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Circulation. 1995;92:748-755

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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.

Franz-Josef Neumann, MD; Ilka Ott, MD; Meinrad Gawaz, MD; Gert Richardt, MD; Heidi Holzapfel; Marianne Jochum, PhD; Albert Schömig, MD

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.


*    Abstract
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 *Abstract
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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-{alpha}, 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-{alpha} 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


*    Introduction
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 up arrowAbstract
 *Introduction
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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.


*    Methods
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 *Methods
down arrowResults
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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 1Down).


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  		Table 1. Angiographic Findings and Peak CK Concentration in the Study Group

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 2Down 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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  		Table 2. Baseline Characteristics of the Study Population

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 1Up), 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 1Up). 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-{alpha} (TNF-{alpha}) 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-{alpha}; 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.


*    Results
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*Results
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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 1Up). 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 1Up). 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 2Up).

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 1Down). 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 1Down). 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 2Down). Coronary sinus and arterial blood differences in the concentrations of IL-8 significantly increased with reperfusion and remained elevated during the observation period (Fig 2Down). Arterial concentrations of IL-6 and of IL-8 did not change significantly (Table 3Down). Concentrations of TNF-{alpha} 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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  		Figure 1. Plot of the coronary sinus and arterial blood differences in interleukin-6 immunoreactivity before, immediately after, and 5 minutes after recanalization of the left anterior descending coronary artery in acute myocardial infarction. Probability values indicate the level of significance for the difference to the values before recanalization.



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  		Figure 2. Plot of the coronary sinus and arterial blood differences in interleukin-8 immunoreactivity before, immediately after, and 5 minutes after recanalization of the left anterior descending coronary artery in acute myocardial infarction. Probability values indicate the level of significance for the difference to the values before recanalization.


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  		Table 3. Arterial Blood Variables in the Study Group

In the control group, significant changes in the concentrations of IL-6 and IL-8 were not found (Table 4Down).


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  		Table 4. Coronary Sinus and Arterial Blood Differences in the Control Group

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 3Down and 4Down). Immediately after recanalization, however, surface expression on neutrophils of CD11b (Fig 3Down) 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 4Down) 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 3Down and 4Down). Significant systemic changes in the surface expression on neutrophils of CD11b or L-selectin were not detected in the study group (Table 3Up). In the control group, surface expression on neutrophils of CD11b and L-selectin essentially remained unaffected by the intervention (Table 4Up).



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  		Figure 3. Plot of the coronary sinus and arterial blood differences in the surface expression of CD11b on neutrophils before, immediately after, and 5 minutes after recanalization of the left anterior descending coronary artery in acute myocardial infarction. Results are expressed as mean channel of fluorescence intensity (mean fl). Probability values indicate the level of significance for the difference to the values before recanalization.



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  		Figure 4. Plot of coronary sinus and arterial blood differences in the surface expression of L-selectin on neutrophils before, immediately after, and 5 minutes after recanalization of the left anterior descending coronary artery in acute myocardial infarction. Results are expressed as mean channel of fluorescence intensity (mean fl). Probability values indicate the level of significance for the difference to the values before recanalization.

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 4Up).

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 5Down). 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 4Up).



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  		Figure 5. Plot of coronary sinus and arterial blood differences in thrombomodulin immunoreactivity before, immediately after, and 5 minutes after recanalization of the left anterior descending coronary artery in acute myocardial infarction. Probability values indicate the level of significance for the difference to the values before recanalization.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
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-{alpha} and IL-1ß are predominantly leukocyte-derived cytokines. Endothelial cells have not been shown to produce TNF-{alpha}15 and are only a minor source of IL-1ß.17 Hypoxia increases the production of TNF-{alpha} and IL-1ß by human mononuclear cells.18 Nevertheless, we did not find significant transcardiac gradients in TNF-{alpha} 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-{alpha} 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-{alpha}. 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.


*    Acknowledgments
 
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.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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