Download Serum Levels of the Interleukin-1 Receptor Family

Serum Levels of the Interleukin-1 Receptor Family Member
ST2 Predict Mortality and Clinical Outcome in Acute
Myocardial Infarction
Masahisa Shimpo, MD, PhD; David A. Morrow, MD, MPH; Ellen O. Weinberg, PhD;
Marc S. Sabatine, MD, MPH; Sabina A. Murphy, MPH; Elliott M. Antman, MD; Richard T. Lee, MD
Downloaded from http://circ.ahajournals.org/ by guest on August 3, 2017
Background—Mechanically overloaded cardiomyocytes secrete a soluble interleukin-1 receptor family member called
ST2. Serum levels of ST2 are associated with prognosis in nonischemic heart failure, but the predictive value of ST2
in patients with acute myocardial infarction is unknown.
Methods and Results—ST2 levels were measured in serum from 810 patients with acute myocardial infarction in the
Thrombolysis In Myocardial Infarction (TIMI) 14 (362 patients) and Enoxaparin and TNK-tPA With or Without
GPIIb/IIIa Inhibitor as Reperfusion Strategy in STEMI (ENTIRE)-TIMI 23 (448 patients) clinical trials. Baseline levels
of ST2 were significantly higher in those patients who died (0.379 versus 0.233 ng/mL, P⫽0.0001) or developed new
congestive heart failure (0.287 versus 0.233 ng/mL, P⫽0.009) by 30 days. In an analysis of outcomes at 30 days by ST2
quartiles, both death (P⫽0.001) and the combined death/heart failure end point (P⫽0.001) showed a significant graded
association with levels of ST2; furthermore, in-hospital death (P⫽0.003) and death/heart failure (P⫽0.004) were also
significantly associated with higher ST2 levels. In a logistic regression analysis that controlled for important clinical
factors, increasing levels of ST2 remained associated with death at 30 days (P⫽0.047). ST2 levels rose during the first
day after infarction and were maximal at 12 hours; ST2 levels at 12 hours were also independently associated with death
at 30 days (P⬍0.001).
Conclusions—Serum levels of the interleukin-1 receptor family member ST2 predict mortality and heart failure in patients
with acute myocardial infarction. These data suggest that ST2 may be a useful biomarker and that this novel
inflammatory receptor may play a role in cardiac pathophysiology. (Circulation. 2004;109:2186-2190.)
Key Words: myocardial infarction 䡲 prognosis 䡲 receptors 䡲 interleukins
T
The relationship between this novel interleukin-1 receptor
family member and clinical outcomes in acute myocardial
infarction is undefined. Thus, the present study was designed
to test the hypothesis that serum ST2 levels are associated
with the risk of death or heart failure in patients presenting
with ST-elevation myocardial infarction (STEMI). To do this,
we measured ST2 levels in serum from patients with STEMI
enrolled in the Thrombolysis in Myocardial Infarction (TIMI)
14 and Enoxaparin and TNK-tPA With or Without GPIIb/IIIa
Inhibitor as Reperfusion Strategy in STEMI (ENTIRE)-TIMI
23 trials.
he ST2 gene (also known as T1, IL1RL1, or Fit1) is a
member of the interleukin-1 receptor host defense/inflammation family.1,2 The protein product of ST2 encodes a
transmembrane receptor form (ST2L) and a truncated soluble
receptor form (ST2) that can be detected in human serum.3,4
Although ST2 is an orphan receptor (ligand currently unknown), it is known that ST2 directs Th2 lymphocyte
function.5 Genomic technology was used to identify ST2 as a
gene markedly induced in mechanically overloaded cardiac
myocytes.6,7 This suggests that ST2 is induced in conditions
of myocardial overload such as myocardial infarction, when
the remaining viable myocardium must bear more stress.
Indeed, soluble ST2 levels are increased in the serum of
patients 1 day after myocardial infarction.6 Furthermore, ST2
serum levels predict outcome in patients with heart failure,
and a change in ST2 over time is also associated with
prognosis.7 These data suggest that measurement of serum
levels of ST2 may provide insight into the hemodynamic
burden of the myocardium.
Methods
Study Populations
The TIMI 14 trial was a randomized, open-label, dose-ranging study
of combination reperfusion therapy for patients with STEMI conducted between March 1997 and July 1998. Specifically, this study
was an angiographic trial that evaluated several combinations of
fibrinolytic with the glycoprotein IIb/IIIa antagonist abciximab.8,9
Received July 28, 2003; de novo received December 15, 2003; revision received February 9, 2004; accepted February 10, 2004.
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Brigham and Women’s Hospital has filed for a patent on ST2, with Dr Lee as inventor.
Correspondence to Richard T. Lee, MD, Cardiovascular Division, Brigham and Women’s Hospital, 65 Landsdowne St, Cambridge, MA 02139. E-mail
[email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000127958.21003.5A
2186
Shimpo et al
TABLE 1.
ST2 and Myocardial Infarction
2187
Baseline Clinical Characteristics According to Quartiles of ST2
Range, ng/mL
n
Quartile 1
Quartile 2
Quartile 3
Quartile 4
0.085–0.179
0.180–0.235
0.236–0.346
0.347–6.88
204
202
202
Ptrend
P Q4 vs Q1
⬍0.0001
⬍0.0001
202
Time from chest pain to randomization, h
2.8⫾1.6
3.1⫾1.5
3.2⫾1.4
4.0⫾1.9
Age, y
58⫾10
58⫾10
58⫾11
58⫾10
0.9
1.0
Male, %
74
77
85
81
0.03
0.09
White, %
88
89
90
88
0.9
1.0
25
24
36
33
0
0
Angina
26
24
26
Diabetes
14
14
15
Family history of CAD
73
73
Hypercholesterolemia
22
Current smoker
57
Past medical history, %
Hypertension
Congestive heart failure
0.02
0.09
0.1
0.2
32
0.3
0.2
16
0.9
0.5
73
73
0.2
0.08
21
21
29
0.2
0.1
48
49
48
0.2
0.06
1.5
1.0
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Physical findings
Weight, kg
Systolic BP, mm Hg
Heart rate, bpm
Killip class II through IV, %
83⫾16
81⫾15
82⫾14
83⫾15
0.4
0.8
139⫾21
138⫾22
142⫾23
143⫾22
0.1
0.05
71⫾17
74⫾17
72⫾16
80⫾18
2.0
1.5
3.6
4.5
0.001
0.3
⬍0.0001
0.2
Diagnostic testing
cTnI ⬎0.1 ng/mL,* %
9
BNP ⬎80 pg/mL,* %
1.8
5.4
CRP ⬎1.5 ng/mL, %
2.1
8.8
1.0⫾0.21
1.0⫾0.20
Creatinine, mg/dL
Anterior myocardial infarction, %
23
26
0.001
7.2
14.4
0.003
0.001
8.1
11.4
0.006
⬍0.0001
1.0⫾0.25
1.1⫾0.28
28
33
36
42
48
55
45
50
Extent of CAD (50% stenosis), %
1 vessel
2 vessel
38
28
34
30
3 vessel
15
18
20
20
58⫾14
58⫾15
57⫾15
57⫾14
Ejection fraction,† %
⬍0.0001
56
0.1
0.03
0.035
0.004
0.3
0.2
1.0
0.9
Q4 indicates quartile 4; Q1, quartile 1; CAD, coronary artery disease; and BP, blood pressure.
*Measured in the ENTIRE-TIMI 23 population only; n⫽448, except †n⫽469.
The ENTIRE-TIMI 23 trial was an open-label, dose-ranging, multicenter study conducted between February 2000 and September 2001
to evaluate enoxaparin as adjunctive antithrombin therapy with
various forms of pharmacological reperfusion, including full-dose
tenecteplase and half-dose tenecteplase plus abciximab.10 In both
studies, patients were eligible for inclusion if they had a qualifying
episode of ischemic discomfort of at least 30 minutes within 6 hours
(ENTIRE) or 12 hours (TIMI 14) and exhibited at least 0.1-mV
ST-segment elevation in 2 contiguous ECG leads. Exclusion criteria
for both trials included increased risk of hemorrhage, severe renal
insufficiency, and cardiogenic shock.
anti-human ST2 antibody was added into the microwell and incubated. After a second washing, the peroxidase substrate was added,
and the optical density at 450 nm was determined. High-sensitivity
C-reactive protein (hs-CRP, Dade-Behring Inc), creatine kinase-MB
isoenzyme (CK-MB), B-type natriuretic peptide (BNP, Shionoria
BNP), and cardiac troponin I (cTnI; ACS:180, Bayer Diagnostics)
were measured by previously described methods.11–13 Creatine
kinase isoenzyme levels were measured locally at the enrolling site
on admission, at 3 hours, and at 6- to 8-hour intervals for the first 24
hours. Because of sample availability limitations, BNP levels were
measured in samples from ENTIRE-TIMI 23 but not TIMI 14.
Laboratory Analyses
Statistical Analysis
Serum samples collected at baseline and 1, 3, 12, and 24 hours after
enrollment in TIMI 14 were evaluated. Serum samples from the
ENTIRE-TIMI 23 trial were collected only at baseline. Serum was
isolated within 60 minutes of sample collection and stored at ⫺20°C
or colder until shipped to the TIMI Biomarker Core Laboratory
(Boston, Mass), where samples were maintained at ⫺70°C. Soluble
ST2 was measured by a sandwich double monoclonal antibody
ELISA method (Medical & Biological Laboratories Co, Ltd). Serum
samples or standards were incubated in microwells coated with
anti-human ST2 antibody. After washing, peroxidase-conjugated
Patients were divided into quartiles on the basis of their serum levels
of ST2 at the time of enrollment. ST2 levels are described with the
median and 25th and 75th percentiles. The association between
baseline clinical characteristics and quartiles of ST2 were analyzed
with the Kruskal-Wallis test for continuous variables and the ␹2 test
for categorical variables. Correlations between ST2 and other continuous baseline variables were studied with a nonparametric (Spearman) correlation coefficient. For evaluation of association with
clinical outcomes, ST2 was compared between patients who met a
study end point and those who did not with the Wilcoxon rank-sum
2188
Circulation
TABLE 2.
Correlation Between ST2 and Continuous Variables
Variable
May 11, 2004
Spearman’s r
P
0.29
⬍0.0001
Time from chest pain to
randomization, h
Age, y
Weight, kg
⫺0.003
0.9
0.01
0.8
Heart rate, bpm
0.15
⬍0.0001
CK-MB peak
0.08
0.02
TABLE 3. Association Between Baseline ST2 Concentration
and Outcomes
Outcome (30 Days)
Dead
28
0.379 (0.267, 0.611)
Alive
782
0.233 (0.178, 0.340)
Recurrent MI
No MI
cTnI*
0.26
⬍0.0001
CRP
0.10
0.007
CHF
BNP*
0.068
0.15
No CHF
Creatinine
0.09
0.01
Death/CHF
⫺0.005
0.9
No death/CHF
LVEF†
CAD indicates coronary artery disease; LVEF, left ventricular ejection
fraction.
*Measured in the ENTIRE-TIMI 23 population only; n⫽448, except †n⫽469.
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test. Multivariate analysis of the association of ST2 (continuous
variable) with outcomes was performed with logistic regression that
included terms for established predictors of mortality in STEMI.14
Except where stated, results presented are for the combined TIMI 14
and ENTIRE-TIMI 23 study population.
Results
Baseline ST2 and Clinical Variables
Most baseline clinical characteristics, including gender, age,
weight, and extent of coronary artery disease, did not correlate with baseline ST2 levels (Table 1). Few patients in this
population had either a prior history of or presented with
clinical evidence of heart failure. Heart rate (P⬍0.0001) and
systolic blood pressure (P⫽0.05) were associated with ST2
levels, consistent with the theory that ST2 is secreted by
cardiac myocytes under biomechanical stress. Patients with
the highest levels of ST2 were more likely to have presented
with an anterior myocardial infarction (P⫽0.035) and to
present later after chest pain onset (P⬍0.0001). The biomarkers cTnI, BNP, and CRP, which have all been shown to
predict outcome after myocardial infarction,13,15,16 were correlated with ST2 by quartile analysis and, with the exception
of BNP, showed statistically significant but quantitatively
weak correlations when evaluated as continuous variables
(Table 2).
n
Median
(25th, 75th Percentiles),
ng/mL
29
0.213 (0.171, 0.259)
781
0.237 (0.181, 0.348)
21
0.287 (0.237, 0.470)
789
0.233 (0.178, 0.345)
47
0.317 (0.246, 0.590)
763
0.231 (0.177, 0.339)
P
0.0001
0.11
0.009
⬍0.0001
MI indicates myocardial infarction; CHF, congestive heart failure.
events was homogeneous between the 2 individual trials
(TIMI 14 and ENTIRE-TIMI 23, P for heterogeneity⫽0.8).
Evolution of ST2 Serum Levels
Baseline ST2 levels analyzed by quartile were significantly
correlated with the time to randomization (Tables 1 and 2).
This was not surprising, because on the basis of our prior
studies, ST2 levels are anticipated to increase on the first day
after coronary occlusion and to return to normal over the next
14 days.6 Among the TIMI 14 patients, analysis of serial
measurements of serum ST2 in 228 patients revealed an
increase with time, with most patients reaching a peak ST2
level at 12 hours (Figure 2).
Multivariate Analysis
After controlling for established clinical predictors in STEMI,
including age, heart rate, systolic blood pressure, location of
myocardial infarction, Killip class, and time from onset of
chest pain, increasing levels of ST2 (per 1-ng/mL rise)
remained an independent predictor of death at 30 days (OR
1.77, 95% CI 1.01 to 3.12; P⫽0.047). Data on ST2 and 3
established biomarkers (BNP, hs-CRP, and cTnI) were available in ENTIRE-TIMI 23. In this data set, mortality through
30 days showed a significant association with quartiles of
cTnI (quartiles 1 through 4, respectively: 0%, 2.7%, 2.7%,
and 7.9%; P⫽0.009) and BNP (quartiles 1 through 4, respec-
ST2 and Clinical Outcomes
For the combined cohort of 810 patients, baseline ST2 was
significantly associated with clinical outcomes at 30 days
(Table 3). Specifically, levels of ST2 were significantly
higher at presentation among patients who subsequently died
(P⫽0.0001) or who developed new or worsening congestive
heart failure (P⫽0.009) by 30 days after enrollment. Dichotomized at the median, elevated baseline levels of ST2 were
indicative of higher mortality through 30 days of follow-up
(log-rank P⫽0.0009; Figure 1). Moreover, in an analysis by
quartiles of ST2, the risk of death (P⫽0.001) and the
composite of death or congestive heart failure (P⫽0.001)
increased in a graded, stepwise fashion with higher levels of
ST2 (Table 4). This association between ST2 and clinical
Figure 1. Probability of death through 30 days after presentation with STEMI by serum ST2 level at baseline (ST2 less than
median and ST2 greater than or equal to median).
Shimpo et al
TABLE 4.
ST2 and Myocardial Infarction
2189
Association Between Baseline ST2 Quartiles and Outcomes
Outcome
Quartile 1,
%
Quartile 2,
%
Quartile 3,
%
Quartile 4,
%
Ptrend
P Q4
vs Q1
In-hospital
Death
0.98
1.5
3.0
6.4
0.0008
0.003
Recurrent MI
4.4
3.5
0.5
1.5
0.02
0.07
Death/CHF
2.5
4.0
6.4
8.9
0.002
0.004
30-Day
Death
0.98
1.5
4.0
7.4
0.0001
0.001
MI
5.4
4.5
2.5
2.0
0.04
0.1
CHF
1.5
3.0
5.5
4.0
0.08
0.1
Death/CHF
2.5
4.0
8.9
10.4
0.0002
0.001
MI indicates myocardial infarction; CHF, congestive heart failure.
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tively: 0.6%, 1.4%, 0.9%, and 10.7%; P⬍0.001) but not
hs-CRP (quartiles 1 through 4: 4.4%, 1.8%, 1.8%, and 5.4%;
P⫽0.3). The association between ST2 and mortality was no
longer significant when BNP and cTnI were added to the
clinical model (limited to ENTIRE-TIMI 23). The predictive
capacity of ST2 ascertained at later time points (3 and 12
hours in TIMI 14) was also evaluated and revealed a similar
association between ST2 at 12 hours and mortality risk (OR
1.27, 95% CI 1.10 to 1.47; P⫽0.001). In multivariate analysis
that included each of the clinical factors (age, heart rate,
systolic blood pressure, location of myocardial infarction,
Killip class, and time from onset of chest pain) and TIMI flow
grade in the infarct-related artery, ST2 remained independently associated with mortality (P⬍0.01).
Discussion
In the present study, we explored the potential role of serum
measurement of a recently identified receptor of the
interleukin-1 family in acute myocardial infarction. The
soluble form of this receptor is rapidly secreted by cardiac
myocytes when the cells are biomechanically overloaded; this
suggests that the receptor may play a role in conditions in
which the myocardium is suddenly overloaded, such as in
myocardial infarction. To explore this, we measured serum
ST2 levels at the time of presentation in a cohort of patients
with ST-elevation myocardial infarction. The results demonstrate that levels of ST2 at the time of presentation with
STEMI are associated with in-hospital and 30-day mortality.
Furthermore, multivariate analysis demonstrated that ST2
level is independently associated with outcome after controlling for established clinical risk indicators in STEMI.
The significance of these data is twofold. Foremost, these
data suggest that the interleukin-1 receptor family, which
participates in host defense and differentiation of T cells,1
may participate in early events in acute myocardial infarction.
These data support further investigation of this receptor as a
potential novel target for modifying prognosis in patients
with myocardial infarction. Secondarily, ST2 represents a
novel biomarker that offers prognostic information in patients
with acute myocardial infarction that is independent of
clinical predictors. The present report extends our prior work
demonstrating an association between ST2 and mortality
among patients with nonischemic congestive heart failure,7
another condition of myocardial overload.
The mechanisms of induction and regulation of ST2
expression in acute myocardial infarction are not known. The
mechanical overload may induce ST2, but in addition, proinflammatory cytokines from damaged tissues may activate
neighboring cells to produce ST2. ST2 has been shown to
regulate the expression of proinflammatory cytokines from
Figure 2. Evolution of ST2 serum levels over 24
hours after presentation for acute myocardial
infarction. Each line represents 1 of 228 patients in
TIMI 14 study who had serum samples available at
all 5 time points. Peak values occurred at 12 hours
in most patients, although some patients with particularly high levels had peak values at 24 hours.
2190
Circulation
May 11, 2004
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macrophage, which may serve to prevent uncontrolled inflammatory reactions. It has also been shown that ST2
released in response to stress or injury can contribute toward
the polarization of T helper cells to the Th2 phenotype.
Myocardial infarction is associated with humoral (eg, cytokines and reactive oxygen species) and cell-mediated (eg,
neutrophils and mononuclear cells) inflammatory reactions,
which are a prerequisite for healing and scar formation. ST2
may contribute to this process, which can affect prognosis.
Although not excluded by the present study, it is unlikely
that the relationship of ST2 and outcome after myocardial
infarction is simply a reflection of the association of chronic
elevations in inflammatory markers such as CRP and risk of
myocardial infarction. ST2, like BNP, may be synthesized by
cardiac myocytes themselves, and data from patients without
apparent ischemic disease suggest that ST2 predicts prognosis in the absence of coronary artery disease. Furthermore,
preliminary data suggest that ST2 levels in outpatients with
stable coronary artery disease are unrelated to CRP levels
(unpublished observations). Moreover, ST2 showed only a
very modest (r⫽0.10) correlation with hs-CRP in the present
data set. Although the present data support the complementary value of ST2 for risk assessment when added to a robust
clinical model, ST2 did not contribute additional information
to BNP and cTnI in the smaller data set limited to ENTIRETIMI 23. Notably, levels of ST2 were only weakly correlated
with a measure of myonecrosis (cTnI) and were not associated with the plasma concentration of BNP, which suggests
that ST2 reflects pathophysiology distinct from these established biomarkers. Additional studies are necessary to evaluate carefully the prognostic value of ST2 in conjunction with
other available biomarkers. The study end points of TIMI 14
and ENTIRE-TIMI 23 were predetermined to be 30 days after
enrollment, and thus longer-term follow-up was not available.
Although ST2 may be secreted by mechanically overloaded cardiac myocytes, many cells can secrete ST2. Thus,
elevations in serum ST2 are not specific for acute myocardial
infarction. In addition to nonischemic heart failure,7 patients
with asthma17 or autoimmune diseases such as systemic lupus
erythematosus18 may also have increased serum ST2 levels.
Thus, ST2 measurement is unlikely to be useful in the initial
diagnosis of myocardial infarction. However, ST2 levels
correlate inversely with ejection fraction in patients with
nonischemic heart failure,7 and additional studies with serial
evaluations of ventricular function are necessary to determine
whether the source of ST2 in patients with myocardial
infarction is the overloaded myocardium.
These data lend validity to the concept that genomic
technology can reveal a new potential pathophysiological
pathway in a common disease. ST2 was identified initially
through studies of the interleukin-1 family, but its role in
myocardial disease was only recently suggested by genomic
studies with DNA microarrays. Studies with DNA microarrays allow identification of potential new disease pathways,
but this is only an initial step in understanding the role of the
pathway. The association between ST2 and outcome in the
present study now provides important data that support a role
for ST2 in acute myocardial infarction. However, additional
studies of the function of ST2 in myocardial infarction are
needed. Furthermore, the ligand for the soluble and membrane ST2 receptors remains unidentified, and understanding
the potentially competing roles of the membrane and soluble
receptors will require identification of the ligand.
Acknowledgments
This study was supported in part by grants from the National Heart,
Lung, and Blood Institute. Dr Shimpo was supported in part by Japan
Heart Foundation/Bayer Yakuhin Research Grant Abroad, the Cell
Science Research Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research.
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Serum Levels of the Interleukin-1 Receptor Family Member ST2 Predict Mortality and
Clinical Outcome in Acute Myocardial Infarction
Masahisa Shimpo, David A. Morrow, Ellen O. Weinberg, Marc S. Sabatine, Sabina A. Murphy,
Elliott M. Antman and Richard T. Lee
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Circulation. 2004;109:2186-2190; originally published online April 26, 2004;
doi: 10.1161/01.CIR.0000127958.21003.5A
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Copyright © 2004 American Heart Association, Inc. All rights reserved.
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