European Journal of Heart Failure 2003 5(1):23-25; doi:10.1016/S1388-9842(02)00117-4
© 2002 European Society of Cardiology
Plasma concentrations of interleukin-2 soluble receptor in mild ischaemic left ventricular dysfunction
Antonio Abbatea,
Elena Vecileb,
Nicola Fiottic,
Carlo Giansantec,
Gianfranco Guarnieric,
Germano Di Sciasciod and
Aldo Dobrinab,*
a Institute of Cardiology, Catholic University of the Sacred Heart Rome, Italy
b Department of Physiology and Pathology, University of Trieste Via Fleming 22, Trieste, 34127 Italy
c Department of Clinical Medicine, University of Trieste Trieste, Italy
d Department of Cardiovascular Sciences University Campus Bio-Medico of Rome, Rome, Italy
* Corresponding author. Fax: +39-040-567862 E-mail address: dobrina{at}univ.trieste.it
Key Words: Inflammation • Immune system • Heart failure • Myocardial ischaemia
Received November 19, 2001; Revised February 13, 2002; Accepted March 26, 2002
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1. Background
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Inflammation is increasingly thought to play a key role in promoting
coronary atherosclerosis
[1]. Inflammatory markers, such as
C-reactive protein (CRP) have been found to be elevated in patients
with acute coronary syndromes and to be predictive of adverse
cardiac events
[2–
5]. Similarly, increased levels of inflammatory
cytokines have been shown in congestive heart failure
[6] (CHF)
and follow the progression of the disease to its terminal phases
[7] (end-stage CHF). Whether activation of the inflammatory-immune
system is induced in the early phases of ischaemic left ventricular
dysfunction (LVD) remains to be determined.
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2. Aim of the study
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In the present study, we evaluated plasma levels of the prototypical
acute phase protein CRP, Interleukin-1 receptor antagonist (IL-1Ra)
which is synthesized and released by activated monocyte-macrophages
at sites of tissue damage/inflammation and Interleukin-2 soluble
receptor (sIL-2R), a specific marker of T-lymphocyte activation,
in patients with mild ischaemic LVD.
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3. Methods
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Plasma levels of CRP, IL-1Ra and sIL-2R were determined in 40
consecutive patients referred to the catheterization laboratory
for left ventricle and coronary angiography with suspected coronary
artery disease (median age 61 years, six females). Nineteen
patients (48%) had recent onset of rest angina while the other
patients (52%) had a clinical history of stable effort-induced
angina. In all cases significant coronary artery disease was
demonstrated at angiography. History of previous myocardial
infarction was present in 22 cases (55%). At the time of enrollment,
none of the patients had clinical or laboratory evidence (nor
was there a suspicion) of malignancy, infections, inflammatory
diseases, or recent (<2 months) surgery or trauma. In all
patients, white blood cell count and erythrocyte sedimentation
rate were in the normal range. Venous blood samples to assess
CRP, IL-1Ra and sIL-2R levels were collected 3–6 h before
heart catheterization. Syringes were anticoagulated with sodium
citrate for detection of CRP and ethylenediaminetetraacetic
acid (EDTA) for detection of sIL2-R and IL-1Ra. Each extract
was frozen at –80 °C, until it was assayed. CRP, sIL-2R
and IL-1Ra were determined by enzyme-linked immuno-assay kits
purchased from Immunodiagnostik (CRP) or R&D Systems (IL-1Ra
and sIL-2R). Values are expressed as median and interquartile
range. The Chi-square test was applied to compare discrete variables
and the non-parametric U-Mann Whitney test was used to compare
continuous non-paired not normally distributed variables. The
Spearman rank test was used for correlations between variables.
P values <0.05 were considered significant.
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4. Results
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Left ventricular ejection fraction (LVEF), calculated on quantitative
angiography, ranged from 35 to 70%, median 60%. LVEF values
between 51 and 70% were considered in the normal range. Mild
to moderate LVD (LVEF
50%) was present in 13 cases (32%). Symptoms
consistent with NYHA class II were reported by eight of the
13 patients (61%) while the other five patients were asymptomatic
(class I). Cardiovascular risk factors and clinical characteristics
of the patients in the two groups are shown in
Table 1. Soluble
IL-2R plasma levels, but not CRP or IL-1Ra, were found to be
significantly elevated in patients with LVD compared to the
others [1605 pg/ml (1390–1773pg/ml) vs. 1183 pg/ml (1001–1485
pg/ml);
P=0.03] (
Fig. 1a). Consistent with previous observations
[8], plasma sIL-2R levels were significantly correlated with
the age of the patients (
R=+0.44;
P=0.01). In addition, we found
a significant correlation between sIL-2R and LVEF at angiography
(
R=–0.30;
P=0.03) (
Fig. 1a) at univariate analysis, but
not to other demographic or clinical factors (including presence
of previous myocardial infarction). At multivariate analysis,
both LVEF and age remained significantly correlated with plasma
sIL-2R (
P=0.01 and 0.009, respectively). When subgroup analysis
was performed, by considering data from 19 patients aged 60
or younger, a significant negative correlation between LVEF
and sIL-2R levels was found (
R=–0.60;
P=0.005). In this
subset of patients, the difference in sIL-2R between those with
depressed (35–50%) vs. preserved (>50%) LVEF was even
more evident [1680 pg/ml (1484–1805 pg/ml) vs. 1125 pg/ml
(937–1215 pg/ml), respectively;
P=0.004] (
Fig. 1b). Soluble
IL-2R levels were not correlated with cardiac risk factors,
clinical pattern, previous myocardial infarction, number of
vessels affected at coronary angiography, CRP, or IL-1Ra plasma
levels. Prevalence of LVD among patients with sIL-2R levels
above median was significantly greater vs. the others in the
entire population [53 vs. 17%, RR 3.68 (1.19–11.42);
P=0.024](
Fig. 2a)
and particularly in the subgroup of patients aged 60 or younger
[67 vs. 0%,
P=0.002] (
Fig. 2b).
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Fig. 1 (a) In patients with coronary artery disease, sIL-2R levels correlate significantly with left ventricular function, expressed as left ventricular ejection fraction (LVEF) (R=–0.3; P=0.03). Patients with depressed LVEF have significantly higher levels compared to the others (solid bar indicates median value and the box shows the interquartile range). (b) The correlation between sIL-2R levels and LVEF is particularly evident in patients younger than 60 (R=–0.6; P=0.005). sIL-2R=Interleukin-2 soluble receptor; LVEF=left ventricular ejection fraction.
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5. Conclusion
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Activated T-cells release IL-2 and a soluble form of the IL-2
receptor, consisting in the
chain of the
β
complex that
constitutes the functional membrane receptor
[8]. The sIL-2R
has a low affinity for IL-2 and a still poorly defined anti-inflammatory
activity. It represents, however, a reliable marker of T-lymphocyte
activation
[8]. Selective elevation of sIL-2R in mild ischaemic
LVD suggests activation and, hence, involvement of antigen-specific
T-lymphocytes in this condition. In contrast to NYHA class III–IV
CHF, mild phases of the disease (class I–II) constitute
a fairly asymptomatic condition, well tolerated by the patients
although irreversibly associated with myocardial damage and
progression of the disease. Inflammatory cytokines (e.g. TNF-
)
and Brain-type Natriuretic Peptide (BNP) plasma levels were
found to be very useful markers in severe disease or in acute
decompensation of chronic CHF, while they offer minimal help
in the detection of its earlier stages
[6,
7,
9,
10]. In turn,
elevated CRP levels are considered unfavorable prognostic factors
in ischaemic heart disease in regard to acute events. Of note,
neither CRP nor IL-1Ra levels, CAD extent on angiography, or
prior myocardial infarction correlated with plasma sIL-2R levels
or with the presence of LVD in these patients. Hence, T-lymphocyte
activation appears to be independent from classic clinical predictors
and independent from the acute phase reaction. Further studies
are required to confirm our data, which suggest a role of T-lymphocytes
in promoting LVD and to evaluate the potential diagnostic value
of elevated plasma sIL-2R levels. Consistent with our findings,
elevated sIL-2R levels were found in idiopathic dilated cardiomyopathy
[11] and associated with a worse prognosis
[12].
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1. Background
2. Aim of the...