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Clinical and Prognostic Significance of sST2 in Heart Failure
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 74, NO. 17, 2019
ª 2019 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
THE PRESENT AND FUTURE JACC REVIEW TOPIC OF THE WEEK
Clinical and Prognostic Significance of sST2 in Heart Failure JACC Review Topic of the Week Alberto Aimo, MD,a James L. Januzzi, JR, MD,b Antoni Bayes-Genis, MD, PHD,c Giuseppe Vergaro, MD, PHD,a,d Paolo Sciarrone, MD,d Claudio Passino, MD,a,d Michele Emdin, MD, PHDa,d
ABSTRACT Soluble suppression of tumorigenesis-2 (sST2) is released in response to vascular congestion and inflammatory and profibrotic stimuli, and is a strong, independent predictor of mortality and heart failure (HF) hospitalization in patients with acute or chronic HF. sST2 meets 2 fundamental criteria for clinically useful biomarkers: accurate, repeated measurements are available at a reasonable cost, and the biomarker provides information not already available from a careful clinical assessment. In particular, the prognostic value of sST2 is additive to natriuretic peptides and (in the case of chronic HF) to high-sensitivity troponin T. Nevertheless, the need for a multibiomarker approach to risk stratification and the role of sST2 as a guide to therapy decision-making remain to be established. Four years after a consensus document on sST2, and following major advances in the comprehension of the clinical value of this biomarker, the authors felt it worthwhile to reappraise current knowledge on sST2 in HF. (J Am Coll Cardiol 2019;74:2193–203) © 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.
L
aboratory diagnostics plays a major role in the
biomarkers, a growing body of evidence points to
diagnosis, risk stratification, therapy decision-
the clinical relevance of soluble suppression of
making, and monitoring of patients with heart
tumorigenesis-2 (sST2), which was first classified as
failure (HF). As proposed by Dr. Braunwald, bio-
an indicator of myocyte stress (1), but is mainly pro-
markers of HF can be classified according to the
duced in extracardiac tissues (2–4) in response to in-
main pathophysiological determinant of circulating
flammatory and fibrotic stimuli (5). Four years after
concentrations: inflammation, oxidative stress, extra-
the publication of a Consensus Document dedicated
cellular matrix remodeling, neurohormones, myocyte
to sST2 (6), and following major advances in our
injury, and myocyte stress (1). The most established
comprehension of the clinical value of this biomarker,
biomarkers are natriuretic peptides and troponins,
we update current knowledge on sST2 in HF with a
reflecting hemodynamic overload and cardiomyocyte
particular focus on its main application, that is,
damage, respectively. Besides these cardiac-specific
outcome prediction.
From the aInstitute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; bMassachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts; cHospital Universitari Germans Trias i Pujol, Badalona (Barcelona), CIBERCV, Listen to this manuscript’s
Barcelona, Spain; and the dCardiology Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy. Dr. Januzzi is supported
audio summary by
in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from
Editor-in-Chief
Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex, and Prevencio; has received consulting income from Abbott,
Dr. Valentin Fuster on
Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Critical Diagnostics; and participates in Clinical Endpoint Committees/
JACC.org.
Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. Dr. Bayes-Genis has received grant support from Roche Diagnosis; has received lecture honoraria from Roche Diagnostics and Critical Diagnostics; and has received consulting income from Roche Diagnostics, Critical Diagnostics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. David A. Morrow, MD, served as Guest Associate Editor for this paper. Manuscript received June 27, 2019; revised manuscript received August 7, 2019, accepted August 31, 2019.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2019.08.1039
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sST2 in Heart Failure
sST2 BIOLOGY
ABBREVIATIONS
HIGHLIGHTS
AND ACRONYMS
In 1989, ST2 was first identified by 2 inde-
HF = heart failure
pendent laboratories working on growth-
hs-TnT = high-sensitivity
stimulated fibroblasts (7,8). The definition
troponin T
“suppression of tumorigenesis” derives from
IL = interleukin LV = left ventricle/ventricular NT-proBNP = N-terminal
the hypothesis that ST2 might blunt uncontrolled cell proliferation; the researcher Shinichi Tominaga had previously identified
fragment of pro-brain natriuretic peptide
another protein called ST1 (9). Since the first
sST2 = soluble suppression of
description of ST2, it was noted that it
tumorigenesis-2
sST2 is released in response to vascular congestion, inflammatory, and profibrotic stimuli. sST2 is a strong predictor of outcome in HF. The prognostic value of sST2 in HF is additive to natriuretic peptides.
had structural similarity to interleukin (IL)-1
variation at the gene locus predominantly regulates
receptors (7); hence, its alternative definition: “IL-1
ST2 expression (15). While ST2L is constitutively
receptor like-1.” Nonetheless, the function of this
expressed primarily in hematopoietic cells (Th2 and
protein remained unclear for several years.
mast cells), the expression of sST2 is largely induced
In 2002, Weinberg et al. (10) analyzed the expression of 7,000 genes in cardiomyocytes under-
in response to mechanical stretch and to inflammatory and pro-fibrotic stimuli (5).
going mechanical strain, and found that ST2 mark-
The major source of circulating sST2 in patients
edly increased as a response to this stimulus. In the
with HF has not been fully established, although
following years, IL-33 was identified as the ligand of
extracardiac production seems predominant: sST2
ST2 (11). IL-33 is mainly expressed by stromal cells
levels in HF are 10% higher in the peripheral venous
(fibroblasts, smooth muscle, epithelial, and endo-
blood, compared with the coronary sinus (2), and
thelial cells) (5), and signals to local immune cells the
there is no evident myocardial gradient of sST2 (16).
presence of tissue damage after exposure to patho-
Furthermore, in HF with preserved ejection fraction,
gens, injury-induced stress, or necrotic death (5).
sST2 concentrations are associated with systemic
Within the heart, IL-33 inhibits cardiomyocyte hy-
inflammation, right ventricular dysfunction, and
pertrophy and fibrosis in response to stimuli such as
systemic congestion, but not with indexes of left
angiotensin-II or phenylephrine, both in isolated
ventricular (LV) morphology or function (3,17). The
cardiomyocytes and in the murine model (12),
lungs have been proposed as an important site of sST2
possibly through the modulation of nuclear factor
production in HF (4). While the mechanisms of
kappa-light-chain-enhancer of activated B cells ac-
intracellular ST2L proteolysis have been clarified (18),
tivity (5,12). Furthermore, IL-33 reduces apoptosis by
to our knowledge the sites of degradation of sST2 and
induction of antiapoptotic factors and suppression of
the specific proteases involved have not been eluci-
caspase-3
dated so far.
activity
(13).
IL-33
exerts
these
car-
dioprotective effects by binding ST2-ligand (ST2L), which is a receptor expressed on plasma membrane
sST2 ASSAYS
of cardiomyocytes and fibroblasts, containing an extracellular domain of 3 linked immunoglobulin-
The assay methods for sST2 are thought to measure
like motifs, a transmembrane segment, and an
both free sST2 and sST2 complexed with IL-33,
intracellular Toll/IL-1 receptor cytoplasmic domain.
although it is not clear which epitopes are detected
sST2 is a circulating form of this receptor, which
by the antibodies against sST2 used for the different
lacks the transmembrane and cytoplasmic domains
methods (19). Among the 4 main ELISA assays (Pres-
and acts as a decoy receptor for IL-33 (5,12) (Central
age assay, Critical Diagnostics, San Diego, California;
Illustration).
MBL International, Woburn, Massachusetts; Ray
The gene named ST2 is located on human chro-
Biotech, Peachtree Corners, Georgia; R&D, Minneap-
mosome 2q12 and is part of the larger IL-1 gene clus-
olis, Minnesota), the Presage is the only one that has
ter. The ST2 gene has a proximal and a distal
received the Conformitè Européenne Mark and has
promoter; alternative promoter splicing and 3ʹ pro-
been cleared by the U.S. Food and Drug Administra-
cessing of the mRNA are believed to account for the
tion. Assay automation is expected in the near future,
production of either sST2 or ST2L (5,14). The mecha-
and should reduce dosage times considerably. As
nisms regulating the expression of sST2 and ST2L
established for the Presage assay, sST2 concentra-
have not been clarified (5), however common genetic
tions appear to be independent of fasting status,
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sST2 in Heart Failure
C ENTR AL I LL U STRA T I O N Biology and Clinical Application of Suppression of Tumorigenesis-2
Aimo, A. et al. J Am Coll Cardiol. 2019;74(17):2193–203.
Soluble suppression of tumorigenesis-2 (sST2) is produced mostly by alveolar cells and vessel wall cells, and to a lower extent by cardiac fibroblasts and cardiomyocytes. Interleukin (IL)-33 is released by stromal cells in cardiac and extracardiac tissues; it binds membrane suppression of tumorigenesis-2 (ST2) receptors on cardiomyocytes and cardiac fibroblasts, blunting myocardial hypertrophy and fibrosis and inhibiting cardiomyocyte apoptosis. sST2 acts as a decoy receptor for IL-33, reducing these positive effects. sST2 measurement holds prognostic significance in acute or chronic heart failure (HF). NP ¼ natriuretic peptide.
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sST2 in Heart Failure
T A B L E 1 Analytical Performance of Assays for Soluble ST2
Assay/Kit
Limit of Detection
Measurement Range
Intra-assay CV
Presage ST2 kit
1.3 ng/ml
Up to 200 ng/ml
<7%
<9%
Human ST2 ELISA kit
0.032 ng/ml
Up to 20 ng/ml
<6%
<6%
Human IL-1 R4/ST2 ELISA kit
0.002 ng/ml
Up to 1.2 ng/ml
<10%
<12%
ST2/IL-1 R4 DuoSet ELISA or Quantikine ELISA
0.005 ng/ml
Up to 2.0 ng/ml
<6%
<8%
Manufacturer
Critical Diagnostics (San Diego, California) MBL International (Woburn, Massachusetts) RayBiotech (Peachtree Corners, Georgia) R&D Systems (Minneapolis, Minnesota)
Interassay CV
Modified with permission from Mueller and Jaffe (19), 2015. CV ¼ coefficient of variation; ST2 ¼ suppression of tumorigenesis-2.
unaffected by freeze-thaw cycles, and with minimal
cardiac stretch, myocardial injury, and fibrosis; and
effects by hemolysis, lipemia, icterus, or rheumatoid
with abnormal echocardiographic parameters, but not
factor (19).
with renal function (25). Higher sST2 concentrations
The analytical characteristics of sST2 assay are
were associated with an elevated risk of incident HF
discussed in dedicated publications (19,20), and
and cardiovascular death, although the prognostic
summarized in Table 1. Notably, sST2 has a lower
significance
reference change value than B-type natriuretic pep-
NT-proBNP or both NT-proBNP and high-sensitivity
tide (BNP) or N-terminal pro–B-type natriuretic pep-
troponin T (hs-TnT) to the model (25). Among 3,428
tide (NT-proBNP) both in healthy subjects (21), and in
participants in the Framingham Heart Study, sST2
patients with chronic HF (22); therefore, variations in
levels predicted death, incident HF, and major car-
sST2 across serial measurements could reflect more
diovascular events independently from standard
closely changes in clinical status than variations in
cardiovascular risk factors, as well as from other
natriuretic peptides.
biomarkers of cardiovascular stress (growth-derived
sST2 TO DIAGNOSE HF OR PREDICT ITS DEVELOPMENT Reference values of plasma sST2 were defined by using the Presage assay on 3 cohorts of apparently healthy adult subjects: 1 European and 2 American (men: 4 to 31, 9 to 50, and 11 to 45 ng/ml; women: 2 to
resulted
attenuated
when
adding
factor-15, hs-TnI, BNP, hs-C-reactive protein) (26). In the Dallas Heart Study (n ¼ 3,294), sST2 was predictive
of
all-cause
and
cardiovascular
mortality
regardless of the presence of HF at baseline, although the predictive value for incident HF was not explored (27).
sST2 FOR RISK STRATIFICATION IN ACUTE HF
21, 7 to 33, and 9 to 35 ng/ml, respectively) (19). Additionally, data from the Framingham Heart Study
The prognostic significance of sST2 was first reported
provided important information regarding distribu-
in 2003. In a subanalysis of the PRAISE-2 (Prospective
tion and clinical correlates in a generally healthy,
Randomized
ambulatory population (23). Unlike cardiac-specific
study, conducted on 161 patients with HF and New
biomarkers such as natriuretic peptides, there is
York Heart Association functional class III or IV,
overlap among sST2 levels in healthy subjects, HF
baseline sST2 levels were correlated with natriuretic
patients, or people affected by inflammatory disor-
peptides, and their variation within 2 weeks was
ders (pneumonia, chronic obstructive pulmonary
predictive of all-cause mortality and need for heart
disease) (20). sST2 measurement is then not helpful
transplantation regardless of natriuretic peptide
to discriminate between cardiac and noncardiac dys-
levels (28). A strong prognostic value of sST2, inde-
pnea (24).
pendent from NT-proBNP, emerged in a cohort of 593
Amlodipine
Survival
Evaluation-2)
sST2 levels are lower in healthy women than men,
patients presenting at the emergency department
contrary to HF, where no significant sex-related dif-
with acute dyspnea (confirmed in the subset of 209
ferences in circulating concentrations and prognostic
patients with final HF diagnosis) (24), and in a pop-
significance of sST2 have been reported. In elderly,
ulation of 346 patients with acute HF (29). In the
community-dwelling individuals (n ¼ 3,915), circu-
latter study, mortality increased progressively with
lating sST2 was associated with older age, African-
sST2 deciles, exceeding 50% in the tenth decile; when
American race, and traditional cardiovascular risk
both ST2 and natriuretic peptides were elevated, the
factors; with other biomarkers of inflammation,
highest rates of death were observed in cumulative
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T A B L E 2 Proposed Cut-Offs of sST2 in Patients With Acute or Chronic Heart Failure and in Apparently Healthy Individuals
Study Type
N
Setting
Assay
Proposed sST2 Cut-Off (ng/ml)
Endpoints
Method for Cut-Off Selection
Original study
3,915
Elderly individuals
Presage
35
Incident HF, CV death
Cut-off previously proposed in CHF
Rehman et al. (29), 2008
Original study
346
AHF
Presage
49
All-cause death (1-yr)
Youden index
Pascual-Figal et al. (31), 2011
Original study
107
AHF
Presage
65
All-cause death
Youden index
Pascual-Figal et al. (30), 2019
Original study
316
AHF
Presage
35
All-cause death (1-yr)
Cut-off previously proposed in CHF
Original study
1,141
CHF
Presage
35
All-cause death or heart transplant
Youden index
Individual patient 4,268 data meta-analysis
CHF
Presage
28
All-cause and CV death, HF hospitalization
Youden index
First Author (Ref. #), Year
Parikh et al. (25), 2016
Ky et al. (37), 2011 Emdin et al. (40), 2018
The 35-ng/ml cut-off has been adopted by the U.S. Food and Drug Administration as a prognostic cut-off (21). AHF ¼ acute heart failure; CHF ¼ chronic heart failure; HF ¼ heart failure; sST2 ¼ soluble suppression of tumorigenesis-2.
hazard analysis (p < 0.001). In the presence of a low
increase of baseline log2-sST2: 1.30; 95% confidence
ST2 level, natriuretic peptides did not predict mor-
interval: 1.08 to 1.56; p ¼ 0.005). When repeated
tality (29). The risk threshold commonly used in
measurements were taken into account, the hazard
chronic HF (i.e., 35 ng/ml) has been evaluated in a
ratio per 1-SD increase of sST2 during follow-up was
recent study, displaying a modest prognostic perfor-
1.85 (95% confidence interval: 1.02 to 3.33; p ¼ 0.044),
mance (30); higher risk thresholds have been pro-
after adjustment for clinical factors and repeated
posed, most notably 49 (29) and 65 ng/ml (31,32)
measurements of NT-proBNP. Furthermore, ST2
(Table 2).
levels started to increase several weeks before the
Studies evaluating the prognostic significance of
occurrence of the primary endpoint (35) (Figure 1).
sST2 in acute HF have consistently reported that this
In a recent subanalysis of the PIONEER-HF (Com-
biomarker helps refine risk stratification, particularly
parison of Sacubitril/valsartan vs. Enalapril on Effect
for fatal endpoints. A meta-analysis by our group
on
showed that sST2 levels, measured both on admission
[NT-proBNP] in Patients Stabilized from an Acute HF
and at discharge, predict all-cause and cardiovascular
Episode) trial, baseline sST2 concentrations yielded
mortality. Moreover, unlike measurement at the time
prognostic significance for the composite outcome of
of admission, sST2 plasma concentration at discharge
cardiovascular
yielded prognostic significance for hospital read-
Notably, patients in the sacubitril/valsartan arm dis-
mission for HF (33).
played a greater reduction in circulating sST2 than
N-terminal
pro-brain
death
or
natriuretic
HF
peptide
rehospitalization.
The usefulness of serial sST2 measurement in
enalapril after as early as 1 week, as well as a better
acute HF has been specifically evaluated by several
outcome. sST2 levels decreased less than hs-TnT or
studies. In a population of 150 patients undergoing
NT-proBNP (6.4% vs. 15.8% and 29.4%, respectively),
daily blood sampling for sST2, percent change in ST2
possibly reflecting a lower impact of decongestion on
was strongly predictive of 90-day mortality: patients
sST2 levels than hs-TnT or NT-proBNP (36).
whose ST2 values decreased by 15.5% or more during the study period had a 7% chance of death, whereas
sST2 FOR RISK STRATIFICATION IN
patients whose ST2 levels failed to decrease by 15.5%
CHRONIC HF
in this time interval had a 33% chance of death. The prognostic value of sST2 changes was again inde-
In 2011, Ky et al. (37) performed a meta-analysis of
pendent from variations in NT-proBNP (34). In a
sST2 for prognosticating outcomes in chronic HF in 3
multicenter study from the Netherlands, 496 patients
cohorts. These results were further validated in the
with acute HF underwent repeated blood sampling
HF-ACTION (Heart Failure: A Controlled Trial Inves-
(on admission; at days 2 and 4; at discharge; after 2
tigating Outcomes of Exercise Training) cohort (38),
and 4 weeks; and at 3, 6, 9, and 12 months). After
leading to regulatory approval in the United States. In
adjustment for clinical factors and NT-proBNP, base-
2016, a much larger meta-analysis, considering
line sST2 was associated with an increased risk of the
pooled data from 7 studies and 6,372 patients, re-
primary endpoint (composite of all-cause mortality
ported that unadjusted sST2 values predict all-cause
and HF rehospitalization: hazard ratio per 1-SD
and cardiovascular mortality in chronic HF (39). The
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sST2 in Heart Failure
F I G U R E 1 Trends of sST2 and Outcome After a Hospitalization for HF
100
80 sST2 (ng/mL)
2198
60
40
20
140
120
100
80 60 Time to Event (Days)
Patients with Event
40
20
0
Patients without Event
EVENT
Soluble suppression of tumorigenesis-2 (sST2) trends and individual sST2 values during follow-up after a heart failure (HF) hospitalization are reported. Patients experiencing the “event” (all-cause death or new HF hospitalization) (blue) and those who did not (red) are distinguished. Reproduced with permission from van Vark et al. (35).
sST2 >35-ng/ml cut-off was associated with a signifi-
While galectin-3 (another biomarker of inflam-
cantly higher risk of mortality at 1 year, also when
mation and fibrosis) has been reported to be more
adjusting for several covariates (39). An analysis of
predictive than sST2 in acute HF (43), several pa-
4,268 individual patient data from 11 cohorts found
pers suggest that sST2 holds superior prognostic
that the risk of all-cause death, cardiovascular death,
meaning than galectin-3 in chronic HF (44). sST2
and HF hospitalization increases exponentially with
was also equally predictive of outcome in either
sST2 levels, with 28 ng/ml identified as the best cut-
reduced or preserved ejection fraction (40,45), and
off at receiver-operating characteristic curves for the
independently predicted reverse remodeling (i.e.,
3 endpoints (40). When considering median values of
the improvement of LV geometry and function in
sST2, NT-proBNP, and hs-TnT (27 ng/ml, 1,360 ng/l,
response to guideline-recommended HF therapy),
and 18 ng/l, respectively), patients with only sST2 $
thus favorably affecting long-term outcome (46,47).
median had an increased risk of all-cause death, car-
Lupón et al. (46,47) have developed and validated
diovascular death, and HF hospitalization by 100%,
the ST2-R2 score, which includes sST2 <48 ng/ml
50%, and 10%, respectively, compared with those
(3 points), nonischemic etiology (5 points), absence
with no biomarker $ median; those with the 3
of left bundle branch block (4 points), history of
biomarkers $ median had a risk increased by 850%,
HF <1 year (2 points), LV ejection fraction <24%
640%, and 590%, respectively; and those with sST2
(1
and another biomarker $ median had an intermediate
(2 points). The likelihood of reverse remodeling
risk profile, with a greater risk of all-cause death
(assessed over 1 year) increased in parallel with the
associated with the combination of sST2 and hs-
score points, while the risk of mortality decreased
TnT $ median (Figure 2). The prognostic value of
(46,47).
point),
and
treatment
with
beta-blockers
sST2 was independent from NT-proBNP, hs-TnT, and
The Barcelona Bio-HF score includes sST2 and 10
other variables with prognostic significance (40). In
other variables, and predicts the risk of death at 1, 2,
the same study, age, sex, body mass index, and renal
and 3 years with good performance (Online Figure 1)
function did not correlate with sST2 concentrations
(48). This score, which provides a further demon-
(40), as confirmed in other studies (41,42).
stration of the strong prognostic value of sST2 in
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sST2 in Heart Failure
F I G U R E 2 Additive Value of sST2 to NT-proBNP and hs-TnT for Outcome Prediction in Chronic HF
> sST2 597 241 163
964
392 423
264 > NT
> TnT
< NT, < sST2, < TnT 1,224 Whole Population 4,268 RR 10 9 8 7 6 5 4 3 2 1 0 CV Hospitalization < NT < TnT < sST2
> NT < TnT < sST2
< NT > TnT < sST2
< NT < TnT > sST2
CV Death > NT > TnT < sST2
All-Cause Death > NT < TnT > sST2
< NT > TnT > sST2
> NT > TnT > sST2
Relative risk (RR) of 3 endpoints (all-cause death, cardiovascular [CV] death, and HF hospitalization) were computed. Patients were classified according to median biomarker levels: N-terminal fragment of pro-brain natriuretic peptide (NT) 1,360 ng/l; high-sensitivity troponin T (TnT) 18 ng/l; sST2 27 ng/ml. Reproduced with permission from Emdin et al. (40). Abbreviations as in Figure 1.
chronic HF, particularly for the prediction of fatal
Elevated sST2 was shown to predict sudden cardiac
outcomes, could possibly be expanded by including
death in patients with chronic HF, with additive
the use of sacubitril valsartan and mineralocorticoid
prognostic significance to NT-proBNP (49). sST2 has
receptor antagonists.
also been proposed as a predictor of risk of death or
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sST2 in Heart Failure
T A B L E 3 Guideline Recommendations on the Clinical Use of sST2 in Either CHF or AHF
Society
Year (Ref. #)
Setting
Recommendation
Class
LOE
2013 (57)
CHF
Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
B
Measurement of biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
No specific recommendation.
—
ACC/AHA
Gaggin et al. (56) reported that rising sST2 over 1 year’s time identified patients at higher risk for progressive LV dysfunction (odds ratio: 1.22; p ¼ 0.01). These results were recapitulated by Lupón et al.
2017 (58)
2013 (57)
CHF
AHF
(46,47)
with
the
ST2-R2
score
to
predict
LV
remodeling.
GUIDELINE RECOMMENDATIONS B-NR
The 2013 American College of Cardiology Foundation/ American Heart Association HF guidelines recomA
mended to assess biomarkers of inflammation and fibrosis to refine prognostic stratification, albeit with a low class of recommendation (IIb; Level of Evidence: B for chronic HF, Level of Evidence: A for
ESC 2016 (59)
—
—
acute HF) (57), and not citing any specific biomarker. The 2017 update of these guidelines includes a similar
ACC/AHA ¼ American College of Cardiology/American Heart Association; ESC ¼ European Society of Cardiology; LOE ¼ Level of Evidence; NR ¼ nonrandomized; other abbreviations as in Table 2.
recommendation for chronic HF, whereas acute HF is not mentioned (58). On the other hand, the 2016 European Society of Cardiology Guidelines state that the evidence of sST2 and other emerging biomarkers is
ventricular arrhythmias in patients eligible for car-
still not so compelling to recommend their use in
diac resynchronization therapy and defibrillation.
clinical practice (59) (Table 3).
Among 684 patients from the MADIT (Multicenter Automated Defibrillator Implantation Trial), elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmias even when adjusting for BNP. Patients presenting lower baseline sST2 (<35 ng/ml) had greater risk reduction with cardiac resynchronization therapy and defibrillation (p ¼ 0.006) (50). In patients with stage D HF, elevated concentrations of sST2 were associated with higher risk for failure of HF treatment and impending mortality/transplant/ventricular assist device placement (51). sST2 tends to decrease after LV assist device implantation (52), and that sST2 levels after heart transplantation are associated with a higher risk of cellular rejection and longterm risk of mortality (53).
sST2 IN HF: OPEN QUESTIONS AND FUTURE PERSPECTIVES Similar to natriuretic peptides (60) and troponins (61,62), and different from almost all other biomarkers listed by Dr. Braunwald back in 2008 (1), sST2 meets 2 fundamental criteria for clinically useful biomarkers: 1) accurate, repeated measurements are available at a reasonable cost, with assay automatization in the next future likely providing further impulse to its diffusion; and 2) it provides additive information to a careful clinical assessment, especially for risk stratification (Table 4). However, our knowledge of sST2 and of its assay methodology is far from being complete, starting from the mechanisms regulating sST2 production in healthy subjects and
sST2, CARDIAC STRUCTURE, AND FUNCTION
diseased patients, and the binding sites of sST2 assays. Even more important, at least from a clinical
Circulating levels of sST2 are not as closely associated
perspective, we are still striving to understand when
with parameters of cardiac structure and function, in
and how to measure sST2 levels, and how to translate
agreement with the notion of a predominant extrac-
this information into better patient care.
ardiac production of this biomarker. In chronic HF,
In acute HF, it seems reasonable to suggest that
higher sST2 has been associated with LV diastolic
sST2 be measured at least on admission and at the
dysfunction, increased
systolic
planned discharge. Patients whose sST2 levels do not
pressure, and hypokinesis (54). In arrhythmogenic
decrease might be considered to be at higher risk,
right ventricular cardiomyopathy, the function of
which may suggest a prolongation of the hospital
both ventricles decreased with increasing plasma
stay, a more rapid up-titration of HF drugs (after he-
sST2, suggesting more extensive fibrofatty replace-
modynamic stabilization), as well as more frequent
ment. Accordingly, sST2 was higher in patients with
visits after discharge or the use of monitoring systems
ventricular arrhythmias than in those without, even
to detect pulmonary congestion. In the chronic
after adjusting for right ventricular function (55).
setting, point sST2 values predict outcome and
right
ventricular
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sST2 in Heart Failure
T A B L E 4 Clinical Value of NPs, Cardiac hs Troponins, and sST2 in HF
NPs hs-troponins sST2
Multimarker strategy (AHF: ST2 þ NPs) (CHF: sST2 þ NPs þ hs-troponins)
Diagnosis: HF
Risk Stratification: AHF
Risk Stratification: CHF
Guide to Treatment
þþþ (57–59)
þþþ (57–59)
þþþ (57–59)
þ/
n/a (key to ACS diagnosis)
þþ (62)
þþ (61)
n/a
(24)
þþ þ Admission and discharge sST2: Strong, independent predictor univariate predictors of all-cause of outcome (all-cause death, CV and CV death after discharge (33). death, HF hospitalization) (40). Predictor of reverse remodeling Discharge sST2: univariate predictor (46,47). of HF hospitalization (33). % change in ST2 during Predictor of SCD (49) and benefit from CRT-D (50). hospitalization: predictor of 90-day mortality (34). sST2 increase over time: predictive of 1-year all-cause death or HF hospitalization (35).
n/a
n/a
þþ þ Prognostic value of admission Additive prognostic value of sST2 independent from NT-proBNP sST2 to NPs and hs-troponins (24,29). (40,48). Percent change in ST2 predictive of 90-day mortality regardless of variations in NT-proBNP (34). Increase in sST2 over time of 1-year all-cause death or HF hospitalization independent from repeated NTproBNP measurements (35).
n/a
Numbers in parentheses are reference citations. þþþ ¼ strong evidence, guideline-recommended; þþ ¼ clear-cut evidence from individual patient data meta-analyses; þ ¼ evidence from multiple original studies and/or pooled data meta-analyses; þ/ ¼ controversial issue; ¼ negative evidence from the literature; n/a: not available data; ACS ¼ acute coronary syndrome; CRT-D ¼ cardiac resynchronization therapy and defibrillation; hs ¼ high-sensitivity; NP ¼ natriuretic peptide; NT-proBNP ¼ N-terminal fragment of pro–B-type natriuretic peptide; SCD ¼ sudden cardiac death; other abbreviations as in Table 2.
reverse remodeling in patients with chronic HF on
research is to establish if a sST2-guided management
guideline-recommended treatment. sST2 measure-
of acute or chronic HF patients could have a positive
ment is then a valuable tool for risk stratification,
effect on patient symptoms and disease evolution.
either alone or together with natriuretic peptides and troponins, but the possibility to guide HF treatment
ADDRESS FOR CORRESPONDENCE:
on this basis (e.g., up-titrating or switching drugs, or
Emdin, Scuola Superiore Sant’Anna and Fonda-
deciding whether to refer a patient with nonischemic
zione Toscana Gabriele Monasterio, Via G. Moruzzi
dilated cardiomyopathy and mild systolic dysfunc-
1—56124 Pisa, Italy. E-mail: [email protected] OR
tion for defibrillator implantation) remains to be
[email protected]. Twitter: @MicheleEmdin,
investigated. Overall, the main challenge of future
@JJheart_doc.
Dr.
Michele
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21. Wu AH, Wians F, Jaffe A. Biological variation of galectin-3 and soluble ST2 for chronic heart failure: implication on interpretation of test results. Am Heart J 2013;165:995–9. 22. Piper S, deCourcey J, Sherwood R, et al. Biologic variability of soluble ST2 in patients with stable chronic heart failure and implications for monitoring. Am J Cardiol 2016;118:95–8. 23. Coglianese EE, Larson MG, Vasan RS, et al. Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the Framingham Heart Study. Clin Chem 2012;58: 1673–81. 24. Januzzi JL Jr., Peacock WF, Maisel AS, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607–13. 25. Parikh RH, Seliger SL, Christenson R, et al. Soluble ST2 for prediction of heart failure and cardiovascular death in an elderly, communitydwelling population. J Am Heart Assoc 2016;5: e003188. 26. Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation 2012;126:1596–604. 27. Chen LQ, de Lemos JA, Das SR, et al. Soluble ST2 is associated with all-cause and cardiovascular mortality in a population-based cohort: the Dallas Heart Study. Clin Chem 2013;59:536–46.
36. Morrow DA, Velazquez EJ, DeVore AD, et al. Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEERHF trial. Eur Heart J 2019 May 15 [E-pub ahead of print]. 37. Ky B, French B, McCloskey K, et al. Highsensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail 2011;4: 180–7. 38. Felker GM, Fiuzat M, Thompson V, et al. Soluble ST2 in ambulatory patients with heart failure: Association with functional capacity and longterm outcomes. Circ Heart Fail 2013;6:1172–9. 39. Aimo A, Vergaro G, Passino C, et al. Prognostic value of soluble suppression of tumorigenicity-2 in chronic heart failure: a meta-analysis. J Am Coll Cardiol HF 2017;5:280–6. 40. Emdin M, Aimo A, Vergaro G, et al. sST2 predicts outcome in chronic heart failure beyond NT-proBNP and high-sensitivity troponin T. J Am Coll Cardiol 2018;72:2309–20. 41. Wojtczak-Soska K, Pietrucha T, Sakowicz A, et al. Soluble ST2 protein in chronic heart failure is independent of traditional factors. Arch Med Sci 2013;9:21–6. 42. Bayes-Genis A, Zamora E, de Antonio M, et al. Soluble ST2 serum concentration and renal function in heart failure. J Card Fail 2013;19:768–75. 43. Mueller T, Gegenhuber A, Leitner I, et al. Diagnostic and prognostic accuracy of galectin-3
and soluble ST2 for acute heart failure. Clin Chim Acta 2016;463:158–64. 44. Bayes-Genis A, de Antonio M, Vila J, et al. Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3. J Am Coll Cardiol 2014;63:158–66. 45. Sanders-van Wijk S, van Empel V, Davarzani N, et al. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail 2015;17:1006–14. 46. Lupón J, Gaggin HK, de Antonio M, et al. Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score. Int J Cardiol 2015;184:337–43. 47. Lupón J, Sanders-van Wijk S, Januzzi JL, et al. Prediction of survival and magnitude of reverse remodeling using the ST2-R2 score in heart failure: a multicenter study. Int J Cardiol 2016;204:242–7. 48. Lupón J, de Antonio M, Vila J, Peñafiel J, et al. Development of a novel heart failure risk tool: the Barcelona bio-heart failure risk calculator (BCN bio-HF calculator). PLoS One 2014;9:e85466. 49. Pascual-Figal DA, Ordonez-Llanos J, Tornel PL, et al. Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. J Am Coll Cardiol 2009;54:2174–9. 50. Skali H, Gerwien R, Meyer TE, et al. Soluble ST2 and risk of arrhythmias, heart failure, or death in patients with mildly symptomatic heart failure: results from MADIT-CRT. J Cardiovasc Transl Res 2016;9:421–8. 51. Zilinski JL, Shah RV, Gaggin HK, et al. Measurement of multiple biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter guided therapy. Crit Care 2012;16:R135. 52. Ahmad T, Wang T, O’Brien EC, et al. Effects of left ventricular assist device support on biomarkers of cardiovascular stress, fibrosis, fluid homeostasis, inflammation, and renal injury. J Am Coll Cardiol HF 2015;3:30–9. 53. Januzzi JL, Horne BD, Moore SA, et al. Interleukin receptor family member ST2 concentrations in patients following heart transplantation. Biomarkers 2013;18:250–6. 54. deFilippi C, Daniels LB, Bayes-Genis A. Structural heart disease and ST2: cross-sectional and longitudinal associations with echocardiography. Am J Cardiol 2015;115:59B–63B. 55. Broch K, Leren IS, Saberniak J, et al. Soluble ST2 is associated with disease severity in arrhythmogenic right ventricular cardiomyopathy. Biomarkers 2017;22:367–71. 56. Gaggin HK, Szymonifka J, Bhardwaj A, et al. Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highlysensitive troponin T measurements in patients with chronic heart failure. J Am Coll Cardiol HF 2014;2:65–72. 57. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/
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American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2013;62:e147–239. 58. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/ AHA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70: 776–803. 59. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and
sST2 in Heart Failure
chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18: 891–975. 60. Ibrahim NE, Januzzi JL Jr. The future of biomarker-guided therapy for heart failure after the Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) Study. Curr Heart Fail Rep 2018;15: 37–43. 61. Aimo A, Januzzi JL Jr., Vergaro G, et al. Prognostic value of high-sensitivity troponin T in chronic heart failure: an individual patient
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KEY WORDS biomarker, heart failure, outcome, sST2
A PP END IX For a supplemental figure, please see the online version of this paper.
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VOL. 74, NO. 17, 2019
ª 2019 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
THE PRESENT AND FUTURE JACC REVIEW TOPIC OF THE WEEK
Clinical and Prognostic Significance of sST2 in Heart Failure JACC Review Topic of the Week Alberto Aimo, MD,a James L. Januzzi, JR, MD,b Antoni Bayes-Genis, MD, PHD,c Giuseppe Vergaro, MD, PHD,a,d Paolo Sciarrone, MD,d Claudio Passino, MD,a,d Michele Emdin, MD, PHDa,d
ABSTRACT Soluble suppression of tumorigenesis-2 (sST2) is released in response to vascular congestion and inflammatory and profibrotic stimuli, and is a strong, independent predictor of mortality and heart failure (HF) hospitalization in patients with acute or chronic HF. sST2 meets 2 fundamental criteria for clinically useful biomarkers: accurate, repeated measurements are available at a reasonable cost, and the biomarker provides information not already available from a careful clinical assessment. In particular, the prognostic value of sST2 is additive to natriuretic peptides and (in the case of chronic HF) to high-sensitivity troponin T. Nevertheless, the need for a multibiomarker approach to risk stratification and the role of sST2 as a guide to therapy decision-making remain to be established. Four years after a consensus document on sST2, and following major advances in the comprehension of the clinical value of this biomarker, the authors felt it worthwhile to reappraise current knowledge on sST2 in HF. (J Am Coll Cardiol 2019;74:2193–203) © 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.
L
aboratory diagnostics plays a major role in the
biomarkers, a growing body of evidence points to
diagnosis, risk stratification, therapy decision-
the clinical relevance of soluble suppression of
making, and monitoring of patients with heart
tumorigenesis-2 (sST2), which was first classified as
failure (HF). As proposed by Dr. Braunwald, bio-
an indicator of myocyte stress (1), but is mainly pro-
markers of HF can be classified according to the
duced in extracardiac tissues (2–4) in response to in-
main pathophysiological determinant of circulating
flammatory and fibrotic stimuli (5). Four years after
concentrations: inflammation, oxidative stress, extra-
the publication of a Consensus Document dedicated
cellular matrix remodeling, neurohormones, myocyte
to sST2 (6), and following major advances in our
injury, and myocyte stress (1). The most established
comprehension of the clinical value of this biomarker,
biomarkers are natriuretic peptides and troponins,
we update current knowledge on sST2 in HF with a
reflecting hemodynamic overload and cardiomyocyte
particular focus on its main application, that is,
damage, respectively. Besides these cardiac-specific
outcome prediction.
From the aInstitute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; bMassachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts; cHospital Universitari Germans Trias i Pujol, Badalona (Barcelona), CIBERCV, Listen to this manuscript’s
Barcelona, Spain; and the dCardiology Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy. Dr. Januzzi is supported
audio summary by
in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from
Editor-in-Chief
Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex, and Prevencio; has received consulting income from Abbott,
Dr. Valentin Fuster on
Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Critical Diagnostics; and participates in Clinical Endpoint Committees/
JACC.org.
Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. Dr. Bayes-Genis has received grant support from Roche Diagnosis; has received lecture honoraria from Roche Diagnostics and Critical Diagnostics; and has received consulting income from Roche Diagnostics, Critical Diagnostics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. David A. Morrow, MD, served as Guest Associate Editor for this paper. Manuscript received June 27, 2019; revised manuscript received August 7, 2019, accepted August 31, 2019.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2019.08.1039
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sST2 in Heart Failure
sST2 BIOLOGY
ABBREVIATIONS
HIGHLIGHTS
AND ACRONYMS
In 1989, ST2 was first identified by 2 inde-
HF = heart failure
pendent laboratories working on growth-
hs-TnT = high-sensitivity
stimulated fibroblasts (7,8). The definition
troponin T
“suppression of tumorigenesis” derives from
IL = interleukin LV = left ventricle/ventricular NT-proBNP = N-terminal
the hypothesis that ST2 might blunt uncontrolled cell proliferation; the researcher Shinichi Tominaga had previously identified
fragment of pro-brain natriuretic peptide
another protein called ST1 (9). Since the first
sST2 = soluble suppression of
description of ST2, it was noted that it
tumorigenesis-2
sST2 is released in response to vascular congestion, inflammatory, and profibrotic stimuli. sST2 is a strong predictor of outcome in HF. The prognostic value of sST2 in HF is additive to natriuretic peptides.
had structural similarity to interleukin (IL)-1
variation at the gene locus predominantly regulates
receptors (7); hence, its alternative definition: “IL-1
ST2 expression (15). While ST2L is constitutively
receptor like-1.” Nonetheless, the function of this
expressed primarily in hematopoietic cells (Th2 and
protein remained unclear for several years.
mast cells), the expression of sST2 is largely induced
In 2002, Weinberg et al. (10) analyzed the expression of 7,000 genes in cardiomyocytes under-
in response to mechanical stretch and to inflammatory and pro-fibrotic stimuli (5).
going mechanical strain, and found that ST2 mark-
The major source of circulating sST2 in patients
edly increased as a response to this stimulus. In the
with HF has not been fully established, although
following years, IL-33 was identified as the ligand of
extracardiac production seems predominant: sST2
ST2 (11). IL-33 is mainly expressed by stromal cells
levels in HF are 10% higher in the peripheral venous
(fibroblasts, smooth muscle, epithelial, and endo-
blood, compared with the coronary sinus (2), and
thelial cells) (5), and signals to local immune cells the
there is no evident myocardial gradient of sST2 (16).
presence of tissue damage after exposure to patho-
Furthermore, in HF with preserved ejection fraction,
gens, injury-induced stress, or necrotic death (5).
sST2 concentrations are associated with systemic
Within the heart, IL-33 inhibits cardiomyocyte hy-
inflammation, right ventricular dysfunction, and
pertrophy and fibrosis in response to stimuli such as
systemic congestion, but not with indexes of left
angiotensin-II or phenylephrine, both in isolated
ventricular (LV) morphology or function (3,17). The
cardiomyocytes and in the murine model (12),
lungs have been proposed as an important site of sST2
possibly through the modulation of nuclear factor
production in HF (4). While the mechanisms of
kappa-light-chain-enhancer of activated B cells ac-
intracellular ST2L proteolysis have been clarified (18),
tivity (5,12). Furthermore, IL-33 reduces apoptosis by
to our knowledge the sites of degradation of sST2 and
induction of antiapoptotic factors and suppression of
the specific proteases involved have not been eluci-
caspase-3
dated so far.
activity
(13).
IL-33
exerts
these
car-
dioprotective effects by binding ST2-ligand (ST2L), which is a receptor expressed on plasma membrane
sST2 ASSAYS
of cardiomyocytes and fibroblasts, containing an extracellular domain of 3 linked immunoglobulin-
The assay methods for sST2 are thought to measure
like motifs, a transmembrane segment, and an
both free sST2 and sST2 complexed with IL-33,
intracellular Toll/IL-1 receptor cytoplasmic domain.
although it is not clear which epitopes are detected
sST2 is a circulating form of this receptor, which
by the antibodies against sST2 used for the different
lacks the transmembrane and cytoplasmic domains
methods (19). Among the 4 main ELISA assays (Pres-
and acts as a decoy receptor for IL-33 (5,12) (Central
age assay, Critical Diagnostics, San Diego, California;
Illustration).
MBL International, Woburn, Massachusetts; Ray
The gene named ST2 is located on human chro-
Biotech, Peachtree Corners, Georgia; R&D, Minneap-
mosome 2q12 and is part of the larger IL-1 gene clus-
olis, Minnesota), the Presage is the only one that has
ter. The ST2 gene has a proximal and a distal
received the Conformitè Européenne Mark and has
promoter; alternative promoter splicing and 3ʹ pro-
been cleared by the U.S. Food and Drug Administra-
cessing of the mRNA are believed to account for the
tion. Assay automation is expected in the near future,
production of either sST2 or ST2L (5,14). The mecha-
and should reduce dosage times considerably. As
nisms regulating the expression of sST2 and ST2L
established for the Presage assay, sST2 concentra-
have not been clarified (5), however common genetic
tions appear to be independent of fasting status,
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sST2 in Heart Failure
C ENTR AL I LL U STRA T I O N Biology and Clinical Application of Suppression of Tumorigenesis-2
Aimo, A. et al. J Am Coll Cardiol. 2019;74(17):2193–203.
Soluble suppression of tumorigenesis-2 (sST2) is produced mostly by alveolar cells and vessel wall cells, and to a lower extent by cardiac fibroblasts and cardiomyocytes. Interleukin (IL)-33 is released by stromal cells in cardiac and extracardiac tissues; it binds membrane suppression of tumorigenesis-2 (ST2) receptors on cardiomyocytes and cardiac fibroblasts, blunting myocardial hypertrophy and fibrosis and inhibiting cardiomyocyte apoptosis. sST2 acts as a decoy receptor for IL-33, reducing these positive effects. sST2 measurement holds prognostic significance in acute or chronic heart failure (HF). NP ¼ natriuretic peptide.
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sST2 in Heart Failure
T A B L E 1 Analytical Performance of Assays for Soluble ST2
Assay/Kit
Limit of Detection
Measurement Range
Intra-assay CV
Presage ST2 kit
1.3 ng/ml
Up to 200 ng/ml
<7%
<9%
Human ST2 ELISA kit
0.032 ng/ml
Up to 20 ng/ml
<6%
<6%
Human IL-1 R4/ST2 ELISA kit
0.002 ng/ml
Up to 1.2 ng/ml
<10%
<12%
ST2/IL-1 R4 DuoSet ELISA or Quantikine ELISA
0.005 ng/ml
Up to 2.0 ng/ml
<6%
<8%
Manufacturer
Critical Diagnostics (San Diego, California) MBL International (Woburn, Massachusetts) RayBiotech (Peachtree Corners, Georgia) R&D Systems (Minneapolis, Minnesota)
Interassay CV
Modified with permission from Mueller and Jaffe (19), 2015. CV ¼ coefficient of variation; ST2 ¼ suppression of tumorigenesis-2.
unaffected by freeze-thaw cycles, and with minimal
cardiac stretch, myocardial injury, and fibrosis; and
effects by hemolysis, lipemia, icterus, or rheumatoid
with abnormal echocardiographic parameters, but not
factor (19).
with renal function (25). Higher sST2 concentrations
The analytical characteristics of sST2 assay are
were associated with an elevated risk of incident HF
discussed in dedicated publications (19,20), and
and cardiovascular death, although the prognostic
summarized in Table 1. Notably, sST2 has a lower
significance
reference change value than B-type natriuretic pep-
NT-proBNP or both NT-proBNP and high-sensitivity
tide (BNP) or N-terminal pro–B-type natriuretic pep-
troponin T (hs-TnT) to the model (25). Among 3,428
tide (NT-proBNP) both in healthy subjects (21), and in
participants in the Framingham Heart Study, sST2
patients with chronic HF (22); therefore, variations in
levels predicted death, incident HF, and major car-
sST2 across serial measurements could reflect more
diovascular events independently from standard
closely changes in clinical status than variations in
cardiovascular risk factors, as well as from other
natriuretic peptides.
biomarkers of cardiovascular stress (growth-derived
sST2 TO DIAGNOSE HF OR PREDICT ITS DEVELOPMENT Reference values of plasma sST2 were defined by using the Presage assay on 3 cohorts of apparently healthy adult subjects: 1 European and 2 American (men: 4 to 31, 9 to 50, and 11 to 45 ng/ml; women: 2 to
resulted
attenuated
when
adding
factor-15, hs-TnI, BNP, hs-C-reactive protein) (26). In the Dallas Heart Study (n ¼ 3,294), sST2 was predictive
of
all-cause
and
cardiovascular
mortality
regardless of the presence of HF at baseline, although the predictive value for incident HF was not explored (27).
sST2 FOR RISK STRATIFICATION IN ACUTE HF
21, 7 to 33, and 9 to 35 ng/ml, respectively) (19). Additionally, data from the Framingham Heart Study
The prognostic significance of sST2 was first reported
provided important information regarding distribu-
in 2003. In a subanalysis of the PRAISE-2 (Prospective
tion and clinical correlates in a generally healthy,
Randomized
ambulatory population (23). Unlike cardiac-specific
study, conducted on 161 patients with HF and New
biomarkers such as natriuretic peptides, there is
York Heart Association functional class III or IV,
overlap among sST2 levels in healthy subjects, HF
baseline sST2 levels were correlated with natriuretic
patients, or people affected by inflammatory disor-
peptides, and their variation within 2 weeks was
ders (pneumonia, chronic obstructive pulmonary
predictive of all-cause mortality and need for heart
disease) (20). sST2 measurement is then not helpful
transplantation regardless of natriuretic peptide
to discriminate between cardiac and noncardiac dys-
levels (28). A strong prognostic value of sST2, inde-
pnea (24).
pendent from NT-proBNP, emerged in a cohort of 593
Amlodipine
Survival
Evaluation-2)
sST2 levels are lower in healthy women than men,
patients presenting at the emergency department
contrary to HF, where no significant sex-related dif-
with acute dyspnea (confirmed in the subset of 209
ferences in circulating concentrations and prognostic
patients with final HF diagnosis) (24), and in a pop-
significance of sST2 have been reported. In elderly,
ulation of 346 patients with acute HF (29). In the
community-dwelling individuals (n ¼ 3,915), circu-
latter study, mortality increased progressively with
lating sST2 was associated with older age, African-
sST2 deciles, exceeding 50% in the tenth decile; when
American race, and traditional cardiovascular risk
both ST2 and natriuretic peptides were elevated, the
factors; with other biomarkers of inflammation,
highest rates of death were observed in cumulative
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2197
sST2 in Heart Failure
T A B L E 2 Proposed Cut-Offs of sST2 in Patients With Acute or Chronic Heart Failure and in Apparently Healthy Individuals
Study Type
N
Setting
Assay
Proposed sST2 Cut-Off (ng/ml)
Endpoints
Method for Cut-Off Selection
Original study
3,915
Elderly individuals
Presage
35
Incident HF, CV death
Cut-off previously proposed in CHF
Rehman et al. (29), 2008
Original study
346
AHF
Presage
49
All-cause death (1-yr)
Youden index
Pascual-Figal et al. (31), 2011
Original study
107
AHF
Presage
65
All-cause death
Youden index
Pascual-Figal et al. (30), 2019
Original study
316
AHF
Presage
35
All-cause death (1-yr)
Cut-off previously proposed in CHF
Original study
1,141
CHF
Presage
35
All-cause death or heart transplant
Youden index
Individual patient 4,268 data meta-analysis
CHF
Presage
28
All-cause and CV death, HF hospitalization
Youden index
First Author (Ref. #), Year
Parikh et al. (25), 2016
Ky et al. (37), 2011 Emdin et al. (40), 2018
The 35-ng/ml cut-off has been adopted by the U.S. Food and Drug Administration as a prognostic cut-off (21). AHF ¼ acute heart failure; CHF ¼ chronic heart failure; HF ¼ heart failure; sST2 ¼ soluble suppression of tumorigenesis-2.
hazard analysis (p < 0.001). In the presence of a low
increase of baseline log2-sST2: 1.30; 95% confidence
ST2 level, natriuretic peptides did not predict mor-
interval: 1.08 to 1.56; p ¼ 0.005). When repeated
tality (29). The risk threshold commonly used in
measurements were taken into account, the hazard
chronic HF (i.e., 35 ng/ml) has been evaluated in a
ratio per 1-SD increase of sST2 during follow-up was
recent study, displaying a modest prognostic perfor-
1.85 (95% confidence interval: 1.02 to 3.33; p ¼ 0.044),
mance (30); higher risk thresholds have been pro-
after adjustment for clinical factors and repeated
posed, most notably 49 (29) and 65 ng/ml (31,32)
measurements of NT-proBNP. Furthermore, ST2
(Table 2).
levels started to increase several weeks before the
Studies evaluating the prognostic significance of
occurrence of the primary endpoint (35) (Figure 1).
sST2 in acute HF have consistently reported that this
In a recent subanalysis of the PIONEER-HF (Com-
biomarker helps refine risk stratification, particularly
parison of Sacubitril/valsartan vs. Enalapril on Effect
for fatal endpoints. A meta-analysis by our group
on
showed that sST2 levels, measured both on admission
[NT-proBNP] in Patients Stabilized from an Acute HF
and at discharge, predict all-cause and cardiovascular
Episode) trial, baseline sST2 concentrations yielded
mortality. Moreover, unlike measurement at the time
prognostic significance for the composite outcome of
of admission, sST2 plasma concentration at discharge
cardiovascular
yielded prognostic significance for hospital read-
Notably, patients in the sacubitril/valsartan arm dis-
mission for HF (33).
played a greater reduction in circulating sST2 than
N-terminal
pro-brain
death
or
natriuretic
HF
peptide
rehospitalization.
The usefulness of serial sST2 measurement in
enalapril after as early as 1 week, as well as a better
acute HF has been specifically evaluated by several
outcome. sST2 levels decreased less than hs-TnT or
studies. In a population of 150 patients undergoing
NT-proBNP (6.4% vs. 15.8% and 29.4%, respectively),
daily blood sampling for sST2, percent change in ST2
possibly reflecting a lower impact of decongestion on
was strongly predictive of 90-day mortality: patients
sST2 levels than hs-TnT or NT-proBNP (36).
whose ST2 values decreased by 15.5% or more during the study period had a 7% chance of death, whereas
sST2 FOR RISK STRATIFICATION IN
patients whose ST2 levels failed to decrease by 15.5%
CHRONIC HF
in this time interval had a 33% chance of death. The prognostic value of sST2 changes was again inde-
In 2011, Ky et al. (37) performed a meta-analysis of
pendent from variations in NT-proBNP (34). In a
sST2 for prognosticating outcomes in chronic HF in 3
multicenter study from the Netherlands, 496 patients
cohorts. These results were further validated in the
with acute HF underwent repeated blood sampling
HF-ACTION (Heart Failure: A Controlled Trial Inves-
(on admission; at days 2 and 4; at discharge; after 2
tigating Outcomes of Exercise Training) cohort (38),
and 4 weeks; and at 3, 6, 9, and 12 months). After
leading to regulatory approval in the United States. In
adjustment for clinical factors and NT-proBNP, base-
2016, a much larger meta-analysis, considering
line sST2 was associated with an increased risk of the
pooled data from 7 studies and 6,372 patients, re-
primary endpoint (composite of all-cause mortality
ported that unadjusted sST2 values predict all-cause
and HF rehospitalization: hazard ratio per 1-SD
and cardiovascular mortality in chronic HF (39). The
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sST2 in Heart Failure
F I G U R E 1 Trends of sST2 and Outcome After a Hospitalization for HF
100
80 sST2 (ng/mL)
2198
60
40
20
140
120
100
80 60 Time to Event (Days)
Patients with Event
40
20
0
Patients without Event
EVENT
Soluble suppression of tumorigenesis-2 (sST2) trends and individual sST2 values during follow-up after a heart failure (HF) hospitalization are reported. Patients experiencing the “event” (all-cause death or new HF hospitalization) (blue) and those who did not (red) are distinguished. Reproduced with permission from van Vark et al. (35).
sST2 >35-ng/ml cut-off was associated with a signifi-
While galectin-3 (another biomarker of inflam-
cantly higher risk of mortality at 1 year, also when
mation and fibrosis) has been reported to be more
adjusting for several covariates (39). An analysis of
predictive than sST2 in acute HF (43), several pa-
4,268 individual patient data from 11 cohorts found
pers suggest that sST2 holds superior prognostic
that the risk of all-cause death, cardiovascular death,
meaning than galectin-3 in chronic HF (44). sST2
and HF hospitalization increases exponentially with
was also equally predictive of outcome in either
sST2 levels, with 28 ng/ml identified as the best cut-
reduced or preserved ejection fraction (40,45), and
off at receiver-operating characteristic curves for the
independently predicted reverse remodeling (i.e.,
3 endpoints (40). When considering median values of
the improvement of LV geometry and function in
sST2, NT-proBNP, and hs-TnT (27 ng/ml, 1,360 ng/l,
response to guideline-recommended HF therapy),
and 18 ng/l, respectively), patients with only sST2 $
thus favorably affecting long-term outcome (46,47).
median had an increased risk of all-cause death, car-
Lupón et al. (46,47) have developed and validated
diovascular death, and HF hospitalization by 100%,
the ST2-R2 score, which includes sST2 <48 ng/ml
50%, and 10%, respectively, compared with those
(3 points), nonischemic etiology (5 points), absence
with no biomarker $ median; those with the 3
of left bundle branch block (4 points), history of
biomarkers $ median had a risk increased by 850%,
HF <1 year (2 points), LV ejection fraction <24%
640%, and 590%, respectively; and those with sST2
(1
and another biomarker $ median had an intermediate
(2 points). The likelihood of reverse remodeling
risk profile, with a greater risk of all-cause death
(assessed over 1 year) increased in parallel with the
associated with the combination of sST2 and hs-
score points, while the risk of mortality decreased
TnT $ median (Figure 2). The prognostic value of
(46,47).
point),
and
treatment
with
beta-blockers
sST2 was independent from NT-proBNP, hs-TnT, and
The Barcelona Bio-HF score includes sST2 and 10
other variables with prognostic significance (40). In
other variables, and predicts the risk of death at 1, 2,
the same study, age, sex, body mass index, and renal
and 3 years with good performance (Online Figure 1)
function did not correlate with sST2 concentrations
(48). This score, which provides a further demon-
(40), as confirmed in other studies (41,42).
stration of the strong prognostic value of sST2 in
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sST2 in Heart Failure
F I G U R E 2 Additive Value of sST2 to NT-proBNP and hs-TnT for Outcome Prediction in Chronic HF
> sST2 597 241 163
964
392 423
264 > NT
> TnT
< NT, < sST2, < TnT 1,224 Whole Population 4,268 RR 10 9 8 7 6 5 4 3 2 1 0 CV Hospitalization < NT < TnT < sST2
> NT < TnT < sST2
< NT > TnT < sST2
< NT < TnT > sST2
CV Death > NT > TnT < sST2
All-Cause Death > NT < TnT > sST2
< NT > TnT > sST2
> NT > TnT > sST2
Relative risk (RR) of 3 endpoints (all-cause death, cardiovascular [CV] death, and HF hospitalization) were computed. Patients were classified according to median biomarker levels: N-terminal fragment of pro-brain natriuretic peptide (NT) 1,360 ng/l; high-sensitivity troponin T (TnT) 18 ng/l; sST2 27 ng/ml. Reproduced with permission from Emdin et al. (40). Abbreviations as in Figure 1.
chronic HF, particularly for the prediction of fatal
Elevated sST2 was shown to predict sudden cardiac
outcomes, could possibly be expanded by including
death in patients with chronic HF, with additive
the use of sacubitril valsartan and mineralocorticoid
prognostic significance to NT-proBNP (49). sST2 has
receptor antagonists.
also been proposed as a predictor of risk of death or
2199
2200
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sST2 in Heart Failure
T A B L E 3 Guideline Recommendations on the Clinical Use of sST2 in Either CHF or AHF
Society
Year (Ref. #)
Setting
Recommendation
Class
LOE
2013 (57)
CHF
Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
B
Measurement of biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification.
IIb
No specific recommendation.
—
ACC/AHA
Gaggin et al. (56) reported that rising sST2 over 1 year’s time identified patients at higher risk for progressive LV dysfunction (odds ratio: 1.22; p ¼ 0.01). These results were recapitulated by Lupón et al.
2017 (58)
2013 (57)
CHF
AHF
(46,47)
with
the
ST2-R2
score
to
predict
LV
remodeling.
GUIDELINE RECOMMENDATIONS B-NR
The 2013 American College of Cardiology Foundation/ American Heart Association HF guidelines recomA
mended to assess biomarkers of inflammation and fibrosis to refine prognostic stratification, albeit with a low class of recommendation (IIb; Level of Evidence: B for chronic HF, Level of Evidence: A for
ESC 2016 (59)
—
—
acute HF) (57), and not citing any specific biomarker. The 2017 update of these guidelines includes a similar
ACC/AHA ¼ American College of Cardiology/American Heart Association; ESC ¼ European Society of Cardiology; LOE ¼ Level of Evidence; NR ¼ nonrandomized; other abbreviations as in Table 2.
recommendation for chronic HF, whereas acute HF is not mentioned (58). On the other hand, the 2016 European Society of Cardiology Guidelines state that the evidence of sST2 and other emerging biomarkers is
ventricular arrhythmias in patients eligible for car-
still not so compelling to recommend their use in
diac resynchronization therapy and defibrillation.
clinical practice (59) (Table 3).
Among 684 patients from the MADIT (Multicenter Automated Defibrillator Implantation Trial), elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmias even when adjusting for BNP. Patients presenting lower baseline sST2 (<35 ng/ml) had greater risk reduction with cardiac resynchronization therapy and defibrillation (p ¼ 0.006) (50). In patients with stage D HF, elevated concentrations of sST2 were associated with higher risk for failure of HF treatment and impending mortality/transplant/ventricular assist device placement (51). sST2 tends to decrease after LV assist device implantation (52), and that sST2 levels after heart transplantation are associated with a higher risk of cellular rejection and longterm risk of mortality (53).
sST2 IN HF: OPEN QUESTIONS AND FUTURE PERSPECTIVES Similar to natriuretic peptides (60) and troponins (61,62), and different from almost all other biomarkers listed by Dr. Braunwald back in 2008 (1), sST2 meets 2 fundamental criteria for clinically useful biomarkers: 1) accurate, repeated measurements are available at a reasonable cost, with assay automatization in the next future likely providing further impulse to its diffusion; and 2) it provides additive information to a careful clinical assessment, especially for risk stratification (Table 4). However, our knowledge of sST2 and of its assay methodology is far from being complete, starting from the mechanisms regulating sST2 production in healthy subjects and
sST2, CARDIAC STRUCTURE, AND FUNCTION
diseased patients, and the binding sites of sST2 assays. Even more important, at least from a clinical
Circulating levels of sST2 are not as closely associated
perspective, we are still striving to understand when
with parameters of cardiac structure and function, in
and how to measure sST2 levels, and how to translate
agreement with the notion of a predominant extrac-
this information into better patient care.
ardiac production of this biomarker. In chronic HF,
In acute HF, it seems reasonable to suggest that
higher sST2 has been associated with LV diastolic
sST2 be measured at least on admission and at the
dysfunction, increased
systolic
planned discharge. Patients whose sST2 levels do not
pressure, and hypokinesis (54). In arrhythmogenic
decrease might be considered to be at higher risk,
right ventricular cardiomyopathy, the function of
which may suggest a prolongation of the hospital
both ventricles decreased with increasing plasma
stay, a more rapid up-titration of HF drugs (after he-
sST2, suggesting more extensive fibrofatty replace-
modynamic stabilization), as well as more frequent
ment. Accordingly, sST2 was higher in patients with
visits after discharge or the use of monitoring systems
ventricular arrhythmias than in those without, even
to detect pulmonary congestion. In the chronic
after adjusting for right ventricular function (55).
setting, point sST2 values predict outcome and
right
ventricular
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sST2 in Heart Failure
T A B L E 4 Clinical Value of NPs, Cardiac hs Troponins, and sST2 in HF
NPs hs-troponins sST2
Multimarker strategy (AHF: ST2 þ NPs) (CHF: sST2 þ NPs þ hs-troponins)
Diagnosis: HF
Risk Stratification: AHF
Risk Stratification: CHF
Guide to Treatment
þþþ (57–59)
þþþ (57–59)
þþþ (57–59)
þ/
n/a (key to ACS diagnosis)
þþ (62)
þþ (61)
n/a
(24)
þþ þ Admission and discharge sST2: Strong, independent predictor univariate predictors of all-cause of outcome (all-cause death, CV and CV death after discharge (33). death, HF hospitalization) (40). Predictor of reverse remodeling Discharge sST2: univariate predictor (46,47). of HF hospitalization (33). % change in ST2 during Predictor of SCD (49) and benefit from CRT-D (50). hospitalization: predictor of 90-day mortality (34). sST2 increase over time: predictive of 1-year all-cause death or HF hospitalization (35).
n/a
n/a
þþ þ Prognostic value of admission Additive prognostic value of sST2 independent from NT-proBNP sST2 to NPs and hs-troponins (24,29). (40,48). Percent change in ST2 predictive of 90-day mortality regardless of variations in NT-proBNP (34). Increase in sST2 over time of 1-year all-cause death or HF hospitalization independent from repeated NTproBNP measurements (35).
n/a
Numbers in parentheses are reference citations. þþþ ¼ strong evidence, guideline-recommended; þþ ¼ clear-cut evidence from individual patient data meta-analyses; þ ¼ evidence from multiple original studies and/or pooled data meta-analyses; þ/ ¼ controversial issue; ¼ negative evidence from the literature; n/a: not available data; ACS ¼ acute coronary syndrome; CRT-D ¼ cardiac resynchronization therapy and defibrillation; hs ¼ high-sensitivity; NP ¼ natriuretic peptide; NT-proBNP ¼ N-terminal fragment of pro–B-type natriuretic peptide; SCD ¼ sudden cardiac death; other abbreviations as in Table 2.
reverse remodeling in patients with chronic HF on
research is to establish if a sST2-guided management
guideline-recommended treatment. sST2 measure-
of acute or chronic HF patients could have a positive
ment is then a valuable tool for risk stratification,
effect on patient symptoms and disease evolution.
either alone or together with natriuretic peptides and troponins, but the possibility to guide HF treatment
ADDRESS FOR CORRESPONDENCE:
on this basis (e.g., up-titrating or switching drugs, or
Emdin, Scuola Superiore Sant’Anna and Fonda-
deciding whether to refer a patient with nonischemic
zione Toscana Gabriele Monasterio, Via G. Moruzzi
dilated cardiomyopathy and mild systolic dysfunc-
1—56124 Pisa, Italy. E-mail: [email protected] OR
tion for defibrillator implantation) remains to be
[email protected]. Twitter: @MicheleEmdin,
investigated. Overall, the main challenge of future
@JJheart_doc.
Dr.
Michele
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KEY WORDS biomarker, heart failure, outcome, sST2
A PP END IX For a supplemental figure, please see the online version of this paper.
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