Download Increased production of inflammatory cytokines in patients

Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 38, No. 7, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(01)01660-6
Increased Production of Inflammatory Cytokines
in Patients With Silent Myocardial Ischemia
Antonino Mazzone, MD,* Chiara Cusa, MD,* Iolanda Mazzucchelli, BSC,* Monia Vezzoli, MD,*
Elena Ottini, MD,* Roberta Pacifici, BSC,† Piergiorgio Zuccaro, MD,† Colomba Falcone, MD‡
Milan, Rome and Pavia, Italy
The aim of the study was to examine the inflammatory cytokines in patients with myocardial
ischemia to evaluate whether silent ischemia patients exibit any particular cytokine pattern.
BACKGROUND Silent myocardial ischemia is frequently observed in patients with coronary artery disease.
Various endogenous mechanisms control a patient’s perceived intensity of pain. Among them,
the inflammatory process and the related cytokine production are known to modulate the
threshold for activating the primary afferent nociceptors.
METHODS
Seventy-eight patients with reproducible exercise-induced myocardial ischemia were studied:
34 symptomatic patients, with rest and/or stress angina; 44 asymptomatic patients, with no
symptoms during daily life activities or during positive exercise stress test. Venous blood
samples were taken from all patients to evaluate the expression of CD11b receptors both on
neutrophils and monocytes. Frozen plasma samples (at ⫺80°C) were used to quantify the
anti-inflammatory (interleukin-4 and -10, transforming growth factor-␤) and the proinflammatory cytokines (tumor necrosis factor-␣, interferon-␥, interleukin-1␤ and -6).
RESULTS
In asymptomatic patients lower CD11b receptor expression and higher concentration of
anti-inflammatory cytokines were observed. Proinflammatory cytokine production was similar
in the two groups.
CONCLUSIONS The data suggest that an “anti-inflammatory pattern” of cytokine production correlates with
silent ischemia and that the immune and inflammatory system activation may be crucial for
angina symptoms. (J Am Coll Cardiol 2001;38:1895–901) © 2001 by the American College
of Cardiology
OBJECTIVES
Immunocytes and cytokines are known to play a key role in
the pathogenesis of the atherosclerotic process and coronary
artery disease (CAD) (1,2). Silent myocardial ischemia
frequently occurs at rest, during daily life activities or after
physical or emotional exertion (3– 6); moreover, history of
anginal pain might not be reported after acute myocardial
infarction (MI) or during an angioplasty-induced coronary
occlusion (7,8). The mechanisms responsible for silent
ischemia are not well understood, and individual differences
in pain threshold may only partially explain the variability in
pain perception (3– 6). Patients with silent ischemia usually
show a generalized hyposensitivity and higher pain threshold as compared with symptomatic patients (5– 8); production of the endogenous opiates may be partially responsible
for decreased perception of pain (3).
The relationship between inflammatory process and atherosclerosis has been extensively debated, but no data have
yet been reported to describe the link between inflammatory
system activation and silent myocardial ischemia. All stages
of the atherosclerotic process are characterized by systemic
endothelial dysfunction with subsequent endothelial damage and inflammation (1,2); these mechanisms are also
involved in the atherosclerotic plaque instability and rupture
(1,9 –12), which may occur in acute ischemic event. Several
From the *Department of Internal Medicine, Legnano Hospital, Milan; †Clinical
Biochemistry Department, National Institute of Health, Rome; and ‡Department of
Cardiology, IRCCS S. Matteo Hospital, Pavia, Italy. This work was supported by
grant 03/99 from IRCCS, S. Matteo Hospital, Pavia, Italy.
Manuscript received March 20, 2001; revised manuscript received August 7, 2001,
accepted August 27, 2001.
other studies suggest that inflammatory cytokines may
directly damage the endothelial surface, leading to ischemia,
underlining the direct link between proinflammatory cytokine blood concentrations and cardiovascular risk (13–15).
Cytokine production also correlates with clinical manifestations of acute coronary syndrome (14,15). Local vascular and perivascular inflammation occurs within the injured
tissue. Immunocyte recruitment results from a multistep,
sequential engagement of various adhesion molecules
(1,9,11,16,17). The activated phagocytes (granulocytes and
monocytes) express the CD11b/CD18 adhesion molecule,
thus mediating their sticking adhesion to the endothelial
cells and leading to phagocyte chemotaxis toward the
inflamed tissue.
In addition, the CD11b/CD18 binds to the activated
complement factor (C3a), enhancing the inflammatory
process, and recognizes fibrinogen-coated surfaces, leading
to neutrophil-clot adhesion and fibrin digestion (11,17).
Within the inflammatory site, the activated phagocytes
release the cytokines interferon-gamma (IFN-␥), interleukin (IL)-4, IL-10 and transforming growth factor-beta
(TGF-␤), which further enhance cellular migration; other
proinflammatory cytokines such as IL-1␤, tumor necrosis
factor (TNF)-␣ and IL-6 are known to be released within
inflamed tissue (18 –20). Peripheral inflammation stimulates
peripheral nerve endings causing hyperalgesia, which is due
to enhanced localized inflammatory mediators (18,19); the
local release of cytokines and endogenous opioids might be
able to modulate the threshold for peripheral nerve-ending
activation. Pain perception may result from microenviron-
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Silent Myocardial Ischemia and Inflammatory Cytokines
Abbreviations
CAD ⫽
CGRP ⫽
ECG ⫽
IFN-␥ ⫽
IL
⫽
MAb ⫽
MESF ⫽
MI
⫽
NF-␬B ⫽
PBR
⫽
SP
⫽
TGF-␤ ⫽
TNF-␣ ⫽
and Acronyms
coronary artery disease
calcitonin gene-related peptide
electrocardiogram or electrocardiographic
interferon-gamma
interleukin
monoclonal antibodies
molecules of equivalent soluble fluorescein
myocardial infarction
nuclear factor-␬B
peripheral benzodiazepine receptor
substance P
transforming growth factor-beta
tumor necrosis factor-alpha
mental balances between proinflammatory (IL-1␤, TNF-␣,
IL-6, and IFN-␥) and anti-inflammatory (IL-4, IL-10)
cytokines (19,20).
In our study we investigated inflammatory cytokines in
patients with transient myocardial ischemia to determine
whether silent ischemia correlates with any particular pattern of cytokine production. Inflammatory system activation
markers were detected in patients with symptomatic angina
and in patients with silent myocardial ischemia episodes.
The CD11b adhesion molecule expression was detected on
phagocytes, and proinflammatory (IL-1␤, TNF-␣, IL-6
and IFN-␥) and anti-inflammatory cytokine (IL-4, IL-10
and TGF-␤) production was quantified in ischemic patients.
METHODS
Patient selection. Seventy-eight male patients were studied: 34 patients with anginal pain during daily life activities
(group P) and 44 patients with silent ischemia (group A).
Two positive exercise stress tests documenting transient
myocardial ischemia were performed in each patient. Patients who always refer anginal symptoms were enrolled in
group P; patients who do not complain of anginal pain were
enrolled in group A. Only male patients were studied.
Patients with intercurrent inflammatory conditions, and
patients who were on nonsteroidal anti-inflammatory drugs
and steroids, were excluded. Pharmacologic washout was
performed. Calcium channel antagonists and nitrates were
halted 48 h before the test. Beta-blockers were gradually
reduced and stopped 1 week before the examination. No
patients were receiving digoxin. Informed written consent
for all tests was obtained from the studied subjects. The
Ethical Committee of our hospital approved the study.
Exercise stress testing. All patients carried out a multistage bicycle ergometric stress test. The initial workload was
25 W and the subsequent stepwise increments were 25 W
every 2 min at a pedalling frequency of 60 rpm. Standard
12-lead electrocardiogram (ECG) and blood pressure were
recorded in basal conditions with the patient lying in a
supine position for 10 min and subsequently just before the
test, at the end of each stage, at the appearance of ECG
JACC Vol. 38, No. 7, 2001
December 2001:1895–901
signs of ischemia and/or of anginal pain, at peak exercise
and every 3 min during recovery. Three ECG leads (D3, V5,
V6) were continuously monitored and displayed on an
oscilloscope throughout the test. During the test the patients were repeatedly asked about the onset of angina or
other symptoms. A positive ECG response was defined as
the occurrence of at least 1-mm ST-segment depression, as
compared with the baseline tracing. The ischemic threshold
was defined as the appearance of a 1-mm flat or downsloping ST depression 0.08 s after the J point; the angina
threshold was defined as the time of the first report of chest
pain during the test. The multistage bicycle ergometric
stress test was stopped when moderate-to-severe angina,
dyspnea, muscle fatigue, ST-segment depression ⬎3 mm or
major arrhythmia occurred. The rate-pressure product
(heart rate ⫻ systolic blood pressure) was calculated in basal
conditions, at the ischemic threshold and at peak exercise.
Coronary arteriography. All patients underwent cardiac
ventriculography and sones selective coronary arteriography
within 7 ⫾ 5 days after the exercise stress test. Left
ventriculography was performed before coronary arteriography in the 30° right anterior oblique projection; ventricular
volumes and left ejection fraction were calculated by the
standard area-length method. Significant CAD was defined
as narrowing of 50% or more of the lumen of at least one of
the three main arteries or their major branches.
Flow cytometry analysis. Cell-surface receptors were detected by direct immunofluorescence signal evaluated by
using flow cytometry (11,21). Blood samples were taken
from forearm vein at 8:00 AM before exercise stress test. The
samples were immediately processed in whole blood so as to
avoid any in vitro manipulation that might activate phagocytes. The following monoclonal antibodies (MAbs) were
tested: anti-CD11b/CD18; LFA-1 as anti-CD11a/CD18,
and anti-mouse control FITC— obtained from Becton
Dickinson (Milan, Italy). Analysis was performed by flow
cytometry using fluorescence-activated cell sorter (Becton
Dickinson). The fluorescence signal arising from the MAbs
specifically bound to receptors was converted to molecules
of equivalent soluble fluorescein (MESF) and quantified by
using standardized fluorescein microbeads (quantum 26
FITC 7.3-␮m diameter hydrophobic microspheres, FACS,
Research Triangle Park, North Carolina, obtained by Becton Dickinson, Milan, Italy).
Cytokine assay. Quantitative measurement of IL-1␤,
IL-4, IL-6, IL-10, TNF-␣ and IFN-␥ was performed using
a solid-phase sandwich ELISA test with microtiter plate
precoated with the specific MAb (Biosource, Celbio, Milan,
Italy). Quantitative measurement of TGF-␤1 was performed using a solid-phase enzyme amplified sensitivity
immunoassay with microtiter plate precoated with the
specific MAb (Biosource; Celbio, Milan, Italy). Tests were
performed according to the supplier’s instructions. Patient
sample and cytokines standard samples were assayed simultaneously, in duplicate. The standard curve for the IL-1␤
assay ranged from 0.31 to 20 pg/ml; for IL-4 it was 0.39 to
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Table 1. Clinical, Angiographic and Ergometric Data in Symptomatic (Group P) and
Asymptomatic Patients (Group A) With Coronary Artery Disease
Clinical features
Mean age (yrs ⫾ SD)
Arterial hypertension
Hyperlipidemia
Diabetes mellitus
Smoking
Coronary angiography
One-vessel disease
Multivessel disease
Ejection fraction (%) ⫾ SD
LVEDV (ml) ⫾ SD
LVEDP (mm Hg) ⫾ SD
Exercise stress test
Baseline RPP (beats/min ⫻ mm Hg) ⫾ SD
Peak RPP (beats/min ⫻ mm Hg) ⫾ SD
Peak ST depression (mm) ⫾ SD
Group P
(n ⴝ 34)
Group A
(n ⴝ 44)
p Value
60.7 ⫾ 8.6
4
10
3
9
64.9 ⫾ 9.4
6
14
4
12
NS
NS
NS
NS
NS
10
14
58.1 ⫾ 10.2
115 ⫾ 26
16.4 ⫾ 8.1
7
26
60.1 ⫾ 9.4
124 ⫾ 21
14.6 ⫾ 3.9
NS
NS
NS
NS
NS
9.243 ⫾ 2.232
21.043 ⫾ 4.585
1.92 ⫾ 1.51
9.623 ⫾ 2.056
22.347 ⫾ 6.573
2.24 ⫾ 1.82
NS
NS
NS
LVEDV ⫽ left ventricular end-diastolic volume; LVEDP ⫽ left ventricular end-diastolic pressure; RPP ⫽ rate-pressure
product.
12.5 pg/ml; for IL-6 it was 0.16 to 5.0 pg/ml; for IL-10 it
was 0.78 to 25 pg/ml; for TNF-␣ it was 0.5 to 16 pg/ml; for
IFN-␥ it was 15.6 to 500 pg/ml, and for TGF-␤1 it was 16
to 2,000 pg/ml. The sensitivity of assays were: 0.19 pg/ml
for IL-1␤; 0.27 pg/ml for IL-4; 0.10 pg/ml for IL-6;
0.21 pg/ml for IL-10; 0.1 pg/ml for TNF-␣; 4 pg/ml for
IFN-␥; and 2 pg/ml for TGF-␤1. Plasma samples were
appropriately diluted with a phosphate-buffered solution to
enter calibration curve ranges. Assay performance was tested
using two concentrations of cytokines in plasma throughout
the procedure. Mean intra- and interassay coefficients of
variation were always ⬍6%.
Statistical analysis. Results are expressed as mean ⫾ SD.
The Mann-Whitney nonparametric analysis was used to
investigate differences between the two different groups.
The StatView program for Apple Computers was utilized,
and p values ⬍0.05 were considered statistically significant.
RESULTS
Seventy-eight patients (mean age 62.5 ⫾ 8.6 years) were
included in the study. Group P consisted of 34 anginal
patients: 19 patients with effort angina, 4 patients with
angina at rest and 11 patients with mixed angina. Silent
ischemia was documented during exercise stress test in 44
patients (group A); 27 patients with silent ischemic episodes
during daily life activities and documented by Holter recording were also included within group A. Clinical data are
reported in Table 1. There were no statistically significant
differences in age, ECG-documented severity of angina,
hypertension, hyperlipidemia, diabetes and smoking. Coronary angiography results were similar within the two
groups. All patients in group P complained of angina during
exercise test; moderate to severe dyspnea was experienced
during exercise stress test in group A patients. The entity of
ST-segment depression at peak exercise was similar in the
two groups. No difference was found in the CD11a/CD18
expression on monocytes. The CD11b/CD18 expression
was lower in asymptomatic patients both on granulocytes
and monocytes (p ⬍ 0.01) (Fig. 1). In symptomatic patients,
MESF values (⫻ 103/cells) were 68.1 ⫾ 7 for granulocytes
and 80.8 ⫾ 6 for monocytes; in asymptomatic patients,
MESF values (⫻ 103/cells) were 56.4 ⫾ 7 for granulocytes
and 48.4 ⫾ 8 for monocytes. In asymptomatic patients,
anti-inflammatory cytokine levels were significantly higher:
IL-4, 0.634 ⫾ 0.062 ng/ml vs. 1.790 ⫾ 0.195 ng/ml,
p ⬍ 0.005; IL-10, 5.804 ⫾ 0.364 ng/ml vs. 15.350 ⫾
1.129 ng/ml, p ⬍ 0.001; TGF-␤, 2.511 ⫾ 0.232 ng/ml vs.
9.671 ⫾ 0.533 ng/ml, p ⬍ 0.001 (Fig. 2A). Proinflammatory cytokine concentrations were similar in the two groups:
IL-1␤, 0.376 ⫾ 0.027 ng/ml vs. 0.412 ⫾ 0.025 ng/ml, p ⫽
NS; IL-6, 2.581 ⫾ 0.534 ng/ml vs. 2.805 ⫾ 0.426 ng/ml,
p ⫽ NS; TNF-␣, 5.746 ⫾ 0.401 ng/ml vs. 5.733 ⫾
0.322 ng/ml, p ⫽ NS; IFN-␥, 26.362 ⫾ 2.193 pg/ml vs.
24.860 ⫾ 3.406 pg/ml, p ⫽ NS (Fig. 2B).
DISCUSSION
Our data show that, patients with asymptomatic ischemia,
there is higher production of anti-inflammatory cytokines
with lower expression of CD11b/CD18 adhesion molecule
on phagocytes. These observations may indicate that the
clinical feature of silent myocardial ischemia might correlate
with a particular biochemical pattern of inflammatory system activation.
Inflammation opioid system and peripheral benzodiazepine receptors. Inflammation is involved in the pathogenesis of atherosclerotic process, in plaque instability and
rupture and in tissue injury during MI. In this regard,
several studies showed that unstable and complicated atherosclerotic plaque might result from recruitment of neutrophils and monocytes within the plaque owing to local
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December 2001:1895–901
Figure 1. CD11b/CD18 adhesion molecule expression in asymptomatic patients (group A) and in patients complaining of angina pain (group P).
Asymptomatic patients express lower level of adhesion molecule both on neutrophils and on monocytes. Open bars ⫽ silent ischemia; solid bars ⫽
symptomatic ischemia. MESF ⫽ molecules of equivalent soluble fluorescein.
production of inflammatory metabolites and cytokines (9 –
12). The local inflammatory reaction further mediates tissue
damage and may be responsible for the modulation of the
pain transmission pathways (1,2,10,13,15). Immunocytes
locally release inflammatory cytokines as well as betaendorphins, thus interfering with the endogenous opioidmediating system (3,4,8,20,21–27). The resulting inflammatory microenvironmental production may alter the
threshold for activation of peripheral nerve endings
(1,2,10,13,15). Higher threshold of pain transmission pathway activation has been demonstrated during strenuous
exercise and after physical training due to increased plasma
levels of endogenous opioids (see beta-endorphins), as part
of physiological stress response (4,8).
During myocardial ischemia, the endogenous opioids,
which derive from local immune cells, interact with specific
receptors on sensory nerves, leading to strong and clinically
measurable analgesia (5,21,22,24 –27). It has also to be
stressed that morphine, which is the best pain-relieving
drug currently available for cardiac patients, is able to
decrease leukocyte activation and to exert anti-inflammatory
properties (3,22,24 –29). In this regard, our previous studies
showed that morphine and other opioid peptides downregulate the expression of CD11b/CD18 receptor on phagocytes, decreasing phagocyte– endothelial cell interactions
(23). We would also like to focus briefly on peripheral
benzodiazepine receptors (PBRs), which are expressed on
leukocyte surfaces. Higher PBR expression correlates with
higher threshold for pain transmission pathway activation
and with acute systemic stress response. Moreover, in a
dose-related manner, PBR interferes with inflammatory
response and cytokine release (30,31) and may modulate the
perception of pain (32). Our previous work showed that
PBRs are strongly expressed on the leukocytes of patients
with silent myocardial ischemia (21).
Inflammatory cytokines and pain. The T-lymphocyte and
monocyte infiltrates within atherosclerotic lesions may be
responsible for plaque instability and acute coronary events
(1,13,33–35). The T-lymphocyte responses can be categorized as proinflammatory (Th1 type) or anti-inflammatory
(Th2 type) (34,35). The Th1 type activation leads to
proinflammatory cytokine release (TNF-␣, IL-1␤, IL-6,
and IL-8), whereas Th2 lymphocyte activation leads to
endorphin and anti-inflammatory cytokine (IL-4 and IL10) release. The proinflammatory pattern activation seems
to intensify nociception, whereas Th2 lymphocyte production (36) seems to reduce the pain perception.
Several observations suggest that inflammatory cytokines
orchestrate nociception and also suggest the role of proinflammatory and anti-inflammatory cytokines in the perception of pain. Particularly, proinflammatory cytokines are
known to induce the release of pain mediators, such as
bradykinin and calcitonin gene-related peptide (CGRP)
and to activate vagal afferents (37). The IL-1␤ is a proinflammatory cytokine able to induce hyperalgesia. Central
administration of IL-1␤ enhances the nociceptive neuronal
response (38 – 40) and, in monoarthritic rat, dosedependently enhances the spinal-cord– evoked release of
substance P (SP) and CGRP (41). By contrast, the IL-1
receptor antagonist attenuated the IL-1␤–induced hyperal-
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December 2001:1895–901
Figure 2. Cytokine plasma levels in asymptomatic patients (group A) and
in patients complaining of angina (group P); A, anti-inflammatory cytokines; B, proinflammatory cytokines. Open bars ⫽ silent ischemia; solid
bars ⫽ symptomatic ischemia. IFN-␥ ⫽ interferon-gamma; IL ⫽ interleukin; TGFbeta ⫽ transforming growth factor-beta; TNF-alpha ⫽ tumor
necrosis factor-alpha.
gesia (40,42). The TNF-␣ induces pain and hyperalgesia
after injection; the effects are mediated by direct sensitization of primary afferent nociceptors and by upregulation of
other proinflammatory proteins. Both subcutaneous (43)
and intraplantar (44) TNF-␣ injections contribute to hyperalgesia and inflammation; this evokes ongoing activity in
type C nociceptors, causes significant and dose-related
increases in skin vascular permeability (43), induces proinflammatory cytokine production (IL-1, IL-6, IL-8), and
triggers the cyclooxygenase-dependent pathways to synthesize prostaglandins (43). In experimental inflammation,
pentoxifylline was demonstrated to inhibit TNF-␣ release,
with consequent decrease of pain-related behavior (44).
By contrast, anti-inflammatory cytokine IL-10 administration was demonstrated to reverse the dynorphin-induced
allodynia, which is a model of neuropathic pain in the
mouse, thus suggesting that allodynia might be modulated
by the inflammatory cytokine system (45). The IL-10
inhibits the positive inflammatory feed-forward loop by
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Silent Myocardial Ischemia and Inflammatory Cytokines
1899
inhibiting the initial induction and the subsequent amplification of proinflammatory cytokines (46). A single peripheral administration of IL-10 was demonstrated to decrease
the nerve injury-induced thermal hyperalgesia (46,47) and
the intradermal endotoxin-induced hyperalgesia (48). Our
data show that IL-10 levels increase significantly in asymptomatic patients. Transforming growth factor-␤ stimulates
connective tissue growth and collagen formation, and it can
virtually and strongly inhibit all the immune and hematopoietic functions, especially if present before cell activation
(49,50). It also has a role in mediating inflammation and
cytotoxic reactions (49 –51): TGF-␤ blocks the IFN-␥–
induced cell activation, thus increasing the production of
ROS, prostaglandins and nitric oxide; IL-4 has similar
effects to that of TGF-␤ in limiting the inflammatory
hyperalgesia (51,52).
Role of the transcription factor nuclear factor-␬B. Cytokine production is primarily regulated at the transcriptional level (53,54) by specific transcriptional factors linking
the receptor-driven cytoplasmic signaling events with
changes in gene expression. The nuclear factor-␬B (NF-␬B)
activation induces nociceptive protein production such as
proinflammatory cytokines, inducible nitric oxide synthase
(S), cyclo-oxygenase (COX-2) and pre-prodynorphin. Several stimuli, such as proinflammatory cytokines, oxidative
stress, nerve growth factor, and protein kinase C, can
activate NF-␬B (53–56). The relevance of NF-␬B to
nociception is supported by the observation that hyperalgesic doses of nerve growth factor in vivo activate NF-␬B in
dorsal root ganglia (56). Moreover, capsaicin-induced hyperalgesia associates with enhanced expression of NF-␬B
(56). Anti-inflammatory cytokine administration (such as
IL-10) correlates with NF-␬B reduced activity and with
decreased intensity of pain perception (47). Our data may
suggest that alterations of anti-inflammatory cytokine production might exert an inhibitory effect on NF-␬B, which is
crucial for nociception, leading to an ischemic angina
episode.
Study limitations. Our results showed that an antiinflammatory pattern of cytokine production is activated in
patients with silent myocardial ischemia. The data suggest
that silent ischemia might result from a particular microenvironmental pattern of inflammatory system activation leading to higher threshold for the stimulation of peripheral
nerve endings. The findings should be interpreted cautiously. Cytokines have a very short half-life in the bloodstream, and their biologic effects seem to be more related to
the length of cytokine exposure than to their absolute
circulating concentrations; in addition, cytokine levels were
detected only once in the study, and our observational study
did not include any follow-up controls. Sequential measurement of circulating cytokines and clinical correlation with
patients’ symptoms and illness stages are necessary to further
confirm our data. Moreover, we lack a biologic model
describing stimuli able to cause Th1 or Th2 activation in
cardiovascular patients, and we did not investigate whether
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Silent Myocardial Ischemia and Inflammatory Cytokines
a particular pattern of cytokines might correlate with clinical
outcome.
In addition, we also cannot exclude the idea that inflammatory cell activation and cytokine release are epiphenomena occurring during myocardial ischemia, without any
pathogenetic implication with the basic illness. Moreover,
pain perception might only depend on individual pain
threshold and/or other unknown mechanisms. Nevertheless,
the positive association described between silent myocardial
ischemia and anti-inflammatory cytokine production cannot
be excluded.
Conclusions. The significant increase of levels of antiinflammatory cytokines together with the decrease of leukocyte adhesion molecule expression might identify one of
the mechanisms for silent ischemia. In patients with silent
ischemia it might be possible that the Th2 activation will
induce higher production of anti-inflammatory cytokines
together with endogenous opioid production and higher
expression of PBRs. The anti-inflammatory cytokines
might be able to block the pain transmission pathway
activation by increasing the threshold for nerve activation.
In addition, the anti-inflammatory cytokines will exert a
prolonged inhibitory effect on transcription factor NF-␬B,
leading to reduction and/or elimination of pain-mediating
substances. Further studies are needed to explain the effects
of these cytokines on clinical progression and prognosis and
on the atherosclerotic process. These findings might also
indicate that immune system cytokine production can modulate nociception, thus providing us with data on widespread clinical implications.
Acknowledgment
We thank Elizabeth De Jung for the final English language
version of this article.
JACC Vol. 38, No. 7, 2001
December 2001:1895–901
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Reprint requests and correspondence: Dr. Antonino Mazzone,
Chief of Internal Medicine and Oncology, Hospital of Legnano,
Via Candiani 2, 20025 Legnano, Milano, Italy. E-mail: medicina
2legnano@ao-legnano.
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