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Archives of Cardiovascular Disease (2014) xxx, xxx—xxx

Available online at

ScienceDirectwww.sciencedirect.com

REVIEW

Prognostic markers of acute decompensatedheart failure: The emerging roles of cardiacbiomarkers and prognostic scores

Marqueurs pronostiques de l’insuffisance cardiaque aiguëdécompensée : place croissante des biomarqueurs et des scorespronostiques

Alain Cohen-Solal a,b,c,d,∗, Said Laribi a,e,Shiro Ishiharaa,f, Giuseppe Vergaroa,g,Mathilde Baudetc, Damien Logearta,b,c,d,Alexandre Mebazaaa,b,d,h, Etienne Gayata,b,d,h,Nicolas Vodovara, Domingo A. Pascual-Figal i,Marie-France Serondea,j

a UMR-S 942 ‘‘Biomarqueurs et Insuffisances Cardiaques’’, Paris, Franceb Université Paris Diderot, Sorbonne Paris Cité, Paris, Francec Cardiology department, hôpital Lariboisière, Assistance publique—Hôpitaux de Paris, 2, rueAmbroise-Paré, 75010 Paris, Franced DHU FIRE, Sorbonne Paris Cité, Paris, Francee Emergency department, hôpital Lariboisière, Assistance publique—Hôpitaux de Paris, Paris,Francef Cardiology department, Steel Memorial Yawata Hospital, Kitakyushu, Japang Cardiology and cardiovascular medicine division, Fondazione Toscana Gabriele Monasterioper la Ricerca Medica e di Sanità Pubblica, CNR-Regione Toscana, Pisa, Italy

Please cite this article in press as: Cohen-Solal A, et al. Prognostic markers of acute decompensatedheart failure: The emerging roles of cardiac biomarkers and prognostic scores. Arch Cardiovasc Dis (2014),http://dx.doi.org/10.1016/j.acvd.2014.10.002

Abbreviations: ADHF, Acute decompensated heart failure; AHF, Acute heart failure; BNP, B-type natriuretic peptide; BUN, Blood ureanitrogen; CHF, Chronic heart failure; COPD, Chronic obstructive pulmonary disease; CRP, C-reactive protein; Gal-3, Galectin-3; GFR, Glomeru-lar filtration rate; HF, Heart failure; hsTn, High-sensitivity troponin; ICU, Intensive care unit; IL, Interleukin; KIM-1, Kidney injury molecule1; MR-proADM, Mid-regional pro-adrenomedullin; MR-proANP, Mid-regional pro-atrial natriuretic peptide; NGAL, Neutrophil gelatinase-associated lipocalin; NP, Natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SBP, Systolic blood pressure; sST2,Soluble ST2; ST2L, Membrane-bound ST2.

∗ Corresponding author. Cardiology department, hôpital Lariboisière, Assistance publique—Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010Paris, France.

E-mail address: alain.cohen-solal@inserm.fr (A. Cohen-Solal).

http://dx.doi.org/10.1016/j.acvd.2014.10.0021875-2136/© 2014 Elsevier Masson SAS. All rights reserved.

ARTICLE IN PRESS+ModelACVD-780; No. of Pages 11

2 A. Cohen-Solal et al.

h Anaesthesia-ICU department, hôpital Lariboisière, Assistance publique—Hôpitaux de Paris,Paris, Francei Cardiology department, hospital Virgen de la Arrixaca, school of medicine, university ofMurcia, Murcia, Spainj Cardiology department, CHU de Besancon, Besancon, France

Received 24 July 2014; received in revised form 25 September 2014; accepted 2 October2014

KEYWORDSAcutedecompensated heartfailure;Prognosis;Scores;Biomarkers;Natriuretic peptides

Summary Rapidly assessing outcome in patients with acute decompensated heart failure isimportant but prognostic factors may differ from those used routinely for stable chronic heartfailure. Multiple plasma biomarkers, besides the classic natriuretic peptides, have recentlyemerged as potential prognosticators. Furthermore, prognostic scores that combine clinical andbiochemical data may also be useful. However, compared with the scores used in chronic heartfailure, scores for acute decompensated heart failure have not been validated. This articlereviews potential biomarkers, with a special focus on biochemical biomarkers, and possibleprognostic scores that could be used by the clinician when assessing outcome in patients withacute heart failure.© 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSInsuffisancecardiaque aiguë ;Pronostic ;Scores de risque ;Biomarqueurs ;Peptidesnatriurétiques

Résumé L’évaluation précoce du pronostic chez les patients atteints d’insuffisance cardiaqueaiguë décompensée est importante mais les facteurs pronostiques peuvent différer de ceuxutilisés couramment pour une insuffisance cardiaque stable chronique. De nouveaux biomar-queurs plasmatiques sont apparus avoir une valeur pronostique ces dernières années, à côtédes classiques peptides natriurétiques. En outre, des scores de risque, combinant les donnéescliniques et biochimiques, peuvent également être utilisés. Cependant, à la différence de ceuxutilisés dans l’insuffisance cardiaque chronique, les scores de risque ont été moins validésdans l’insuffisance cardiaque aiguë décompensée. Cet article passe en revue les biomarqueurspronostiques potentiels, avec un accent particulier sur les marqueurs biochimiques, et les scoresde risque qui pourraient être utilisés plus souvent par le clinicien en charge de patients atteintsd’insuffisance cardiaque aiguë pour prédire rapidement le pronostic.© 2014 Elsevier Masson SAS. Tous droits réservés.

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atients with cardiovascular disease generally have a rela-ively poor prognosis. It is therefore critical for doctors toave simple markers to predict short- and medium-term out-ome in order to optimize therapy and management. Such arognostic evaluation has been successfully developed andpplied in cardiology, particularly for coronary artery dis-ase and myocardial infarction. Similar attempts have beenade in chronic heart failure (CHF) but CHF is a much more

eterogeneous syndrome than acute coronary syndromes.ndeed, the spectrum of CHF has changed over time, with auch higher prevalence of heart failure (HF) with preserved

jection fraction versus HF with systolic dysfunction.Besides CHF, one can no longer ignore the increasing inci-

ence of acute HF (AHF), which is a major cause of deathnd hospital readmission. AHF is either at the origin of CHF

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

de novo AHF) or results from the decompensation of CHFacute decompensated HF [ADHF]). AHF is an even more het-rogeneous condition as it is an acute syndrome that often

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ffects the elderly, in whom co-morbidities are frequent.onsequently, AHF is a highly complex syndrome that hasarely been the focus of attention, until recently, as illus-rated by the limited number of therapeutic trials conductedn this setting (SURVIVE, ASCEND, PROTECT, RELAX, ATOMIC-F). However, it is becoming crucial to conduct studies

n AHF, as its prognosis is quite poor, with 30-day and 6-onth mortality rates of around 10% and 30%, respectively,

ot including the high rate of hospital readmission. Patientanagement for this syndrome is often invasive and some-

imes involves relatively aggressive therapeutic procedures,uch as circulatory support or cardiac transplantation. Its therefore critical to validate prognostic markers at theatient’s admission, during the first days of hospitalizationr at discharge, in order to select the best therapeuticption.

This review discusses the emerging clinical, physiological

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nd biological markers that seem promising, with a view toeveloping a score that will improve AHF patient manage-ent.

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ARTICLEACVD-780; No. of Pages 11

Prognostic markers and scores of acute decompensated hea

Methodological challenges

Before detailing and prioritizing the prognostic markers, itis important to consider a number of methodological chal-lenges.

For which ‘‘acute heart failure’’ setting arewe considering prognostic markers?

AHF or ADHF can take multiple forms. De novo AHF, thefirst manifestation of the disease and subacute decompen-sation of known CHF are very different conditions in terms ofaetiology and underlying associated co-morbidities. In bothcases, severity can be either mild (e.g. hypertensive pul-monary oedema in patients with preserved left ventricularejection fraction) or severe (cardiogenic shock, that is oftenexcluded from the definition of AHF and for which mortalityrate is high). It is therefore important to specify the typeof AHF/ADHF under consideration, when trying to develop ascoring method.

Which doctor would find such a score useful?

One of the specificities of AHF is that it can be man-aged by cardiologists, intensivists, emergency physicians orinternists in an intensive care unit (ICU), cardiology depart-ment or internal medicine ward. The patient is directed toone department or another, depending on his or her profileand the severity of the AHF or associated co-morbidities. Forinstance, patients with co-morbidities are more likely to bemanaged in emergency and internal medicine departments.Furthermore, the therapeutic approaches are often differ-ent: in ICUs there is extensive use of positive inotropes,ventilation, intra-aortic balloon pumps and ultrafiltration,as opposed to less invasive oral or intravenous treatmentin cardiology or internal medicine wards. A more aggressivetherapy may also affect patient prognosis (e.g. iatrogeniceffects). Therefore, patient diversity and the differentdepartmental therapeutic approaches make it difficult toproduce a comprehensive score that can be applied in anycircumstance, as prognostic markers may vary from one sit-uation to another.

When is the best time to evaluate prognosis?

One might imagine that the sooner the prognosis is estab-lished, the better (i.e. at patient admission, including inthe emergency department). However, not all the variablesthat are necessary to calculate a prognostic score may beavailable in the first hours of management, such as echocar-diography and some biomarkers. In addition, the response totreatment, which is a powerful prognostic marker, especiallyin the early days, is only available a few hours after initi-ating treatment. Several studies have also shown that theprognostic scores measured at patient discharge, includingthose involving biomarkers, have a better prognostic valuethan those determined at admission. Some studies have alsohighlighted the prognostic importance of the variations in

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

these markers between admission and discharge. Neverthe-less, from a practical standpoint, it is probably true thatthe sooner the prognosis can be assessed, the better it is forthe patient because they can then be directed towards the

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ost appropriate medical strategy (e.g. from immediate dis-harge after intravenous diuretics to immediate transfer tohe ICU for invasive ventilation and/or cardiac assistance).

hich endpoints should be considered?

he most relevant and undebatable criterion is mortality,specially given the high death rate for this disease. Anotherriterion that is equally relevant in terms of severity andublic health cost is the number of hospital readmissions.he predictive criteria for death and for rehospitalizationay not, as intuitively thought, be the same. Importantly, itay also be relevant to take into account the cause of hospi-

al readmission or death in such a prognostic score. Indeed,n elderly patients or those with HF with preserved ejec-ion fraction, readmission for co-morbidities is as frequents for cardiovascular aetiologies. Furthermore, among read-ission for cardiovascular reasons, one can distinguish those

hat are associated with HF and those that are not (e.g.troke, pulmonary embolism, myocardial infarction, renalailure). Finally, among those hospitalized for HF, it is oftenifficult to distinguish those cases caused by HF or associatedith HF, mixed causes (infection plus cardiac decompensa-

ion) being particularly frequent. Likewise, the evaluationf the cause of death should follow similar criteria.

rognostic criteria: for which follow-upuration?

rognostic criteria may vary depending on whether one isnterested in in-hospital, 1-month, 6-month or even 1-yearortality [1]. Although in-hospital or 1-month mortalityay at first seem most relevant in acute pathologies, it

s clear that we cannot overlook outcome at 6 months.any therapies, such as positive inotropic amines, can

mprove short-term prognosis without beneficial effect andven with deleterious effect, in the long term [2,3]. Inontrast, it is difficult to consider a 6-month or 1-yearrognosis defined at admission as being final, as numerousactors —– particularly medical interventions —– may affectutcome at the medium or long term: for instance, in theecently published RELAX-AHF study, 48-hour treatment witherelaxin seemed to affect 6-month outcome [4]. More-ver, we have seen in the SURVIVE study that one of theost powerful prognostic criteria at 6 months was whethereta-blocker therapy was present at discharge [5]. Thesetudies suggest that discharge may be the best time tovaluate mid- and long-term mortality. However, betweenospitalization discharge and the sixth or twelfth monthfter discharge, many procedures can also be performed:oronary angiography, revascularization, resynchronization,mplantable cardioverter defibrillator implantation, reha-ilitation or educational programmes. All of these maynterfere with the prognosis at 1 year, disrupting prognosticarker values measured at either admission or discharge.

ow can the relevance of a prognostic factor

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

e assessed?

ntil recently, univariate or multivariable models were usedo determine the best single or multiple prognostic criteria.

ARTICLE IN PRESS+ModelACVD-780; No. of Pages 11

4 A. Cohen-Solal et al.

Table 1 Main prognostic scores in ADHF.

Studyreference

Time period Data source Number ofpatients (n)

Mortalityrisk factors

Prediction

EFFECT [67] 1997—2001 Registry 4031 Age; higher respiratory rate;low SBP; increased BUN;hyponatraemia;cerebrovascular disease;dementia; COPD; cirrhosis;cancer; low haemoglobin

30-day mortality1-year mortality

OPTIME-HF [68] 1997—1999 Clinical trial 949 Age; NYHA functional class;SBP; BUN; sodium

60-day mortality; deathor rehospitalization at60 days

ADHERE [7] 2001—2003 Registry 32 229 BUN; creatinine; SBP; age;heart rate

In-hospital mortality

OPTIMIZE-HF [64] 2003—2004 Registry 48 612 Creatinine; sodium; age;heart rate; liver disease;previous CVA/TIA; peripheralvascular disease; race; leftventricular systolicdysfunction; COPD; SBP;previous HF hospitalization

In-hospital mortality

GWTG-HF [65] 2005—2007 Registry 26 837 Age; COPD; heart rate; SBP;sodium; BUN

In-hospital mortality

EFICA [8] 2011 Registry 599 Shock; renal dysfunction;ischaemia; liver dysfunction;previous ADHF episode;co-morbidity; SBP;pulmonary oedema

1-month and 12-monthmortality

IN-HF [10] 2009 Registry 1855 SBP; age;somnolence/confusion;sodium; creatinine; shock;pulmonary oedema

In-hospital mortality

OFICA [11] 2009 Registry 1658 Age; SV arrhythmia; SBP;creatinine; median;natriuretic peptides

In-hospital mortality

PROTECT [66] 2012 Clinical trial BUN; respiratory rate; SBP;heart rate; albumin;cholesterol; diabetes;previous HF hospitalization

MOCA [1] 2013 Registry 5306 Age; sex; SBP and DBP; eGFR;sodium; haemoglobin; heartrate; NT-proBNP; CRP;MR-proADM; sST2

1-month and 12-monthmortality

ADHF: acute decompensated heart failure; BUN: blood urea nitrogen; COPD: chronic obstructive pulmonary disease; CRP: C-reactiveprotein; CVA: cerebral vascular accident; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; HF: heart failure;MR-proADM: mid-regional pro-adrenomedullin; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association;SBP: systolic blood pressure; sST2: soluble ST2; TIA: transient ischaemic attack.

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owever, statistical superiority does not necessarily meanreater clinical relevance, and new statistical methods areow available (such as the New Reclassification Index) whichllow for the clinical relevance of prognostic variables [6].

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

rognostic criteria

hus far, all of these challenges have greatly hinderedhe possibility of obtaining a tool for risk stratification

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n clinical practice. Nevertheless, several studies —– suchs the ADHERE registry [7], EFICA [8], SURVIVE (Mebazaat al., unpublished data), ALARM [9], IN-HF [10] and OFICA11] —– have been carried out to identify prognostic criteriaTable 1). These studies, performed in various popula-

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

ions from various countries, and others based on smalleropulations, have identified different individual progno-tic criteria, which can be grouped under various headingsTable 2).

ARTICLE IN PRESS+ModelACVD-780; No. of Pages 11

Prognostic markers and scores of acute decompensated heart failure (HF) 5

Table 2 Conventional risk factors at admission.

Demographics Age; male; black; poor socialsituation

Medicalhistory

Previous HF hospitalization;diabetes; ischaemic aetiology;vascular disease; co-morbidities

Symptoms andsigns

Congestion; low output; lowBP/shock; high heart rate; high BR;low SvO2; low body mass index

Laboratory High creatinine; low sodium; lowhaemoglobin; high urea/BUN; lowalbumin; high lactates; highnatriuretic peptides; high proADM;high sST2; high CRP; high troponins

BP: blood pressure; BR: breathing rate; BUN: blood urea nitro-gen; CRP: C-reactive protein; HF: heart failure; proADM:

Table 3 Prognostic value of various biomarkers.

In-hospitalmortality

Medium-termmortality

HF rehospi-talization

Creatinine x x xBUN x xCystatin x x xSodium x x xBNP x x xNT-proBNP x x xMR-proANP x x xMR-proADM xTroponin x xCRP x xsST2 x xGalectin-3 x x

BNP: B-type natriuretic peptide; BUN: blood urea nitrogen;CRP: C-reactive protein; MR-proADM: mid-regional pro-adrenomedullin; MR-proANP: mid-regional pro-atrial natriureticpeptide; NT-proBNP: N-terminal pro-B-type natriuretic peptide;

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pro-adrenomedullin; SvO2: venous oxygen saturation.

Patient characteristics: age, sex and weight

Age is a powerful prognostic factor in all studies, with prog-nosis getting poorer with age. The role of sex is less clear,although women often have a better prognosis than men.In terms of body weight and, more specifically, body massindex, contrary to what has frequently been observed inthe general population and in primary prevention, a lowbody mass index carries a worse prognosis than a high bodymass index, as the most cachectic patients seem to have thepoorest prognosis [12].

Heart failure

The duration and severity of the disease, de novo HF ver-sus decompensation of known CHF, cardiogenic shock, signsof congestion assessed by any method (rales, oedema,body weight, etc.) and blood pressure usually emerge asprognosticators in multivariable analyses, for instance, lowblood pressure always predicts grid outcome while hyper-tension generally confers relatively good prognostic value,contrary to what is observed in the normal population.Additional variables can easily be determined from dopplerechocardiography (left ventricular ejection fraction, E/E’ratio, pulmonary arterial function and right ventricular func-tion), although these variables are not always available atthe time of initial patient evaluation.

Co-morbidities

Chronic renal failure, diabetes, chronic obstructive pul-monary disease (COPD) and vascular disease are co-morbidities that are frequently associated with HF,especially in the elderly, and have their own negative impacton outcome.

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

The emerging role of plasma biomarkers

In such a complex scenario, as reflected by the presenceof several methodological issues and a plethora of different

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ndividual risk factors, plasma biomarkers now have a largerognostic role to play, in addition to clinical criteria andhose determined by cardiological examination, such aschocardiography (Table 3). The advantage of such biomark-rs is twofold: they can overcome methodological issues andhey provide more prognostic information than the sum ofndividual risk factors. In addition, they may be availableery early and, if necessary, assessed sequentially. Markersor predicting outcome in AHF [13] may differ from thosesed in CHF.

eart failure biomarkers

atriuretic peptidest admission, natriuretic peptides (NPs), i.e. B-type natri-retic peptide (BNP) and N-terminal proBNP (NT-proBNP),ave been shown to predict in-hospital and post-dischargeortality, independently from and often better than otherrognostic variables. In the ADHERE registry, for instance,

linear relationship was found between BNP concentra-ions and in-hospital mortality [14]. In addition, a Frenchtudy also stressed the value of baseline BNP concentra-ion for assessing in-hospital mortality and 6-month outcome15]. Similar findings have been reported for NT-proBNP. Inhe PRIDE study, conducted on patients presenting at themergency department with acute dyspnoea of cardiac andon-cardiac origin, NT-proBNP concentrations could predicthe 1-year mortality of AHF patients [16]. Many other stud-es have since confirmed these results. Besides the B-typePs, quantification of the mid-regional fragment of the pro-trial natriuretic peptide (MR-proANP), which is used as aurrogate to estimate the concentration of the short-lived

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

NP, has also been shown to be of good prognostic value17], especially when long-term (5-year) outcome is consid-red [11]. In this context, the concentration of MR-proANPs more likely to reflect a left atrial overload than a left

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entricular overload. Thus, elevated concentrations of MR-roANP are probably associated with a longer history of HF,s an increase in the size of the left atrium reflects thehronicity of left ventricular failure.

Interestingly, the concentrations of NPs at dischargexhibit even better prognostic value than those measuredt admission. Indeed, BNP concentrations < 300—400 pg/mLt discharge are predictive of a better outcome than higheralues [15,18,19]. Besides the absolute NP concentration atischarge, a decrease in NP concentration between admis-ion and discharge is also of prognostic value [15]. As showny Logeart et al. [15], Bettencourt et al. [20] and Cohen-olal et al. [21], an insufficient decrease in NT-proBNP or BNPoncentrations in response to treatment for acute destabi-ized HF is associated with poorer outcome. In such a setting,levated NP concentrations that are sustained throughoutospitalization are likely to reflect persisting congestionnd/or severe cardiac remodelling. Therefore, NP dosage atoth admission and discharge should be taken into accountor all patients, to better define their outcome; the value ofosage at intermediate time points has also been confirmed22]. Furthermore, NP concentrations at discharge are alsoritical for establishing a reference value for follow-up; thiss especially important in the case of rehospitalization, ashe NP values at discharge from the initial hospitalizationhould be taken into account to establish a threshold abovehich cardiac decompensation could be considered.

Currently, NP testing constitutes standard of care foratients with HF, as illustrated by recently published guide-ines [23,24], but the use of NPs in clinical practice variesccording to the clinical scenario. In AHF, their usefulnesss unquestionable but the delay in obtaining results mayffect the management and outcome of these patients andherefore limit their benefit [25]. In CHF, their use is mainlyssociated with serial measurements in the specialized set-ing of HF units, as suggested by USA guidelines [24], toollow the progression of the disease.

roponinsroponin is released by cardiomyocytes upon injury. Troponinas classically considered as the marker of acute myocardial

nfarction but is now recognized as a marker of myocardialschaemia, regardless of the cause, when other factors, suchs chemotherapy or radiotherapy, are excluded. In particu-ar, many studies have shown that troponins are increased inHF. In this context, even minor increases in concentrationsave been shown to independently predict both short- andong-term prognosis in AHF [26—30]: the higher the increasen troponin concentration, the greater the severity of theisease and the poorer the outcome.

Using conventional analytical assays, many patients withHF (and sometimes patients with apparently stable CHF)ave detectable cardiac troponins. The newly developedigh-sensitivity troponin (hsTn) assays that are now avail-ble have slightly complicated the picture, as plasmaroponin is now detectable in almost all AHF patients26,31]. Therefore, in the context of AHF, clinicians should

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

ot assume that an elevated hsTn value is necessarily indica-ive of a coronary syndrome but should integrate this valuento the overall clinical picture when encountering such

situation. As for NPs, a high hsTn value at admission is

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redictive of a worse prognosis, as is an increase in concen-ration during hospitalization or at discharge [32—34].

Finally, troponins identify a higher risk of both death andecurrent AHF episodes requiring hospitalization. In this new‘high-sensitivity’’ scenario, cardiac troponins have a gradedssociation with death and remain of independent progno-tic value. However, in a recent study, hsTn appears to haveess prognostic value than other biomarkers, such as NPs,oluble ST2 (sST2) or pro-adrenomedullin (proADM) [1]. Nev-rtheless, given the additive predictive value of troponinsnd NPs [29,30,35,36], troponins must be added to NPs inhe evaluation of AHF, especially at patient admission.

id-regional pro-adrenomedullinhe effects of ADM, an endogenous vasoactive peptideith vasodilatation and diuretic properties, are not entirelynderstood. ADM is produced by many tissues and its plasmaoncentration increases in HF. Similarly to ANP, ADM isnstable and the mid-regional fragment of the proADM (MR-roADM) is used as a surrogate marker. In one prospectivetudy of 287 subjects in Switzerland, MR-proADM allowedisk stratification in patients presenting to the emergencyepartment with dyspnoea, related or not to AHF, and pro-ided high prognostic value in the subset of patients with HF37]. Similarly, in the BACH study, MR-proADM added pro-nostic value to that of NPs in patients presenting to themergency department with dyspnoea [17,22]. Therefore,roADM appears to be a promising prognostic biomarker forhe outcome of AHF, although more studies are needed torecisely define the role of ADM in AHF and to evaluate howoncentrations change with treatment [38].

oluble ST2T2 is emerging as a powerful and reliable prognosticiomarker in cardiology [39—45]; it is a member of the inter-eukin (IL)-1 receptor family, with membrane-bound (ST2L)nd soluble (sST2) forms. ST2L exhibits antihypertrophic,ntifibrotic and antiapoptotic effects through the bindingf IL-33 [41]. In contrast, sST2 is believed to act as a decoyeceptor which sequesters IL-33 from ST2L, thereby neutral-zing the benefits of IL-33 signalling. Indeed, experimentaldministration of purified sST2 has been shown to antago-ize IL-33/ST2L signalling, resulting in a deleterious cardiachenotype marked by myocardial hypertrophy, dilatation ofhe ventricular chamber and reduction of contractility. InHF patients, plasma concentrations of sST2, as a marker forardiac remodelling and fibrosis, have been found to be pre-ictive of mortality in long-term follow-up [39,40,42—45].n addition, the association between sST2 concentration andrognosis has been found to be additive to that of NT-proBNPnd other risk factors, and independent of ejection frac-ion. In the context of AHF, sST2 concentrations identifyatients with a more remodelled ventricle and decompen-ated haemodynamic profile [45].

alectin-3

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

alectin-3 (Gal-3) is an ss-galactoside binding protein whichinds to extracellular matrix proteins, such as fibronectinr laminin. In a murine model of hypertension leading to HF,yocardial Gal-3 was increased and intrapericardial infusion

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Prognostic markers and scores of acute decompensated hea

of Gal-3 produced myocardial collagen deposition, fibrosisand adverse remodelling [46].

The prognostic value of Gal-3 has been assessed inpatients presenting at the emergency department withacute dyspnoea [47]. In this study, Gal-3 concentration wassignificantly higher in the plasma of AHF patients and was abetter predictor of 60-day mortality than NT-proBNP (areaunder the receiver operating characteristic curve analysis).Multivariable analysis confirmed that Gal-3 outperformedNT-proBNP as a prognostic biomarker. In another study, Shahet al. [48] published data from a subpopulation of 115acutely decompensated HF patients and showed by mul-tivariable analysis that Gal-3 was the strongest predictorof 4-year mortality, performing even better than echocar-diographical indices. It is worth mentioning that in theCORONA study, where statins did not show an overall ben-eficial effect on outcome, a benefit was observed amongpatients with elevated baseline concentrations of Gal-3 [49].Similar results were observed in the COACH registry [50],although these patients were not in an acute decompensatedsituation. Finally, Gal-3 concentrations do not seem to varymuch with time and treatment, unlike other markers, suchas NPs. Altogether, Gal-3 emerges as a promising risk markerfor identifying an HF phenotype more prone to decompensa-tion, but further studies are needed, as Gal-3 concentrationsalso seem to be strongly related to inflammation.

Renal biomarkers

Renal dysfunction is an ominous prognostic marker. Var-ious plasma biomarkers, such as cystatin C, neutrophilgelatinase-associated lipocalin (NGAL), urea and kidneyinjury molecule 1 (KIM-1), are now available, besides cre-atinine, for calculating glomerular filtration rate (GFR).

Cystatin CPlasma cystatin C concentration is mainly dependent onGFR because cystatin C is not secreted in the tubule afterfree glomerular filtration. Cystatin C has been found toindependently predict outcome with greater accuracy thancreatinine, estimated GFR or blood urea nitrogen (BUN)[51—54], especially in patients with apparently preservedrenal function (estimated GFR > 60 mL/min).

Neutrophil gelatinase-associated lipocalinNGAL is a protein released by the tubular cells upon acutekidney injury. In ADHF, high NGAL concentrations may reflectearly renal injury [55], and a positive correlation betweenincreased NGAL concentration and worsening of the diseaseor poor prognosis has been shown in ADHF patients [56].

Kidney injury molecule 1Another new tubular biomarker is KIM-1, a membrane phos-phatidylserine receptor expressed at the surface of proximalcells, which is released into the urine upon acute kidneyinjury [57]. KIM-1 appears to be a promising biomarker for

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

evaluating kidney dysfunction, although its prognostic valuein ADHF is yet to be established. More classically, an increasein plasma urea (BUN in the USA) generally reflects alter-ation of both haemodynamics (volaemia) and GFR, and has

Acar

PRESSilure (HF) 7

ften appeared as a potent prognostic factor in the settingf ADHF, especially in the ADHERE registry [7,58—60].

nflammation biomarkers

nflammation has often been implicated in the pathogenesisf ADHF: it is often associated with ADHF even when it is nothe cause. It is therefore not surprising that inflammations also often found as a major prognostic factor, especiallyn ICUs (OFICA, MOCA) [1,11]. C-reactive protein (CRP) ishe biomarker used most frequently for this purpose, butther markers are available, such as myeloperoxidase, solu-le tumour necrosis factor alpha-receptor, procalcitonin andnterleukins.

epatic failure

here is some discrepancy between studies about whetherepatic failure is a prognostic factor in AHF or not (EFICA,URVIVE) (Mebazaa et al., unpublished data) [8,61]. Such aiscrepancy may be caused by difficulties in characterizingepatic failure which exhibits a broad range of features:ytolysis (e.g. transaminases), cholestasis (e.g. bilirubin,lcaline phosphatases) and hepatocellular failure (e.g. pro-hrombin time, coagulation factors, albumin). An increase inlasma lactate may also be seen as a sign of hepatic dysfunc-ion, apart from being a marker of low tissue perfusion andas often emerged as a potent prognostic marker, especiallyn patients admitted to ICUs.

ntegrating risk markers into prognosticcores

ultimarker combination

n general, multiple risk factors coexist in the same patient.utcome prediction may thus be enhanced and more mean-

ngful when all these factors are combined rather than takenndividually. Thus, the prognostic value of biomarkers can beurther increased by using a multimarker approach, whereach biomarker provides insight into different pathophysio-ogical processes. For instance, the combination of markersf myocyte necrosis (cardiac troponin), left ventricular over-oad (NPs), adverse cardiac remodelling (sST2 or Gal-3)nd renal function (creatinine or cystatin C) may providencremental prognostic value. However, the best biomarkerombination for the provision of additive prognostic infor-ation has not yet been established and most likely depends

n the clinical setting.

isk models

ecause of the large number of clinical studies and registrieserformed in CHF, various prognostic scores have been pro-osed (e.g. Seattle Heart Failure Model, Pocock’s risk score)62,63], but it remains to be established whether thesecores also apply to patients with ADHF. Indeed, CHF and

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

DHF are rather different conditions. For instance, clini-al and haemodynamic stability or other organ alterationsre absent in ADHF. In the past few years, numerous clinicalisk models for short- and medium-term mortality of ADHF

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ARTICLECVD-780; No. of Pages 11

atients have been published from data obtained from largeegistries and clinical trials (Table 2).

In terms of in-hospital mortality, the Acute Decompen-ated Heart Failure National Registry (ADHERE) is the mostell-known, as it recruited the greatest number of patients.he registry resulted in a very simple, easy-to-use risk strat-

fication method to predict in-hospital mortality in patientsdmitted with HF [7]. In this study, BUN concentration,erum creatinine concentration and systolic blood pressureSBP) were independent predictors of high risk of in-hospitalortality among 45 variables. One may be surprised that

wo markers of renal function are entered in the modelithout redundancy. The accuracy of this score for pre-icting outcome is, however, based on more than 30 000atients. Another clinical risk model was constructed fromhe large OPTIMIZE-HF registry, where a number of varia-les, such as high serum creatinine, low serum sodium,ge, high heart rate, liver disease, previous cerebral vascu-ar accident/transient ischaemic attack, peripheral vascularisease, white ethnicity, left ventricular systolic dysfunc-ion and COPD were identified as predictors of in-hospitalortality [64]. The data from the American Heart Associa-

ion’s ‘‘Get With the Guidelines-Heart Failure’’ (GWTG-HF)rogramme [65] provided another risk model in which inde-endent predictors of in-hospital mortality were high age,igh heart rate, high BUN concentration and COPD. In theROTECT trial, a predictive model and risk score (0—100)or 7-day outcome was generated using BUN, serum albu-in, cholesterol and SBP, as well as heart and respiratory

ates [66]. In the French OFICA registry that analysedata from 1658 patients hospitalized in France for ADHF11], age, supraventricular arrhythmias, SBP, creatinine andPs were found to be predictive of in-hospital mortal-

ty.Other models have been proposed for the assessment of

hort- and medium-term prognosis. The Enhanced Feedbackor Effective Cardiac Treatment (EFFECT) study database> 4000 patients) in Ontario, Canada, allowed the develop-ent and validation of a model using information available

t hospital admission [67]. In this study, predictors of mor-ality at both 30 days and 1 year included older age, lowerBP, higher respiratory rate, higher BUN, hyponatraemiand some co-morbid conditions, such as cerebrovascularisease, COPD, hepatic cirrhosis, dementia and cancer.nother risk model for predicting post-discharge mortal-

ty was published from the clinical trial ‘‘The Outcomesf a Prospective Trial of Intravenous Milrinone for Exac-rbations of Chronic Heart Failure (OPTIME-CHF)’’ [68].n the 949 patients with ADHF, the variables at admis-ion that predicted death at 60 days and the compositef death and readmissions were older age, New Yorkeart Association class IV symptoms and elevated BUN.

n the RELAX-AHF study [69], which evaluated the effectsf serelaxin in 1395 ADHF patients, changes in markersf cardiac damage (hsTn), renal damage (creatinine andystatin C), hepatic damage (aspartate transaminase andlanine transaminase) and decongestion (NT-proBNP) onay 2 after treatment and worsening HF during admission

Please cite this article in press as: Cohen-Solal A, eheart failure: The emerging roles of cardiac biomarkershttp://dx.doi.org/10.1016/j.acvd.2014.10.002

ere associated with 180-day mortality. Another registryEFICA) [8], which studied patients admitted to the cardi-logy department and the ICU, also identified shock, renalysfunction, ischaemia, liver dysfunction, previous ADHF

vdtb

PRESSA. Cohen-Solal et al.

pisode, co-morbidities, blood pressure and pulmonaryedema as prognostic factors at 6 months. More recently,he large (> 5000 patients) international multicentre MOCAegistry identified age, sex, blood pressure, estimated GFR,odium, haemoglobin, heart rate, NT-proBNP, CRP, MR-roADM and sST2 as being predictive of outcome [1]. Thistudy was particularly interesting as it pooled large popula-ions from various countries and put emphasis on the valuef multiple biomarkers and their combination in assessingutcome.

ynthesis

he physician thus has numerous possibilities for assessingutcome when faced with a patient with ADHF, on top ofhe classical and indisputable clinical and biological varia-les that are easily obtainable, such as age, blood pressure,enal or hepatic dysfunction and early response to therapy.lasma concentrations of NPs have a considerable progno-tic value at baseline and, moreover, at discharge. Newiomarkers not yet entered into routine clinical practice,uch as sST2 and proADM, seem to have at least an equalalue to NPs when assessed in the first days, but not there-fter. The many other plasma biomarkers that have emergedn AHF (more than in acute coronary syndromes), as wells their combinations, need to show clear significant pro-nostic input on top of these variables. On the other hand,everal registries and trials have already provided interest-ng prognostic scores based on simple clinical and biologicalariables. However, none of these scores has been widelyccepted or is considered as part of standard care, asre the GRACE and TIMI scores for patients admitted withcute coronary syndromes. In France, for example, they areot used —– if even known about —– by cardiologists. Thesecores should also be accepted, not only by cardiologists,ut by intensivists and physicians in emergency depart-ents and mobile medical units. Although these scores have

n impressive prognostic accuracy, they should be testedore extensively in elderly patients or in patients with

o-morbidities. None of the scores includes plasma biomark-rs. However, with the development of devices such asablets and smart phones, and of eMedicine in general, its likely that these scores will be integrated into futureractice.

onclusion

n conclusion, the burden of HF shifts from CHF to ADHF,or which outcome predictors, especially those that areeterminable in the first hours after admission, are urgentlyeeded. Thus, there is a clear need for large collaborativetudies to provide a clear prognostic framework for all physi-ians managing these patients (cardiologists, intensivistsnd emergency department doctors). These future stud-es must include biomarkers that are pathophysiologicallyeaningful and are therefore of complementary prognostic

t al. Prognostic markers of acute decompensated and prognostic scores. Arch Cardiovasc Dis (2014),

alue. In addition, prospective studies with a randomizedesign are necessary in order to generate knowledge abouthe impact of stratification of AHF patients, based on eitheriomarkers or prognostic scores in clinical practice.

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Prognostic markers and scores of acute decompensated hea

Disclosure of interest

Alain Cohen-Solal: conferences or boards for/with Abbott,Roche and Thermofisher.

Damien Logeart: conferences for Roche.Alexandre Mebazaa: conferences, boards and studies

for/with Cardiorentis, Orion and Vifor.Said Laribi, Shiro Ishihara, Giuseppe Vergaro, Mathilde

Baudet, Etienne Gayat, Nicolas Vodovar, Domingo A. Pascual-Figal, Marie-France Seronde declare that they have noconflicts of interest concerning this article.

Acknowledgments

This study was funded by grants from The French Federa-tion of Cardiology, the Heart and Research Foundation, theDHU FIRE and an European Commission Seventh FrameworkProgram grant under agreement No. 305507 (HOMAGE).

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