. G.P. Tijssen, and G. T. Sanders C-Reactive Protein and Cardiac Troponin T in Risk Stratification: Differences in Optimal Timing of Tests Early after the Onset of Chest Pain Clin. Chem., October 1, 2000; 46(10): 1597 - 1603. [Abstract] [Full Text] [PDF]
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H. Takano, T. Nagai, M. Asakawa, T. Toyozaki, T. Oka, I. Komuro, T. Saito, and Y. Masuda Peroxisome Proliferator-Activated Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Expression in Neonatal Rat Cardiac Myocytes Circ. Res., September 29, 2000; 87(7): 596 - 602. [Abstract] [Full Text] [PDF]
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N. A HERITY Interleukin 6: a message from the heart Heart, July 1, 2000; 84(1): 9 - 10. [Full Text]
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Y Hojo, U Ikeda, T Katsuki, O Mizuno, H Fukazawa, K Kurosaki, H Fujikawa, and K Shimada Interleukin 6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosis Heart, July 1, 2000; 84(1): 83 - 87. [Abstract] [Full Text] [PDF]
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T. O. Nossuli, V. Lakshminarayanan, G. Baumgarten, G. E. Taffet, C. M. Ballantyne, L. H. Michael, and M. L. Entman A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1049 - H1055. [Abstract] [Full Text] [PDF]
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Y. Hojo, U. Ikeda, Y. Zhu, M. Okada, S. Ueno, H. Arakawa, H. Fujikawa, T.-a. Katsuki, and K. Shimada Expression of vascular endothelial growth factor in patients with acute myocardial infarction J. Am. Coll. Cardiol., March 15, 2000; 35(4): 968 - 973. [Abstract] [Full Text] [PDF]
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P. Massoudy, S. Zahler, T. Freyholdt, R. Henze, A. Barankay, B. F. Becker, S. L. Braun, and H. Meisner SODIUM NITROPRUSSIDE IN PATIENTS WITH COMPROMISED LEFT VENTRICULAR FUNCTION UNDERGOING CORONARY BYPASS: REDUCTION OF CARDIAC PROINFLAMMATORY SUBSTANCES J. Thorac. Cardiovasc. Surg., March 1, 2000; 119(3): 566 - 574. [Abstract] [Full Text] [PDF]
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 D. Zohlnhofer, K. Brand, K. Schipek, G. Pogatsa-Murray, A. Schomig, and F.-J. Neumann Adhesion of Monocyte Very Late Antigen-4 to Endothelial Vascular Cell Adhesion Molecule-1 Induces Interleukin-1{beta}-Dependent Expression of Interleukin-6 in Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 353 - 359. [Abstract] [Full Text] [PDF]
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G. Liuzzo, L. M. Biasucci, J. R. Gallimore, G. Caligiuri, A. Buffon, A. G. Rebuzzi, M. B. Pepys, and A. Maseri Enhanced inflammatory response in patients with preinfarction unstable angina J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1696 - 1703. [Abstract] [Full Text] [PDF]
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F.-J. Neumann, D. Zohlnhofer, L. Fakhoury, I. Ott, M. Gawaz, and A. Schomig Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1420 - 1426. [Abstract] [Full Text] [PDF]
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W. K. Lagrand, C. A. Visser, W. T. Hermens, H. W. M. Niessen, F. W. A. Verheugt, G.-J. Wolbink, and C. E. Hack C-Reactive Protein as a Cardiovascular Risk Factor : More Than an Epiphenomenon? Circulation, July 6, 1999; 100(1): 96 - 102. [Abstract] [Full Text] [PDF]
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S. Wan, M. B. Izzat, T. W. Lee, I. Y.P. Wan, N. L.S. Tang, and A. P.C. Yim Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury Ann. Thorac. Surg., July 1, 1999; 68(1): 52 - 56. [Abstract] [Full Text] [PDF]
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 M. Shibata, K. Ueshima, M. Harada, M. Nakamura, K. Hiramori, S. Endo, N. Sato, H. Mukaida, T. Suzuki, T. Suzuki, et al. Effect of Magnesium Sulfate Pretreatment and Significance of Matrix Metalloproteinase-1 and Interleukin-6 Levels in Coronary Reperfusion Therapy for Patients with Acute Myocardial Infarction Angiology, July 1, 1999; 50(7): 573 - 582. [Abstract] [PDF]
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M. J. Claeys, J. Bosmans, L. Veenstra, P. Jorens, Herbert De Raedt, and C. J. Vrints Determinants and Prognostic Implications of Persistent ST-Segment Elevation After Primary Angioplasty for Acute Myocardial Infarction : Importance of Microvascular Reperfusion Injury on Clinical Outcome Circulation, April 20, 1999; 99(15): 1972 - 1977. [Abstract] [Full Text] [PDF]
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P. W. H. M. Verheggen, M. P. M. de Maat, V. M. Cats, F. Haverkate, A. H. Zwinderman, C. Kluft, and A. V. G. Bruschke Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function Eur. Heart J., April 2, 1999; 20(8): 567 - 574. [Abstract] [PDF]
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P. Massoudy, S. Zahler, A. Barankay, B. F. Becker, J. A. Richter, and H. Meisner Sodium nitroprusside during coronary artery bypass grafting: evidence for an antiinflammatory action Ann. Thorac. Surg., April 1, 1999; 67(4): 1059 - 1064. [Abstract] [Full Text] [PDF]
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A. Liebold, C. Keyl, and D. E. Birnbaum The heart produces but the lungs consume proinflammatory cytokines following cardiopulmonary bypass Eur. J. Cardiothorac. Surg., March 1, 1999; 15(3): 340 - 345. [Abstract] [Full Text] [PDF]
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S. Zahler, P. Massoudy, H. Hartl, C. Hahnel, H. Meisner, and B. F Becker Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass Cardiovasc Res, March 1, 1999; 41(3): 722 - 730. [Abstract] [Full Text] [PDF]
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M. Gwechenberger, L. H. Mendoza, K. A. Youker, N. G. Frangogiannis, C. W. Smith, L. H. Michael, and M. L. Entman Cardiac Myocytes Produce Interleukin-6 in Culture and in Viable Border Zone of Reperfused Infarctions Circulation, February 2, 1999; 99(4): 546 - 551. [Abstract] [Full Text] [PDF]
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S. J. Liu, W. Zhou, and R. H. Kennedy Suppression of beta -adrenergic responsiveness of L-type Ca2+ current by IL-1beta in rat ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H141 - H148. [Abstract] [Full Text] [PDF]
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F.-J. Neumann, R. Blasini, C. Schmitt, E. Alt, J. Dirschinger, M. Gawaz, A. Kastrati, and A. Schomig Effect of Glycoprotein IIb/IIIa Receptor Blockade on Recovery of Coronary Flow and Left Ventricular Function After the Placement of Coronary-Artery Stents in Acute Myocardial Infarction Circulation, December 15, 1998; 98(24): 2695 - 2701. [Abstract] [Full Text] [PDF]
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N. Marx, F.-J. Neumann, D. Zohlnhofer, T. Dickfeld, A. Fischer, S. Heimerl, and A. Schomig Enhancement of Monocyte Procoagulant Activity by Adhesion on Vascular Smooth Muscle Cells and Intercellular Adhesion Molecule-1–Transfected Chinese Hamster Ovary Cells Circulation, September 1, 1998; 98(9): 906 - 911. [Abstract] [Full Text] [PDF]
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P. Yue, B. M. Massie, P. C. Simpson, and C. S. Long Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H250 - H258. [Abstract] [Full Text] [PDF]
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 D. R. Meldrum Tumor necrosis factor in the heart Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R577 - R595. [Abstract] [Full Text] [PDF]
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D. R. Meldrum, J. C. Cleveland Jr, B. S. Cain, X. Meng, and A. H. Harken Increased Myocardial Tumor Necrosis Factor-{alpha} in a Crystalloid-Perfused Model of Cardiac Ischemia-Reperfusion Injury Ann. Thorac. Surg., February 1, 1998; 65(2): 439 - 443. [Abstract] [Full Text] [PDF]
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Y. Miyao, T. Nishikimi, Y. Goto, S. Miyazaki, S. Daikoku, I. Morii, T. Matsumoto, S. Takishita, A. Miyata, H. Matsuo, et al. Increased plasma adrenomedullin levels in patients with acute myocardial infarction in proportion to the clinical severity Heart, January 1, 1998; 79(1): 39 - 44. [Abstract] [Full Text] [PDF]
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K.-i. Kinugawa, T. Shimizu, A. Yao, O. Kohmoto, T. Serizawa, and T. Takahashi Transcriptional Regulation of Inducible Nitric Oxide Synthase in Cultured Neonatal Rat Cardiac Myocytes Circ. Res., December 19, 1997; 81(6): 911 - 921. [Abstract] [Full Text]
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F.-J. Neumann, I. Ott, N. Marx, T. Luther, S. Kenngott, M. Gawaz, M. Kotzsch, and A. Schomig Effect of Human Recombinant Interleukin-6 and Interleukin-8 on Monocyte Procoagulant Activity Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3399 - 3405. [Abstract] [Full Text]
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G. J. Ter Horst and F. Postema Forebrain parasympathetic control of heart activity: retrograde transneuronal viral labeling in rats Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2926 - H2930. [Abstract] [Full Text] [PDF]
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K. Bhagat and P. Vallance Inflammatory Cytokines Impair Endothelium-Dependent Dilatation in Human Veins In Vivo Circulation, November 4, 1997; 96(9): 3042 - 3047. [Abstract] [Full Text]
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C.J.M. Frijns, L.J. Kappelle, J. v. Gijn, H.K. Nieuwenhuis, J.J. Sixma, and R. Fijnheer Soluble Adhesion Molecules Reflect Endothelial Cell Activation in Ischemic Stroke and in Carotid Atherosclerosis Stroke, November 1, 1997; 28(11): 2214 - 2218. [Abstract] [Full Text]
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M. Gawaz, F.-J. Neumann, T. Dickfeld, A. Reininger, H. Adelsberger, A. Gebhardt, and A. Schomig Vitronectin Receptor ({alpha}vß3) Mediates Platelet Adhesion to the Luminal Aspect of Endothelial Cells : Implications for Reperfusion in Acute Myocardial Infarction Circulation, September 16, 1997; 96(6): 1809 - 1818. [Abstract] [Full Text]
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F.-J. Neumann, N. Marx, M. Gawaz, K. Brand, I. Ott, C. Rokitta, C. Sticherling, C. Meinl, A. May, and A. Schomig Induction of Cytokine Expression in Leukocytes by Binding of Thrombin-Stimulated Platelets Circulation, May 20, 1997; 95(10): 2387 - 2394. [Abstract] [Full Text]
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M. Kitakaze, T. Minamino, H. Funaya, K. Node, Y. Shinozaki, H. Mori, and M. Hori Vesnarinone Limits Infarct Size via Adenosine-Dependent Mechanisms in the Canine Heart Circulation, April 15, 1997; 95(8): 2108 - 2114. [Abstract] [Full Text]
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S. Wan, J.-L. LeClerc, and J.-L. Vincent Cytokine Responses to Cardiopulmonary Bypass: Lessons Learned From Cardiac Transplantation Ann. Thorac. Surg., January 1, 1997; 63(1): 269 - 276. [Abstract] [Full Text]
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G. Liuzzo, L. M. Biasucci, A. G. Rebuzzi, J. R. Gallimore, G. Caligiuri, G. A. Lanza, G. Quaranta, C. Monaco, M. B. Pepys, and A. Maseri Plasma Protein Acute-Phase Response in Unstable Angina Is Not Induced by Ischemic Injury Circulation, November 15, 1996; 94(10): 2373 - 2380. [Abstract] [Full Text]
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S. Wan, J.-M. DeSmet, L. Barvais, M. Goldstein, J.-L. Vincent, and J.-L. LeClerc MYOCARDIUM IS A MAJOR SOURCE OF PROINFLAMMATORY CYTOKINES IN PATIENTS UNDERGOING CARDIOPULMONARY BYPASS J. Thorac. Cardiovasc. Surg., September 1, 1996; 112(3): 806 - 811. [Abstract] [Full Text]
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L. M. Biasucci, A. Vitelli, G. Liuzzo, S. Altamura, G. Caligiuri, C. Monaco, A. G. Rebuzzi, G. Ciliberto, and A. Maseri Elevated Levels of Interleukin-6 in Unstable Angina Circulation, September 1, 1996; 94(5): 874 - 877. [Abstract] [Full Text]
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F. M. Sheridan, P. G. Cole, and D. Ramage Leukocyte Adhesion to the Coronary Microvasculature During Ischemia and Reperfusion in an In Vivo Canine Model Circulation, May 15, 1996; 93(10): 1784 - 1787. [Abstract] [Full Text]
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M. Gawaz, F.-J. Neumann, I. Ott, A. Schiessler, and A. Schomig Platelet Function in Acute Myocardial Infarction Treated With Direct Angioplasty Circulation, January 15, 1996; 93(2): 229 - 237. [Abstract] [Full Text]
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