European Journal of Heart Failure 2005 7(1):109-112; doi:10.1016/j.ejheart.2004.03.006
© 2004 European Society of Cardiology
Short-term prognostic value of initial serum levels of interleukin-10 in patients with acute myocarditis
Koichi Fuse*,
Makoto Kodama,
Yuji Okura,
Masahiro Ito,
Kiminori Kato,
Haruo Hanawa and
Yoshifusa Aizawa
Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences 1-754 Asahimachi-dori, Niigata City 951-8510, Japan
* Correspondence author. Pressent address: Toronto General Hospital, 3R-408 Max Bell Research Centre, 101 College Street, Toronto, Ontario, Canada M5G1L7. Tel.: +1-416-340-3705; fax: +1-416-595-9592. E-mail address: fuse{at}kd6.so-net.ne.jp
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Abstract
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The disease course of acute myocarditis has a wide spectrum
and the predictors of the prognosis in patients with acute myocarditis
have not yet been established. In the pathogenesis of myocarditis,
the cytokine environment is important. In this study, we examined
the predictive values of serum levels of interleukin-10 (IL-10)
and IL-12 in the short-term prognosis of patients with acute
myocarditis. Twenty-four consecutive patients who had been diagnosed
as having acute active myocarditis were analyzed and monitored
for 2 months. The patients with myocarditis were divided into
the survival group (
n=16) and the non-survival group (
n=8).
Initial serum levels of IL-10 (
P=0.0015) and IL-12 (
P=0.012)
in the non-survival group were significantly higher than those
of the survival group, and there was a significant correlation
between IL-10 and IL-12 levels (
P<0.0001). The univariate
analyses showed that increased serum levels of IL-10 (hazard
ratio 1.041,
P=0.0004) and IL-12 (hazard ratio 1.128,
P=0.0346)
were significant predictors of mortality. In the Kaplan–Meier
analysis, high levels of IL-10 (
7.0 pg/ml) (
P=0.0239) strongly
predicted high mortality. In conclusion, the elevation in serum
IL-10 levels at the initial phase appeared to predict poor short-term
prognosis in patients with acute myocarditis.
Key Words: Myocarditis • Prognosis • Interleukin-10 • Interleukin-12 • Th1/Th2
Received October 5, 2003; Revised January 20, 2004; Accepted March 20, 2004
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1. Background
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The disease course of acute myocarditis has a wide spectrum
and it is difficult to predict the prognosis
[1–
6]. Recently,
it has been reported that cytokine environment, especially helper
T type 1 (Th1) and helper T type 2 (Th2) balance is important
in the pathogenesis of myocarditis
[7–
10]. We also reported
that Th1/Th2 balance of peripheral lymphocytes reflected the
disease activity in a patient with acute myocarditis
[11]. It
is important that the estimation of the disease activity of
acute myocarditis, which is on going stage or healing stage
at the initial stage, when predicting a prognosis and performing
suitable treatment.
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2. Aims
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In this study, we measured initial serum levels of Interleukin-10
(IL-10), which is anti-inflammatory Th2 cytokine, and IL-12,
which develops the precursor Th cells to Th1 cells and inhibits
the differentiation of Th2 cells, from the patients with histopathology-proven
acute myocarditis and investigated the predictive values in
the short-term outcome.
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3. Methods
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Samples were obtained from 24 patients with biopsy or autopsy-proven
active myocarditis (Dallas criteria). These patients included
17 men and seven women ranging from 15 to 70 years (mean, 49±4
years) and were divided into the survival group (those who could
be discharged from the hospital) and the non-survival group
(those who died during hospitalization). Hemodynamic study was
performed in all patients at the time of hospitalization and
nine patients were treated with percutaneous cardiopulmonary
support (PCPS). Each sample was collected at the time of hospitalization
and was frozen at –80 °C. Serum levels of IL-10 and
IL-12 were determined by enzyme-linked immunosorbent assay kits
(Biosourse International, CA, USA). Informed consent was obtained
from all patients and the protocol was approved by the local
ethics committee on clinical research of our institution.
Statistical comparisons of parameters between both groups were analyzed by the Mann–Whitney's U-test. Univariate Cox regression analyses were used to analyze survival time until death. Correlation was investigated by means of the Spearman's rank correlation method. The Kaplan–Meier analysis was performed on the cumulative rates of survival in patients with acute myocarditis stratified into two groups on the basis of the increased serum levels of IL-10 and IL-12 ( or <7.0 pg/ml and or <4.0 pg/ml, respectively). The differences between survival curves were analyzed by the log-rank test. The values are represented as mean±standard error of mean (S.E.M.). Statistical significance was accepted at P<0.05.
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4. Results
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All patients were followed up until 60 days from the onset of
myocarditis. Eight patients died of cardiac causes during the
follow-up period (mean, 28±7 days; range, 11–59
days). Age, sex, systolic blood pressure, cardiac index (CI),
pulmonary capillary wedge pressure (PCWP) and days from onset
until blood sampling were not significantly different between
survivors and non-survivors. However, hypotension and elevation
of PCWP had a trend toward worse prognosis. Creatine phosphokinase
(CPK) and C-reactive protein (CRP), which are important biochemical
laboratory markers at the time of admission, were also not significantly
different between both groups. Serum levels of IL-10 and IL-12
in the non-survival group (38.6±11.4 pg/ml and 49.2±24.9
pg/ml, respectively) were significantly increased compared with
those of the survival group (6.8±1.1 pg/ml and 5.8±0.9
pg/ml, respectively) (
Table 1). Univariate analyses showed that
high IL-10 (
P=0.0004) and IL-12 (
P=0.0346) levels were significant
predictors of mortality (
Table 2). In the Kaplan–Meier
analysis, patients with high IL-10 levels (
7.0 pg/ml) had a
significantly higher mortality rate than those with low IL-10
levels (<7.0 pg/ml) (
Fig. 1a). However, there was no significant
difference between patients with high IL-12 levels (
4.0 pg/ml)
and those with low IL-12 levels (<4.0 pg/ml) (
Fig. 1b). In
addition, we found a significant correlation between serum levels
of IL-10 and IL-12 (
R=0.78,
P<0.0001) (
Fig. 2). However,
there was no significant correlation between IL-10 or IL-12
levels and systolic blood pressure, CI, PCWP, CPK or CRP levels
(data were not shown).
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Table 1 Comparison of characteristics, hemodynamic data and serum biochemical markers at the time of hospitalization
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5. Conclusions
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We measured serum levels of IL-10 and IL-12 in 24 patients with
acute myocarditis. IL-10 and IL-12 levels significantly increased
in the non-survival group, and a high IL-10 level was shown
to be a significant short-term predictor.
We focused on IL-10 and IL-12, which are both important to the evaluation of the cytokine environment in the pathogenesis of myocarditis. Previous reports have suggested the therapeutic effect of IL-10 [10,12] and IL-12 [13] in experimental myocarditis models. Meanwhile, cardiac myosin and specific T-lymphocytes can induce experimental autoimmune myocarditis when cultured with IL-12 [14]. We hypothesized that the high levels of Th1 cytokine relate to the mortality and high levels of Th2 cytokine causing a spontaneous remission. However, unexpectedly the high levels of IL-10 related to the mortality in our study. On the other hand, some studies have suggested that vigorous initial immune responses have a long-term beneficial effect in patients with myocarditis [2,15]. In human myocarditis, the duration from viral infection until onset of cardiac symptoms and the timing of the shift from Th1 dominance to Th2 dominance are still not clear. The elevated serum IL-10 levels may possibly reflect the initial amount of virus in acute myocarditis. Furthermore, exogenous delivery of IL-10 may be useful especially in the patients with myocarditis that show high levels of IL-10.
The limitations of this study are the small number of patients, and the lack of multivariate analyses. We also need to perform multi-point analyses. Despite those limitations, our study suggests that elevation of initial serum IL-10 levels appeared to be a good serological marker to predict the short-term prognosis in acute myocarditis.
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Abstract
1. Background
, Survivors; 
, Non-survivors.