Journal of Cardiac Failure Vol. 19 No. 12 2013

Heart Failure TherapyeInduced Early ST2 Changes May OfferLong-Term Therapy Guidance

TOBIAS BREIDTHARDT, MD,1,2 CATHRIN BALMELLI, MD,2,3 RAPHAEL TWERENBOLD, MD,2,3 TAMINA MOSIMANN, MD,2,3

JAQUELINE ESPINOLA, MD,5 PHILIP HAAF, MD,3 GREGOR THALMANN, BSc,2,3 BERIT MOEHRING, MD,2

MIRA MUELLER, MD,2,3 BERNADETTE MELLER, MD,2,3 TOBIAS REICHLIN, MD,3,4 KARSTEN MURRAY, MD,2,3

RONNY ZILLER, MD,2,3 PASCAL BENKERT, PhD,6 STEFAN OSSWALD, MD,3 AND CHRISTIAN MUELLER, MD3

Basel and Zurich, Switzerland; Boston, Massachusetts

From the 1DepaSwitzerland; 2DepBasel, SwitzerlandBasel, SwitzerlandSwitzerland; 5Depich, Zurich, SwitzMedicine, BrighamBoston, MassachuManuscript rec

October 28, 2013;

ABSTRACT

Background: Biomarkers may help to monitor and tailor treatment in patients with acute heart failure(AHF).Methods and Results: Levels of ST2, a novel biomarker integrating hypervolemic cardiac strain andproinflammatory signals, were measured at presentation to the emergency department (ED) and after48 hours in 207 patients with AHF. Patients were stratified according to their early ST2 response (re-sponders: ST2 decrease $25%; nonresponders: ST2 decrease !25%) and beta-blocker, renin-angio-tensin-aldosterone system (RAAS) blockade, or diuretic treatment status at hospital discharge. Weassessed the utility of ST2 levels and its changes to predict long-term mortality and the interaction be-tween ST2 levels, treatment at discharge, and 1-year mortality. ST2 levels were higher in nonsurvivorsthan in survivors (median 108 vs 69 ng/mL; P ! .01) and decreased significantly during the 1st 48 hours(median decrease 33%). ST2 decrease was less in nonsurvivors compared with survivors (median �25%vs �42%; P ! .01). In Cox regression, early ST2 changes independently predicted 1-year mortality (haz-ard ratio 1.07 for every increase of 10%; P 5 .02). RAAS blockers at discharge were associated with sur-vival independently from ST2 response, whereas the association of beta-blockers with survival differedmarkedly according to ST2 response, with beneficial effects restricted to ST2 nonresponders (P interac-tion 5 .04). A similar, albeit nonsignificant, trend was observed for diuretics (P interaction 5 .11).Conclusions: ED and serial ST2 measurements are independent predictors of 1-year mortality in AHF.(J Cardiac Fail 2013;19:821e828)Key Words: Acute heart failure, ST2, heart failure therapy, mortality.

Acute heart failure (AHF) is a major medical and socio-economic burden, representing the most common dischargediagnosis in patients O65 years old.1 Additionally it hasa poor prognosis; the 60e90-day mortality rate afterdischarge approaches 10% and almost one-half of all pa-tients aree rehospitalised within the 1st year.2 These alarm-ing figures are further complicated by an ever aging, highly

rtment of Nephrology, University Hospital Basel, Basel,artment of Internal Medicine, University Hospital Basel,; 3Department of Cardiology, University Hospital Basel,; 4Clinical Trial Unit, University Hospital Basel, Basel,artment of Internal Medicine, University Hospital Zur-erland and 6Cardiovascular Division, Department ofand Women’s Hospital and Harvard Medical School,

setts.eived February 9, 2013; revised manuscript receivedrevised manuscript accepted November 6, 2013.

821

comorbid patient population3 in whom cardiovascular pol-ypharmacy is associated with considerable challenges andincreased adverse events.4 Therefore, a rapid and reliablepredictor of treatment response to individual cardiovasculardrug classes might aid physicians in tailoring therapy to theindividual patient to maximize treatment success whileminimizing unnecessary adverse events. This appears to

Reprint requests: PD Dr Tobias Breidthardt, MD, Department ofNephrology, University Hospital Basel, 4031 Basel, Switzerland.Tel: þ41/61 265 2525; Fax: þ41/612655353. E-mail: breidthardtt@uhbs.chThe first 2 authors contributed equally to this work.Funding: Research grants from the Swiss National Science Foundation

(PP00B-102853), Swiss Heart Foundation, Critical Diagnostics, ALERE,BRAHMS, and Department of Internal Medicine, University Hospital Basel.See page 827 for disclosure information.1071-9164/$ - see front matter� 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.cardfail.2013.11.003

822 Journal of Cardiac Failure Vol. 19 No. 12 December 2013

be especially important because, in contrast to the stablechronic heart failure setting, none of the drugs currentlyused at emergency department (ED) presentation, duringin-hospital treatment, or at hospital discharge have beenshown to improve outcome when used in the AHF setting.2

The use of cardiac biomarkers might be helpful to over-come at least some of the current limitations and individu-alize treatment.5e8 Suppression of tumorigenicity 2 is amember of the interleukin-1 receptor family and consistsof both a transmembrane receptor form (ST2L) and a trun-cated soluble receptor form (ST2) that can be detected inserum. Its gene is up-regulated in cardiac myocytes and fi-broblasts subjected to mechanical stress, such as cardiomy-cyte stretch.9 Additionally, both ST2 isoforms are tightlyconnected to the inflammatory cytokine network andsubsequent repair mechanisms.10 Thus elevated ST2 levelsintegrate hypervolemic cardiac strain and proinflammatoryactivity signals. Importantly, the therapeutic effects ofdiuretic and beta-blocker therapy seem to be linked to vol-ume depletion11 and antiinflammatory modulation.12e14

Importantly, in an international multicenter study enrolling1,059 patients, ST2 levels were shown to have greatershort-term prognostic value than B-type natriuretic peptide(BNP) and N-terminal pro-BNP for short-term mortality at30 days.15

We therefore assessed the utility of ST2 levels and itschanges to predict long-term mortality and evaluated theinteraction among ST2 levels, treatment at hospitaldischarge, and 1-year mortality.

Methods

Setting and Study Population

We included 207 consecutive AHF patients presenting to theED of the University Hospital Basel, Switzerland, from April2006 to August 2009. To be eligible for enrollment, patients hadto be O18 years old and present with symptoms and signs ofAHF. AHF was diagnosed and patients were treated for AHF ac-cording to the current European Society of Cardiology guide-lines.2 Patients undergoing chronic hemodialysis were excluded.The study was carried out according to the principles of the Decla-ration of Helsinki. It was approved by the local Ethical Commit-tee. Written informed consent was obtained from everyparticipant.

Clinical Evaluation

All patients underwent an initial clinical assessment thatincluded a clinical history, a physical examination, an electrocar-diogram (ECG), continuous ECG monitoring, pulse oximetry,standard blood measurements including BNP, and chest radiog-raphy. Echocardiography was performed according to the treatingphysician. Left ventricular systolic dysfunction was defined as leftventricular ejection fraction (LVEF) #40%.2

An adjudicated diagnosis of AHF was made by 2 independentcardiologists, who were blinded to the biomarker results, after re-viewing all medical records pertaining to the individual patient(including results of standard investigations, the response to ther-apy, and autopsy data in those patients dying in hospital). In situ-ations of diagnostic disagreement, cases were reviewed and

adjudicated in conjunction with a 3rd cardiologist. The reviewingcardiologist and the authors were not directly involved in the clin-ical care of the study patients.

Biomarker Measurements

Blood samples for determination of ST2 were collected at pre-sentation and after 48 hours. After centrifugation, samples werefrozen at �80�C until assayed in a blinded fashion in a singlebatch with the use of a monoclonal sandwich enzyme-linkedimmunosorbent assay (Presage ST2; Critical Diagnostics, SanDiego, California). All frozen specimens were collected specif-ically for the purpose of analyzing the potential value of novel bio-markers such as ST2 in monitoring and tailoring treatment inAHF. The lower detection limit of the assay is 2 U/mL, the upperdetection limit 200 U/mL.16 The within-run and total coefficientsof variation are !2.5% and !4%. The limit of quantification is3.3 U/mL. The analyte is stable for 48 hours at room temperature,for 7 days at 4�C, and for $2 months at �20�C and �80�C. Thereference change value (describing the maximal change of amarker that can potentially be attributed to preanalytical variation,analytic imprecision, and biologic variation) for healthy individ-uals is 30%.17 Age-independent reference values in a biomarker-selected healthy cohort were 3e28 U/mL in men and 2e16 U/mL in women.16

End Points

The potential of ST2 ED measurements and 48-hour ST2changes to predict mortality were assessed as primary end points.The impact of treatment at hospital discharge on 1-year mortalityaccording to ST2 strata was the secondary end point. Mortalitywas prospectively assessed during follow-up. Patients were con-tacted by telephone every 6 months after the initial presentation.In addition, referring physicians and administrative databases ofthe respective hometowns were contacted in case of uncertaintiesregarding health status or further hospitalizations. Twelve-monthsurvival status could be confirmed in all patients using thismethodology.

Statistical Analysis

The statistical analyses were performed with the use of SPSS/PC version 19.0. A statistical significance level of !.05 wasused. Discrete variables are expressed as n (%) and continuousvariables as mean 6 SD or median (interquartile range [IQR]) un-less stated otherwise. The comparison between survivors and non-survivors was done with the use of chi-square test and Fisher exacttest for categoric variables and t test for continuous variables ifnormally distributed or Mann-Whitney test if not normally distrib-uted. The Spearman rank correlation was used to perform correla-tion analyses. All hypothesis testing was 2 tailed. Cox regressionanalysis was used to demonstrate prognostic independence ofearly ST2 changes from other prognostic factors. Receiver oper-ating characteristic (ROC) curves were used to evaluate the accu-racy of ST2, early ST2 changes, and a clinical risk predictionmodel based on the Acute Decompensated Heart Failure NationalRegistry (ADHERE) to predict death.18

In an analysis of 52,164 AHF patient-records Fonarow et alfound high admission levels of blood urea nitrogen, low admissionsystolic blood pressure, and high levels of serum creatinine to bethe 3 best predictors of mortality.18 A clinical risk predictionmodel based on these 3 parameters and the heart failure (HF)marker BNP was used as a baseline model. Differences of areas

Early ST2 Changes May Offer Guidance � Breidthardt et al 823

under the ROC curve were evaluated with the method of DeLonget al.19 Additionally, integrated discrimination improvement (IDI)analysis was assessed as a method to quantify the differences inthe probabilities for events and nonevents based on the additionof ST2 and early ST2 changes to the baseline model.20 Kaplan-Meier cumulative survival curves were compared with the useof the log-rank test.

Results

Baseline Clinical and Laboratory Characteristics ofStudy Patients

Table 1 presents baseline clinical and biochemical char-acteristics of the study population. The patient cohort waselderly with a median age of 80 years, and 43% werewomen. At presentation, the median BNP level was 1,355pg/mL and the median echocardiographic LVEF 40%. Me-dian follow-up time was 368 days (range 1e1,333 days).

ST2 Levels in AHF

ST2 values at presentation were significantly correlatedwith age (r 5 0.19; P 5 .046), estimated glomerular filtra-tion rate (r 5 �0.20; P 5 .027), C-reactive protein values(r 5 0.42; P ! .001), serum troponin-T (r 5 0.40; P !.001), and leukocyte count (r 5 0.35; P ! .001) but notto BNP levels (r 5 0.16; P 5 .085) or hemoglobin levels(r 5 �0.05; P 5 .569). The median ST2 value of the over-all study population at presentation was 78 ng/mL (IQR46e121).

ST2 Levels and Short-Term Survival Status

Overall, 16 patients (8%) died during the index hospital-ization. There was no significant difference in age (P5 .24),systolic blood pressure (P5 .06), heart rate (0.28), and NewYork Heart Association (NYHA) dyspnea class (0.17) be-tween patients dying in hospital and in-hospital survivors.ST2 levels at presentation were significantly higher in pa-tients dying in hospital (150.0 ng/mL [IQR 90.8e250.4]vs 73.2 ng/mL [IQR 43.2e113.9]; P! .01). However, therewas no correlation between increasing ST2 levels and theduration of the in-hospital stay (P 5 .62).To assess the potential of ED measurements of ST2 to

predict in-hospital mortality, an ROC curve was drawn.The area under the ROC curve (AUC) for ST2 ED measure-ments was 0.81 (95% confidence interval [CI] 0.60e0.93).In univariate Cox regression analysis, ST2 levels at presen-tation significantly predicted in-hospital mortality (hazardratio [HR] 1.11, 95% CI 1.06e1.17, for every additional10 ng/mL; P ! .01). This predictive potential persisted af-ter adjustment for ADHERE risk factors and BNP values atadmission (HR 1.11, 95% CI 1.05e1.17, for every addi-tional 10 ng/mL; P ! .01).

ST2 Levels and Long-Term Survival Status

Overall, 69 patients (33%) died during the study period.Patients dying during follow-up were significantly olderthan survivors, suffered from more severe HF symptoms

at presentation (median NYHA functional class IV vs III;P 5 .01), were more likely to have chronic kidney disease,and were less likely to be treated with beta-blockers orrenin-angiotensin-aldosterone system (RAAS) blockingagents at discharge. ST2 (median 108 [IQR 75e185] vs69 [IQR 42e99] ng/mL; P ! .01), BNP (median 1,763[IQR 1,015e3,214] vs 1,333 [IQR 650e2,005] pg/mL; P! .01), and troponin-T (median 0.04 [0.02e0.07] vs 0.01[0.01e0.03] mg/L; P ! .01) levels at presentation weresignificantly higher in nonsurvivors than in survivors.

To assess the potential of ED measurements of ST2 topredict mortality, an ROC curve was drawn. The AUC forST2 ED measurements was 0.73 (95% CI 0.63e0.83;Table 2), which was similar to the predictive potential ofa clinical prediction model (model 0) based on ADHERErisk factors and BNP (AUC 0.74, 95% CI 0.65e0.85).The addition of ST2 values to this clinical risk score tendedto improve the prognostic accuracy further (AUC 0.80, 95%CI 0.71e0.89; model 1).

ST2 Changes During the 1st 48 Hours and SurvivalStatus

The impact of HF therapy during the 1st 48 hours on ST2levels was assessed. The median ST2 decrease during the 1st48 hours of in-hospital treatment was 33% [�11% to�45%]. Categoric stratification of patients according to ter-tiles of 48-hour ST2 changes clearly separated survivorsfrom nonsurvivors (Fig. 1). Importantly, ST2 levelsdecreased more significantly in survivors than in nonsurvi-vors. It should be noted that the decrease in ST2 was inde-pendent from age (r 5 0.65; P 5 .46), systolic bloodpressure (r 5 �0.46; P 5 .66), LVEF (r 5 0.05; P 5.61), absolute ST2 (r 5 �0.1; P 5 .29), troponin-T (r 50.38; P 5 .82), BNP levels in the ED (r 5 0.01; P 5 .98),the presence of atrial fibrillation (P 5 .63), and the cumula-tive dose of beta-blockers administered during the 1st 48hours (r 5 �0.11; P 5 .29). However, there was a weak,albeit significant, correlation between ST2 changes and thecumulative dose of diuretics administered during the 1st 48hours (r 5 0.18; P 5 .04) and a negative correlation withheart rate at presentation (r 5 �0.19; P 5 .03).

In a Cox regression analysis, the percentage change ofST2 over the 1st 48 hours significantly predicted long-term mortality in univariate analysis (HR 1.05, 95% CI1.02e1.08, for every increase of 10%; P ! .01). In multi-variable Cox regression analysis, the predictive potential ofearly ST2 changes persisted after the adjustment forADHERE risk factors (blood urea nitrogen, systolic bloodpressure, and serum creatinine), traditional markers ofinflammation (total white cell count and high-sensitiveC-reactive protein), BNP, troponin-T, and ST2 levels inthe ED, percentage BNP changes during the 1st 48 hours,and the cumulative diuretic dose administered during the1st 48 hours (HR 1.07, 95% CI 1.02e1.12, for every in-crease of 10%; P ! .01).

In ROC curve analysis, the addition of early ST2 changesto the clinical prediction model achieved an AUC of 0.79

Table 1. Baseline Characteristics in Survivors and Nonsurvivors With Acute Heart Failure

All Patients (n 5 207) Survivors (n 5 138) Nonsurvivors (n 5 69) P Value

Age, years, median (IQR) 80 (74e85) 79 (70e84) 83 (78e87) .03Male, n (%) 118 (57) 74 (54) 44 (64) .55Risk factors, n (%)

Hypertension 152 (73) 99 (72) 53 (77) .52Dyslipidemia 70 (34) 49 (36) 21 (30) .56

History, n (%)Coronary artery disease 100 (48) 62 (45) 38 (55) .20Heart failure 103 (50) 64 (46) 39 (57) .18Diabetes mellitus 69 (33) 42 (30) 27 (39) .24Chronic kidney disease 92 (44) 50 (36) 42 (61) !.01

Vital statusHeart rate, beats/min, median (IQR) 86 (75e102) 85 (75e100) 88 (72e103) .73Systolic blood pressure, mm Hg, mean 6 SD 137 6 26.9 140 6 26.2 130 (627.4) .02Diastolic blood pressure, mm Hg, mean 6 SD 84 6 18.4 85 6 18.5 82 (618.2) .20Oxygen saturation, %, median (IQR) 97 (95e98) 97 (95e98) 96 (93e98) .16

Outpatient treatment at presentation, n (%)Beta-blocker 123 (59) 85 (62) 38 (55) .39Angiotensin-converting enzyme inhibitor 101 (49) 74 (54) 27 (39) .06Angiotensin II blocker 44 (21) 30 (22) 14 (20) .76Diuretics 153 (74) 98 (71) 55 (80) .16Aldosterone antagonist 24 (12) 14 (10) 10 (15) .36

Treatment at discharge, n (%)Beta-blocker 133 (64) 101 (73) 32 (46) !.01Angiotensin-converting enzyme inhibitor 123 (59) 93 (67) 30 (44) !.01Angiotensin II blocker 55 (27) 38 (28) 17 (25) .62Diuretics 171 (83) 119 (86) 52 (75) .06Aldosterone antagonist 35 (17) 22 (16) 13 (19) .48

Symptoms, n (%)Weight gain 82 (46) 54 (39) 28 (41) .84Chest pain 66 (32) 45 (33) 21 (30) .84

Laboratory testsHemoglobin, g/L, mean 6 SD 125 (621.2) 125 (619.8) 122 (620) .71BNP, pg/mL, median (IQR) 1,355 (794e2,444) 1,333 (650e2,005) 1,763 (1,015e3,214) !.01ST2, ng/mL, median (IQR) 78 (46e121) 65 (41e97) 120 (79e187) !.01

Echocardiographic findings (n 5 161)Left ventricular ejection fraction 40 (615.6) 40 (615.7) 39 (615.5) .84

IQR, interquartile range; BNP, B-type natriuretic peptide.

824 Journal of Cardiac Failure Vol. 19 No. 12 December 2013

(95% CI 0.70e0.88; model 2), which was similar to theAUC achieved by model 1 (AUC 0.80, 95% CI0.71e0.89; P vs model 1 5 .76). In integrated discrimina-tion improvement (IDI) analysis, model 2 significantlyimproved the risk stratification compared with the baselinemodel (model 0). Absolute IDI was 0.04, and relative IDIwas 0.25 (P 5 .005).

However, the combined assessment of baseline ST2 andearly ST2 changes provided further prognostic informationin excess of baseline ST2 levels at presentation and the

Table 2. Prediction of 1-Year Mortality by Area Under theReceiver Operating Curve Characteristic (AUC) Plot

Analysis

AUC 95% CI P vs Model 0

Model 0 (ADHERE clinicalmodel/BNP)

0.74 0.64e0.85

ST2 baseline 0.73 0.63e0.83 .76Model 1 (ADHERE clinical

model/BNP/ST2)0.80 0.71e0.89 .06

Model 2 (ADHERE clinicalmodel/BNP/ST2 % change)

0.79 0.70e0.88 .10

Model 3 (ADHERE clinicalmodel/BNP/ST2/ST2 % change)

0.84 0.77e0.92 .02

CI, confidence interval; ADHERE, Acute Decompensated Heart FailureNational Registry; BNP, B-type natriuretic peptide.

clinical model, as presented in Table 2. Model 3 improvedthe AUC to 0.84 (95% CI 0.77e0.92). Similarly, in IDIanalysis, risk stratification was improved by model 3; abso-lute IDI for model 3 versus model 0 was 0.18, yielding arelative IDI of 1.0 (P ! .001; Fig. 2), and for model 3versus model 2 absolute and relative IDIs were 0.13 and0.6, respectively (P ! .001).

Association of Early ST2 Changes, Treatment atDischarge, and Long-Term Mortality

At discharge, 83% of patients were being treated with adiuretic, 77% with an RAAS blocking agent, and 64%with a beta-blocker. In the overall patient population,beta-blocker treatment (P ! .01) and RAAS blockade(P ! .01), but not diuretic therapy, was significantly asso-ciated with improved 1-year survival.

To assess the association among early ST2 changes,treatment at discharge, and 1-year mortality we dividedpatients into groups depending on their early ST2 response(responders: ST2 decrease $25%; nonresponders: ST2decrease !25%) and their beta-blocker, RAAS blockade,or diuretic treatment status at discharge. Table 3 presentsthe baseline characteristics of ST2 responders and

Fig. 1. Kaplan-Meier curves stratified by tertiles of ST2 changeduring the 1st 48 hours.

Early ST2 Changes May Offer Guidance � Breidthardt et al 825

nonresponders. Figure 3 shows the respective Kaplan-Meiercurves.RAAS blockers at discharge were associated with sur-

vival independently from ST2 response, whereas the associ-ation of beta-blockers with survival differed markedlyaccording to ST2 response, with beneficial effects restrictedto ST2 nonresponders (P for interaction, beta-blockers 5.04). A similar, albeit nonsignificant, trend was observedfor diuretics (P for interaction, diuretics 5 .11).Nonresponders not receiving beta-blocker treatment at

discharge experienced an annual mortality rate of w70%.In ST2 nonresponders, beta-blocker treatment was associ-ated with a significant decrease in 1-year mortality to

Fig. 2. Graphic depiction of integrated discriminatory improve-ment (IDI) analysis. IDI can be calculated as the difference be-tween the improvement in average sensitivity and changes inaverage of ‘‘1 � specificity.’’

22%, equaling the mortality rate of ST2 respondersreceiving beta-blocker therapy (treated responders vs treatednonresponders, beta-blockers: P log-rank5 .62). In contrast,beta-blocker therapy was not associated with improved 1-year mortality rates in ST2 responders (P log-rank 5 .10).Similar trends could be observed for diuretic therapy. Theassociation with survival for beta-blocker and diuretic ther-apy in ST2 nonresponders was independent from LVEF andpersisted in patients with preserved LVEF (beta-blockers: Plog-rank 5 .79; diuretics: P log-rank 5 .73).

Discussion

In this investigation we specifically examined thepotential of ED and serial measurements of ST2 to assesslong-term mortality. Additionally, we investigated the asso-ciation of long-term HF therapy with 1-year mortality ac-cording to early ST2 changes in patients presenting withAHF.

We report 5 major findings. First, levels of ST2 at presen-tation to the ED are significantly associated with mortality.Second, early ST2 changes over the 1st 48 hours also aresignificantly associated with long-term mortality. Third,early ST2 changes provide additional prognostic informa-tion when assessed in combination with clinical risk strati-fication models. Fourth, therapy with beta-blockers atdischarge might be associated with a beneficial effect onmortality in ST2 nonresponders, whereas this associationis not be seen in ST2 responders. Fifth, the association ofRAAS blocking agents with survival appears to be indepen-dent of the ST2 response.

Our results extend and corroborate earlier studies assess-ing the association between ST2 levels measured in patientspresenting with acute dyspnea to the ED and mortality. Ja-nuzzi et al were the first to report the prognostic potential ofST2, with the use of a 1st-generation assay, and found ST2levels to be significantly higher in 1-year nonsurvivors thansurvivors.21 Similar results were reported from 2 subse-quent studies with the use of the 2nd-generation PresageST2 assay.15,22 Importantly, these studies consistentlyfound ST2 measurements at presentation to independentlypredict all-cause mortality.15,21

Our findings extend and corroborate the only previousstudy regarding early ST2 changes during AHF hospitaliza-tion.23 Boisot et al collected ST2 samples at 6 time pointsthroughout the in-hospital period of 150 AHF patientsand found ST2 changes between admission and dischargeto be predictive of 90-day all-cause mortality. Patientsshowing in-hospital ST2 changes of !15.5% experienceda 90-day mortality of 33%, whereas patients exhibitingST2 decreases O15.5% displayed a significantly lower90-day mortality rate of 7%.23 Importantly, Boisot et alfound ST2 levels to reach their lowest levels after 4 daysof AHF therapy. Our study adds to these findings by short-ening to 48 hours the observational period for ST2 changesto occur. Importantly, 48-hour risk stratification was inde-pendent from conventional risk factors.

Table 3. Baseline Characteristics of ST2 Responders and Nonresponders

Parameter ST2 Responders ST2 Nonresponders P Value

Age, y, median (IQR) 80 (74e84) 81 (75e86) .30Male 58% 57% .69History

Coronary artery disease 48% 46% .88Heart failure 55% 43% .16Diabetes mellitus 30% 48% .04Chronic kidney disease 47% 56% .15

Vital statusHeart rate, beats/min, median (IQR) 85 (75e110) 84 (71e96) .33Systolic blood pressure, mm Hg, mean 6 SD 135 (623.6) 133 (629.2) .46Diastolic blood pressure, mm Hg, mean 6 SD 85 (620.4) 83 (618.2) .61

Outpatient treatment at presentationBeta-blocker 58% 62% .64Angiotensin-converting enzyme inhibitor 52% 49% .71Diuretics 76% 79% .73

Outpatient treatment at dischargeBeta-blocker 67% 63% .71Angiotensin-converting enzyme inhibitor 59% 61% .89Diuretics 83% 85% .42

Laboratory tests, median (IQR)Creatinine (umol/L) 108 (81e137) 132 (86e188) .05BNP (pg/mL) 1405 (851e2532) 1555 (792e3011) .64ST2 (ng/mL) 84 (50e116) 74 (40e120) .44

Abbreviations as in Table 1.

826 Journal of Cardiac Failure Vol. 19 No. 12 December 2013

In contrast to the stable chronic HF setting, none of thedrugs currently used at ED presentation, during in-hospitaltreatment, or at hospital discharge in patients with AHFhas been shown to improve outcome.2 We therefore triedto assess the potential of biomarker signaling as a novelapproach to individualize treatment at hospital discharge.Beta-blockers and RAAS blocking agents build the back-bone of modern therapy in stable patients with chronic HFand reduced LVEF.24e27 Their utility in AHF patients,particularly the time point to initiate them, is unknown.Additionally, in the face of an ever aging, highly comorbidpatient population,3 in whom cardiovascular polypharmacyis associated with considerable challenges,4 a stepwise initi-ation and up-titration of the guideline-approved chronic HFtherapy might be necessary. Short primary in-hospital stays,prohibiting a stepwise initiation of chronic HF therapy,further amplify this problem.28 In the face of these chal-lenges, clinicians are left with the difficult choice of select-ing a primary drug class before subsequently adding allguideline-recommended therapies. Because AHF syn-dromes differ greatly both in phenotype as well as diseaseseverity from each other, beta-blocker therapy at dischargemay well be more beneficial in some patients than in others.Similar uncertainty underlies the use of diuretics at hospitaldischarge. Although the widespread use of diuretics29 relieson forced diuresis and rapid symptom relief, various studieshave reported an association between diuretic use atdischarge and increased patient mortality.30e32

In the present nonrandomized study of AHF patients,RAAS blocking agents were associated with 1-year survivalindependently from the early ST2 response. However, weobserved beta-blocker therapy to be primarily associatedwith survival in the ST2 nonresponder subgroup. Addition-ally, our data hint toward a potential beneficial effect of

long-term diuretic use in early ST2 nonresponders. It isnoteworthy that no association with survival could beobserved for either beta-blocker or diuretic therapy inST2 responders. Importantly, these findings persisted afteradjusting for LVEF and might open the door to a promisingnew application of early ST2 changes in the long-term ther-apy guidance of AHF patients.

Circulating ST2 levels in AHF integrate inflammatorysignals and cardiac strain; the ST2 gene (T1, IL1RL1, orFitt1) is a member of the interleukin-1 receptor host de-fense family which serve as a gateway to proinflammatorysignaling pathways.10 The transmembrane ST2 isoform(ST2L) has been shown to modulate T-helper 2 cell activ-ity33 and to be involved in the development of immunologictolerance.34 Additionally, recent studies displayed the antifi-brotic and antihypertrophic effects of interleukin (IL) 33 tobe mediated by the ST2L/IL-33 complex.35,36 Importantly,the cardioprotective effects of IL-33 seem to be caused bya direct antiinflammatory effect on cardiac myocytes.35

In contrast to the cardioprotective effects of ST2L/IL-33signaling, the soluble ST2 isoform appears to act as an IL-33 decoy receptor.35,37 By scavenging circulating IL-33,the soluble ST2 isoform inhibits ST2L/I-33einduced cardi-oprotection. In addition, soluble ST2 is secreted by cardiacmyocytes in response to mechanical stretch and volumeoverload.38 Thus, ST2 nonresponders are characterized bypersistent inflammation, inhibited cardioprotection, andhypervolemia.

We hypothesize that the association with survival seenfor beta-blocker and diuretic therapy in ST2 nonrespondersmay directly represent the antiinflammatory and volume-depleting effects of these drug classes. In fact, metoprololhas been shown to reduce the secretion of the proinflamma-tory cytokines tumor necrosis factor a, IL-1b, and IL-6.

Fig. 3. Kaplan-Meier curves stratified by ST2 response and treat-ment status at discharge: (A) beta-blocker (BB) therapy; (B)diuretic (DIU) therapy, 3c: renin-angiotensin-aldosterone systemblockade (RAAS-I).

Early ST2 Changes May Offer Guidance � Breidthardt et al 827

The extent of this cytokine inhibition correlates with the de-gree of hemodynamic improvement in human metoprololtreated HF.12 Similar antiinflammatory and antioxidant ef-fects have been described for carvedilol and bisoprolol.13,14

Several limitations of this study merit consideration. First,it was an observational single-center study, and patientswho died were less likely to be prescribed RAAS blockingagents and beta-blockers, were older, and had poorer renalfunction. However, because baseline characteristics, the pre-scription rates of HF therapies, mortality rates, and the

predictive potential of ED and serial ST2 measurementsclosely follow those of earlier studies,15,21e23,39e41 weconsider our patient population to be representative. Further-more, the association of ED and serial measurements withmortality remained statistically significant after the adjust-ment of baseline differences and important HF risk predic-tors. Second, we did not assess outpatient treatment duringfollow-up, but relied on the treatment information at hospi-tal discharge. Although discharge therapy in this study wassimilar to the results of the EuroeHeart Failure Survey II,39

we can not comment on the effect of possible therapychanges during follow-up. Third, owing to the design ofthe study and the small number of patients receiving aldo-sterone blocking agents at discharge at the time of patientenrollment, we can not comment on the association betweenearly ST2 changes and long-term aldosterone blockade. Thisaspect warrants further study. Fourth, treating physicianswere blinded to the ST2 test results, so we could not assessthe impact of a biomarker-guided treatment strategy on HFdrug prescription rates, treatment costs, and long-termoutcome. Further large-scale observational and eventuallyrandomized controlled studies will be necessary to substan-tiate the hypotheses derived from this study.

In conclusion, ED and serial ST2 measurements are strongand independent predictors of 1-year mortality in AHF.

Acknowledgments

The authors thank the patients who participated in thestudy, the staff of the emergency department, and the labo-ratory technicians (particularly Michael Freese, ClaudiaStelzig, Esther Garrido, Irina Klimmeck, Melanie Wieland,Kirsten Hochholzer, and Fausta Chiaverio) for their mostvaluable efforts.

Disclosures

Prof Dr Mueller has received research support from theSwiss National Science Foundation (PP00B-102853), theSwiss Heart Foundation, Abbott, ALERE, BRAHMS, Roche,Siemens, and the Department of Internal Medicine, Univer-sity Hospital Basel, as well as speaker honoraria fromALERE, Abbott, BRAHMS, Roche, and Siemens. Dr Breid-thardt has received research support from the Swiss NationalScience Foundation and the University of Basel. All of theother authors declare that they have no conflict of interest.

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