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CLINICAL RESEARCH: BIOMARKERS

Soluble ST2 for Predicting Sudden Cardiac Death in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction

Domingo A. Pascual-Figal, MD, PhD^_*,_*, Jordi Ordoñez-Llanos, MD, PhD, Pedro L. Tornel, PhD, Rafael Vázquez, MD, PhD^||, Teresa Puig, MD, PhD, Mariano Valdés, MD, PhD^_*, Juan Cinca, MD, PhD, Antoni Bayes de Luna, MD, PhD^¶, Antoni Bayes-Genis, MD, PhD on behalf of the MUSIC Investigators

^_* Cardiology Service, Virgen de la Arrixaca Hospital and Department of Medicine, University of Murcia, Murcia, Spain
Biochemistry Service, Sant Pau Hospital and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain
Cardiology Service, Sant Pau Hospital, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Biochemistry Service, Virgen de la Arrixaca Hospital, Murcia, Spain
^|| Cardiology Service, Hospital Universitario Puerta del Mar, Cádiz, Spain
^¶ Institut Català de Ciències Cardiovasculars, Barcelona, Spain

Manuscript received June 9, 2009; accepted July 8, 2009.

^_* Reprint requests and correspondence: Dr. Domingo A. Pascual-Figal, Heart Failure Unit, Cardiology Department, University Hospital Virgen de la Arrixaca Ctra Madrid-Cartagena s/n, 30120 Murcia, Spain (Email: dapascual{at}servicam.com).

	Abstract

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Objectives: We studied whether the measurement of the soluble form of ST2 (sST2), an interleukin-1 receptor family member, could identify heart failure (HF) patients at risk of sudden cardiac death (SCD).

Background: The prediction of SCD remains an important challenge in patients with mild-to-moderate chronic HF. Concentrations of sST2 have been found increased and related to worse long-term outcomes in patients with acute HF. Whether sST2 has a prognostic role in SCD is unknown.

Methods: A nested case-control study was performed on 36 cases of SCD and 63 control patients (matched for age, sex, and left ventricular ejection fraction) obtained from the MUSIC (MUerte Súbita en Insuficiencia Cardíaca) registry, a 3-year multicenter registry of ambulatory HF patients (New York Heart Association functional class II to III, left ventricular ejection fraction 45%). Demographic, clinical, echocardiographic, electrical, and biochemical data were collected at enrollment.

Results: Concentrations of sST2 were greater among decedents (0.23 ng/ml [interquartile range 0.16 to 0.43 ng/ml] vs. 0.12 ng/ml [interquartile range 0.06 to 0.23 ng/ml], p = 0.001) and were predictive of experiencing SCD (+0.1 ng/ml, odds ratio: 1.39, 95% confidence interval: 1.09 to 1.78, p = 0.006). On the basis of a combined biomarker status, only 4% of patients experienced SCD for neither sST2 nor N-terminal pro–B-type natriuretic peptide (NT-proBNP) above receiver-operator characteristic-derived cut-off points (0.15 ng/ml and 2,000 ng/l, respectively), 34% for either biomarker above, and 71% for both biomarkers above (p < 0.001 for trend). This combined variable added incremental prognostic value to the multivariable regression model (p < 0.001).

Conclusions: Elevated sST2 concentrations are predictive of SCD in patients with chronic HF and provide complementary information to NT-proBNP levels. A combined biomarker approach may have an impact on clinical decision-making.

Key Words: soluble ST2 • sudden cardiac death • chronic heart failure • B-type natriuretic peptide • biomarkers

Abbreviations and Acronyms   BNP = B-type natriuretic peptide   CI = confidence interval   HF = heart failure   IL = interleukin   IQR = interquartile range   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   NT-proBNP = N-terminal pro–B-type natriuretic peptide   OR = odds ratio   ROC = receiver-operator characteristic   SCD = sudden cardiac death   sST2 = soluble ST2

ST2, an interleukin (IL)-1 receptor family member, has been identified as a novel biomarker for cardiac strain (12,13). Under the induction of separate promoters, the ST2 gene expresses 2 unique proteins: sST2, the circulating form of ST2, and ST2L, which is the transmembrane receptor form and signals through a complex involving IL-33 (14–16). This IL-33/ST2L signaling plays a previously unrecognized cardioprotective role in mechanical overload and exerts antifibrotic actions (17,18). Sanada et al. (17) demonstrated that the sST2 protein acts as a decoy receptor, reversing the protective effects of IL-33/ST2L in a dose-dependent manner, probably by binding IL-33 and preventing signaling through ST2L. Thus, it is postulated that sST2 could be a potential pathophysiological mediator of myocardial fibrosis.

Concentrations of sST2 have been found to be predictive of the rate of mortality in acute coronary syndromes (19,20) and also in the long-term follow-up of patients after an acute HF episode (21–23). Whether sST2 could have a role in the identification of patients at risk of SCD is not known. On the basis of its fibrosis-modulating effect (17,18) and the interaction between cardiac fibrosis and electrical heterogeneity in SCD (11); we hypothesized that sST2 could identify patients at risk of SCD and add useful prognostic information for stratifying care. The aim of this study was to investigate such prognostic value in a nested case-control study of patients with mild-to-moderate HF and LV systolic dysfunction.

	Methods

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Study population and protocol.   The study was a post-hoc, nested case-control study of participants included in the MUSIC (MUerte Súbita en Insuficiencia Cardíaca) study (24,25), a prospective multicenter longitudinal study designed to assess risk predictors of cardiac mortality and SCD in patients with HF in New York Heart Association functional class II to III. Participants were those patients consecutively enrolled in 3 specialist HF clinics, between April 2003 and December 2004, with both LVEF 45% and absence of an implanted cardiac defibrillator (n = 356). All patients received standard management as recommended by contemporary guidelines, including pharmacologic therapy at the maximal tolerated doses (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker 93%, beta-blockers 73%, loop diuretics 86%, spironolactone 56%, digoxin 40%).

All patients were followed for 3 years, and case participants (n = 36) consisted of all individuals who died of SCD. After identifying cases of SCD, controls were those patients who remained alive during follow-up (3 years; n = 247). Patients were sorted according to the time of inclusion, and we attempted to match 2 control patients to each case by using the nearest control subjects that fulfilled the following criteria: same sex, age within ±5 years, and LVEF ± 5%. A total of 63 control subjects were matched to cases. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) recommendations (26) were used in the development of the study.

Detailed information about symptoms, clinical history, 12-lead electrocardiogram, and medication usage was collected at baseline. An echocardiogram was performed at baseline in all patients, and standardized measures were obtained according to the American Society of Echocardiography recommendations (27). The 24-h ambulatory 3-channel electrocardiographic recordings were obtained at baseline and analyzed by the use of ELA Synescope Holter software (ELA Medical, Sorin Group, Paris, France) to evaluate the presence of ventricular arrhythmias. The study protocol was approved by the respective institutional investigation committees, and all patients signed informed consent. Follow-up visits were conducted on an outpatient basis every 6 months or according to patients' clinical status for 3 years.

Definition of SCD.   Cases of death were verified by hospital and autopsy records and by either relatives or the primary physicians who had witnessed the death. Death was defined as "sudden cardiac death" (28) by an "ad-hoc committee" (R.V., J.C., A.B.d.L., and A.B.-G.) if it was: 1) a witnessed death occurring within 60 min from the onset of new symptoms, unless a cause other than cardiac was obvious; 2) an unwitnessed death (<24 h) in the absence of pre-existing progressive circulatory failure or other causes of death; or 3) a death during attempted resuscitation.

Biochemical analysis.   Blood samples were obtained by venipuncture at patient enrollment and aliquots of serum stored at –80°C until analyzed. Concentrations of sST2 were determined by the use of an enzyme-linked immunosorbent assay from Medical & Biological Laboratories Co. (no. 7638, Woburn, Massachusetts) (12). This nonautomated assay, which uses monoclonal antibodies to human sST2 for both capture and detection of sST2, requires several manual steps, and its total imprecision at the concentration found as cut-off point (0.150 ng/ml) was of 18.5% (ranging from 5.7% at 4.0 ng/ml to 20% at 0.0625 ng/ml). The total imprecision we found was close to the recommended as desirable (<15%) in international guidelines (29) for the cut-off values of similar HF biomarkers, as B-type natriuretic peptides (BNPs), measurable with fully automated methods. N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels were measured at the time of patient inclusion by electrochemiluminescence immunoassay by the use of an Elecsys 2010 analyzer (Roche Diagnostics GmbH, Mannheim, Germany) with a total imprecision <3% (30). Both sST2 and NT-proBNP were evaluated in a central laboratory (J.O.-L).

Statistical analysis.   Continuous variables were tested for normal distribution by use of the Kolmogorov-Smirnov test. Variables not normally distributed are expressed as median (interquartile range [IQR]). Normally distributed continuous variables are expressed as mean ± SD. Frequencies of categorical variables were expressed as numbers (percentage) and compared by the Fisher exact test. The comparison of continuous variables between the 2 groups was carried out by use of the Mann-Whitney U nonparametric test. Receiver-operating characteristic (ROC) curve analysis was constructed to determine the optimal cut-off points for NT-proBNP and sST2 for predicting SCD. A new ordinal value was built on the basis of a combined biomarker status, taking into account the presence of neither, either, or both biomarkers above the ROC-derived cut-off points.

Univariable logistic regression analysis was used for studying the association between SCD and biomarkers and was evaluated as continuous variables and as the new combined ordinal variable. The clinical, electrical, echocardiographic, and biochemical characteristics are described in Table 1 were also evaluated in the univariable logistic regression analysis. Variables that showed a significant result (p < 0.05) were included in the multivariable logistic regression model (forward stepwise) to determine those independently related to SCD. The incremental information added by sST2 was studied by taking the optimal regression multivariable model and then adding sST2 to this model. The combined variable sST2/NT-proBNP also was the last variable put into the multivariable model to assess its incremental value added to the other variables. All tests were 2-sided, and a p value <0.05 was considered statistically significant. All data analyses were performed by the use of SPSS version 15.0 software (SPSS Inc., Chicago, Illinois).

	Results

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View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 1 sST2 and NT-proBNP in Patients With SCD and Survivors Box plots showing the baseline concentrations of soluble ST2 (sST2) (A) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) (B) in patients experiencing sudden cardiac death (SCD) and the control survivor group.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Receiver-Operator Characteristic Curve Analysis of sST2 and NT-proBNP Concentrations for Predicting SCD AUC = area under the curve; other abbreviations as in Figure 1.

In a combined biomarker approach, the presence of none, either (p = 0.015), or both elevated biomarkers (p < 0.001) were predictive of SCD (p < 0.001 for trend). As shown in Table 2, this combined variable added incremental prognostic value to the multivariable regression model (p < 0.001). The presence of none, 1, or 2 elevated biomarkers was associated with increasing rates of SCD (Fig. 3); only 4% of patients experienced SCD for neither sST2 nor NT-proBNP above the ROC-derived cut-off points; 34% for either biomarker above and 71% for both biomarkers above.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Events According to the Presence of None, Either, or Both sST2 >0.15 ng/ml and NT-proBNP >2,000 ng/l Red bars = sudden cardiac death; open bars = survivors. Abbreviations as in Figure 1.

	Discussion

Top Abstract Methods Results Discussion Conclusions References

This study is the first to demonstrate a significant association between this novel biomarker and SCD. The authors of previous reports (22,23) already recognized sST2 as a powerful prognosticator for all-cause mortality during the long-term follow-up (1 year) in patients with acute HF. In our population, sST2 added independent prognostic information to predict SCD over the other studied variables, including NT-proBNP. Therefore, this study provides new data about the prognostic value of sST2 in the ambulatory setting of chronic HF and the complementary roles of sST2 and NT-proBNP. Such a multimarker predictive approach, sST2 plus NT-proBNP, also has been reported in patients with acute coronary syndromes and acute HF (20,22,23). In our HF population, elevation of both biomarkers above the cut-off values was associated with a very high rate (71%) of SCD, and interestingly, a very low rate (4%) of SCD existed when both markers were below the cut-off thresholds. At present, no single test reliably predicts SCD in patients with HF (10), but the combination of sST2 and NT-proBNP markedly improves risk stratification to identify high- and low-risk patients; this fact, may have an important impact on clinical decision-making, particularly for delineating optimal preventive strategies.

It is noticeable that the sST2 cut-off value for SCD in HF patients found in this study (0.150 ng/ml) is very close to the 95 percentile of a blood donor population found by Rehman et al. (22) (0.168 ng/ml) and to the cut-off value found in the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study to predict 1-year mortality in acutely dyspneic and acute HF patients (0.200 ng/ml) (31). Therefore, our results support the evidence of a "solid" cut-off value between 0.150 and 0.200 ng/ml for predicting and ruling-out major cardiac events in HF patients. It is likely that sST2 may fluctuate over time, as occurs with BNP, and it has been reported that changes in sST2 concentrations have also a prognostic value (21,32). In this study, we did not collect serial sST2 measures to explore the effect of changes over time, yet the presented data support the predictive value of a single inclusion measurement.

The relationship between ST2 and SCD is at present incompletely characterized, but some hypothesis could arise based on the physiology of IL-33/ST2 pathway. IL-33/ST2 has emerged as an intercellular signaling system that participates in inflammatory responses, autoimmunity, organ fibrosis, and cardiac injury (18). IL-33/ST2 signaling protects the myocardium under mechanical strain and acts as a biomechanically activated fibroblast-cardiomyocyte paracrine system that prevents cardiac hypertrophy and fibrosis (17,18). Sanada et al. (17) suggest that sST2 protein abrogates this adaptative response in a dose-dependent manner by binding IL-33 and preventing signaling through ST2L. Moreover, IL-33/ST2 system might participate in inflammatory and remodeling processes of the myocardium (15,33). Concentration of sST2 correlate positively with parameters of HF severity, as norepinephrine levels, natriuretic peptides levels, diastolic filling pressures, and C-reactive protein levels (21–23,34). It is thus possible that sST2 is not only a biomarker of outcome but also a true pathophysiological mediator of disease progression and predisposition to SCD.

sST2 modulates extracellular matrix remodeling and regulates inflammatory and electrical signals between cardiac cells types that may facilitate lethal cardiac arrhythmias (18,35) or other cardiac events ultimately leading to SCD. Moreover, its relationship with fibrosis and inflammation could explain its complementary role with NT-proBNP; in fact, procollagen and high-sensitivity C-reactive protein also have been shown to be complementary of BNP in the prediction of ventricular tachycardia, among patients with implanted cardioverter-defibrillator (9).

Sudden cardiac death is a hard end point in patients with HF, yet this mode of death is difficult to obtain, and it has been mainly evaluated by clinical trials of primary prevention. The registry from which current data were obtained was specifically designed to study SCD, and therefore patients were closely followed and the mode of death rigorously verified by an independent "ad-hoc committee," as prespecified. However, without cardiac monitoring at the time of death, the assumption of an underlying arrhythmic cause is only presumptive. After 3 years of follow-up, 36 sudden deaths were identified. This is a large group of SCD patients, comparable or greater than those of several published clinical trials on sudden death (4–8,28,36). The greatest-risk patients, those who already had a defibrillator implanted, were excluded. Nevertheless, although the highest- and lowest-risk patients obtain less benefit from risk stratification, the patients at an intermediate risk, like those included in this study, are most benefited by SCD prediction.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
This is the first study to demonstrate that elevated sST2 concentrations are predictive of SCD and provide complementary information to clinical variables and NT-proBNP. Future trials are needed to elucidate whether this novel biomarker, alone or in combination with NT-proBNP, is useful in clinical routine for preventing SCD.

	Footnotes

 
This study was supported by "Red Temática de Investigación Cooperativa MUSIC" and the national network of investigation on heart failure "REDINSCOR": Grants G03/078 and RD06/0003, Instituto de Salud Carlos III, Ministry of Health, Madrid, Spain. Dr. Pascual-Figal has received speaking and research grants from Roche Diagnostics. Dr. Ordoñez-Llanos has received speaking, consulting, and research grants from Roche Diagnostics. Dr. Bayes-Genis has received speaking and research grants from Roche Diagnostics. Critical Diagnostics freely provided the reagents used to measure sST2. The first 2 authors contributed equally to this work.

	References

Top Abstract Methods Results Discussion Conclusions References

 
1. Uretsky BF, Sheahan RG. Primary prevention of sudden cardiac death in heart failure: will the solution be shocking? J Am Coll Cardiol 1997;30:1589-1597.[Abstract]

2. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J Am Coll Cardiol 2006;48:e247-e346.[Free Full Text]

3. Buxton AE, Lee KL, Hafley GE, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial Circulation 2002;106:2466-2472.[Abstract/Free Full Text]

4. Zimetbaum PJ, Buxton AE, Batsford W, et al. Electrocardiographic predictors of arrhythmic death and total mortality in the multicenter unsustained tachycardia trial Circulation 2004;110:766-769.[Abstract/Free Full Text]

5. Doval HC, Nul DR, Grancelli HO, et al. GESICA-GEMA Investigators Nonsustained ventricular tachycardia in severe heart failure. Independent marker of increased mortality due to sudden failure. Circulation 1996;94:3198-3203.[Abstract/Free Full Text]

6. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure Circulation 2002;105:2392-2397.[Abstract/Free Full Text]

7. Hodges M, Bailey JJ, Church TR. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure Circulation 2003;107:e13.[CrossRef][Web of Science][Medline]

8. Watanabe J, Shiba N, Shinozaki T, et al. Prognostic value of plasma brain natriuretic peptide combined with left ventricular dimensions in predicting sudden death of patients with chronic heart failure J Card Fail 2005;11:50-55.[CrossRef][Web of Science][Medline]

9. Blangy H, Sadoul N, Dousset B, et al. Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventricular tachycardia in ICD recipients after myocardial infarction Europace 2007;9:724-729.[Abstract/Free Full Text]

10. Lane RE, Cowie MR, Chow AWC. Prediction and prevention of sudden cardiac death in heart failure Heart 2005;91:674-680.[Free Full Text]

11. Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res 2004;95:754-763.[Abstract/Free Full Text]

12. Kurosawa K, Li H, Tago K, Iwahana H, et al. Construction of ELISA system to quantify human ST2 protein in sera of patients Hybridoma 2000;19:151-159.[CrossRef][Web of Science][Medline]

13. Weinberg EO, Shimpo M, De Keulenaer GW, et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction Circulation 2002;106:2961-2966.[Abstract/Free Full Text]

14. Iwahana H, Yanagisawa K, Ito-Kosaka A, et al. Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells Eur J Biochem 1999;264:397-406.[Web of Science][Medline]

15. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor related protein ST-2 and induces T helper type 2-associated cytokines Immunity 2005;23:479-490.[CrossRef][Web of Science][Medline]

16. Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex J Immunol 2007;179:2551-2555.[Abstract/Free Full Text]

17. Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system J Clin Invest 2007;117:1538-1549.[CrossRef][Web of Science][Medline]

18. Rakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker Nat Rev Drug Discov 2008;7:827-840.[CrossRef][Web of Science][Medline]

19. Shimpo M, Morrow DA, Weinberg EO, et al. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction Circulation 2004;109:2186-2190.[Abstract/Free Full Text]

20. Sabatine MS, Morrow DA, Higgins LJ, et al. Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction Circulation 2008;117:1936-1944.[Abstract/Free Full Text]

21. Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker Circulation 2003;107:721-726.[Abstract/Free Full Text]

22. Rehman SU, Mueller T, Januzzi JL. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure J Am Coll Cardiol 2008;52:1458-1465.[Abstract/Free Full Text]

23. Mueller T, Dieplinger B, Gegenhuber A, Poelz W, Pacher R, Haltmayer M. Increased plasma concentrations of soluble ST2 are predictive for 1-year mortality in patients with acute destabilized heart failure Clin Chem 2008;54:752-756.[Abstract/Free Full Text]

24. Bayes-Genis A, Vazquez R, Puig T, et al. Left atrial enlargement and NT-proBNP as predictors of sudden cardiac death in patients with heart failure Eur J Heart Fail 2007;9:802-807.[Abstract/Free Full Text]

25. Vazquez R, Bayes-Genis A, Cygankiewicz I, et al. The MUSIC risk score: a simple method for predicting mortality in ambulatory patients with chronic heart failure Eur Heart J 2009;30:1088-1096.[Abstract/Free Full Text]

26. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies Lancet 2007;370:1453-1457.[CrossRef][Web of Science][Medline]

27. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 2005;18:1440-1463.[CrossRef][Web of Science][Medline]

28. Tapanainen JM, Lindgren KS, Makikallio TH, Vuolteenaho O, Leppaluoto J, Huikuri HV. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era J Am Coll Cardiol 2004;43:757-763.[Abstract/Free Full Text]

29. Apple FS, Wu AH, Jaffe AS, et al. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: analytical issues for biomarkers of heart failure. National Academy of Clinical Biochemistry; IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine. Circulation 2007;31(116):e95-e98.

30. Pascual-Figal DA, Domingo M, Casas T, et al. Usefulness of clinical and NT-proBNP monitoring for prognostic guidance in destabilized heart failure outpatients Eur Heart J 2008;29:1011-1018.[Abstract/Free Full Text]

31. Januzzi Jr. JL, 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;50:607-613.[Abstract/Free Full Text]

32. Boisot S, Beede J, Isakson S, et al. Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure J Card Fail 2008;14:732-738.[CrossRef][Web of Science][Medline]

33. Timmers L, Sluijter JP, Van Keulen JK, et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction Circ Res 2008;102:257-262.[Abstract/Free Full Text]

34. Bartunek J, Delrue L, Van Durme, et al. Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load J Am Coll Cardiol 2008;52:2166-2174.[Abstract/Free Full Text]

35. Baudino TA, Carver W, Giles W, Borg TK. Cardiac fibroblasts: friend or foe? Am J Physiol Heart Circ Physiol 2006;291:H1015-H1026.[Abstract/Free Full Text]

36. Saxon LA, Bristow MR, Boehmer J, et al. Predictors of sudden cardiac death and appropriate shock in the comparison of medical therapy, pacing, and defibrillation in heart failure (COMPANION) trial Circulation 2006;114:2766-2772.[Abstract/Free Full Text]

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