Mid-regional pro-adrenomedullin and ST2 in heart failure: Contributions to diagnosis and prognosis | Revista Portuguesa de Cardiologia (English edition)

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=> "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Luiz" "apellidos" => "Menezes Falcão" "email" => array:1 [ 0 => "luizmfalcao@sapo.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "University Hospital Santa Maria/CHLN, Lisbon, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "University Hospital Santa Maria/CHLN, Faculty of Medicine of Lisbon, Lisbon, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "A MR-proadrenomedulina e o ST2 na insuficiência cardíaca: contribuição para o diagnóstico e prognóstico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1050 "Ancho" => 2500 "Tamanyo" => 139993 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the production and actions of adrenomedullin (ADM) in heart failure (HF). The pressure/volume overload and ventricular wall stretching seen in HF lead to upregulation of the ADM gene. The preprohormone undergoes cleavage, forming pro-ADM, which is further processed to ADM. ADM causes natriuresis, diuresis, and vasodilation. It is also associated with reduced hypertrophy, ventricular remodeling and fibrosis. The actions of ADM thus have a cardioprotective effect. Due to its in vitro instability, ADM levels cannot be measured directly, but cleavage of pro-ADM also produces mid-regional pro-adrenomedullin, a stable fragment that is easily measured and whose concentrations reflect those of ADM. ADM: adrenomedullin; MR-proADM: mid-regional pro-adrenomedullin." ] ] ] "textoCompleto" => "IntroductionIn the most recent European Society of Cardiology (ESC) guidelines,<a class="elsevierStyleCrossRef" href="#bib0290">1</a> heart failure (HF) is defined as a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. This definition of HF restricts itself to stages at which clinical symptoms are apparent.<a class="elsevierStyleCrossRef" href="#bib0290">1</a> In recent decades, there have been notable advances in the prevention, diagnosis and treatment of cardiovascular disease. However, HF still has a significant impact, as it results in frequent hospitalizations, reduced life expectancy and high expenditure in healthcare systems.<a class="elsevierStyleCrossRef" href="#bib0295">2</a> HF has an estimated prevalence of 1-2% in the adult population of developed countries, but the number of cases in the elderly is higher, affecting at least 10% of individuals aged 70 years or older.<a class="elsevierStyleCrossRef" href="#bib0290">1</a>Considering that the symptoms and signs described are non-specific, the diagnosis of acute HF is not always easy and differential diagnosis can be complicated. The presence of comorbidities such as pulmonary infection also complicates diagnosis due to overlapping symptoms.<a class="elsevierStyleCrossRef" href="#bib0300">3</a> Therefore, the use of biomarkers to provide more accurate diagnosis has been widely studied. Ideally, biomarkers should provide information that is not given by clinical assessment or routine exams, thereby helping medical decisions. They should also be highly sensitive and specific, as well as easily measured, with reasonable costs and rapidly available results.<a class="elsevierStyleCrossRef" href="#bib0300">3</a> The part played by biomarkers is not limited to the diagnosis of HF, as they may also be useful in prognostic assessment.Natriuretic peptides, especially B-type natriuretic peptide (BNP) and its precursor N-terminal pro-B-type natriuretic peptide (NT-proBNP), are currently used in clinical practice and their measurement is recommended by the ESC guidelines for the diagnosis and assessment of HF.<a class="elsevierStyleCrossRef" href="#bib0290">1</a> Their use in the diagnosis of acute HF in patients presenting with acute dyspnea in the emergency department (ED) has been validated by several studies.<a class="elsevierStyleCrossRef" href="#bib0305">4</a> Both BNP and NT-proBNP are very precise in identifying acute HF and their addition to routine clinical assessment is clearly advantageous.<a class="elsevierStyleCrossRefs" href="#bib0310">5–7</a> In terms of diagnostic value, there is no statistical difference between the two biomarkers.<a class="elsevierStyleCrossRef" href="#bib0325">8</a> Natriuretic peptides are also useful in the prognostic assessment of patients hospitalized due to acute HF: higher BNP and NT-proBNP concentrations are associated with higher mortality.<a class="elsevierStyleCrossRefs" href="#bib0330">9–11</a> In patients with stable chronic HF, measurement of natriuretic peptides is also an important follow-up tool.<a class="elsevierStyleCrossRefs" href="#bib0345">12,13</a> Natriuretic peptide-guided therapy has been the subject of considerable study.<a class="elsevierStyleCrossRef" href="#bib0355">14</a> Adjusting therapy in order to attain lower BNP and NT-proBNP levels has been found to be associated with lower hospitalization and mortality rates.<a class="elsevierStyleCrossRefs" href="#bib0360">15,16</a>Despite their important role in HF, natriuretic peptides show some limitations. They are elevated in other conditions as well as HF, such as valvular heart disease, pulmonary hypertension, pulmonary thromboembolism, atrial fibrillation and sepsis.<a class="elsevierStyleCrossRefs" href="#bib0305">4,17</a> Age and kidney failure increase natriuretic peptide levels, while obesity is associated with lower levels.<a class="elsevierStyleCrossRefs" href="#bib0305">4,17</a> These situations can give values in a gray area that requires particularly careful analysis. The investigation of new biomarkers that can complement natriuretic peptides has been the subject of considerable attention.This review focuses on two interesting and promising biomarkers currently under study: adrenomedullin (ADM), mainly a myocyte strain marker, and ST2, mainly a cardiac remodeling marker. These biomarkers reflect different pathological pathways. Their diagnostic and prognostic value will be examined, as will their importance in monitoring of therapy and patient follow-up.AdrenomedullinADM is a 52-amino acid peptide belonging to the calcitonin gene-related peptide family.<a class="elsevierStyleCrossRefs" href="#bib0375">18,19</a> The ADM gene encodes a 185-amino acid preprohormone, which, after cleavage, generates a 164-amino acid prohormone, pro-ADM; pro-ADM is then processed, forming ADM<a class="elsevierStyleCrossRefs" href="#bib0375">18,19</a> and mid-regional pro-adrenomedullin (MR-proADM) (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>). ADM is secreted in various tissues, including the heart, lungs, central nervous system, kidneys and gastrointestinal organs; it is also expressed in endothelial cells, vascular smooth muscle cells, fibroblasts and adipocytes.<a class="elsevierStyleCrossRefs" href="#bib0375">18,19</a> ADM has a hypotensive effect: it stimulates diuresis and natriuresis and also causes vasodilation, lowering blood pressure.<a class="elsevierStyleCrossRef" href="#bib0375">18</a> In HF, as a consequence of pressure/volume overload and ventricular wall stretching, the ADM gene is upregulated in cardiac myocytes. The resulting high ADM levels appear to have a protective effect in the myocardium, as they lead to a decrease in preload and afterload.<a class="elsevierStyleCrossRef" href="#bib0380">19</a> Some studies suggest that ADM additionally inhibits cell growth and hypertrophy; it has also been associated with reductions in remodeling and fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0380">19,20</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>ADM, like natriuretic peptides and many other vasoactive peptides, is cleaved by neprilysin, a ubiquitous enzyme that is mainly expressed in the proximal tubules of nephrons.<a class="elsevierStyleCrossRef" href="#bib0390">21</a> Inhibition of neprilysin has been studied as a way to enhance endogenous neurohumoral systems that are diuretic and natriuretic and able to inhibit hypertrophy and fibrosis in HF.<a class="elsevierStyleCrossRef" href="#bib0395">22</a>Clinical use of ADM was limited for some time because of the in vitro instability of this biomarker: its half-life is short and it is quickly removed from the circulation.<a class="elsevierStyleCrossRef" href="#bib0380">19</a> This problem was solved by the use of MR-proADM, a stable fragment of pro-ADM whose concentrations reflect those of ADM.<a class="elsevierStyleCrossRef" href="#bib0380">19</a>Diagnostic value of MR-proADM in acute heart failureRegarding the use of MR-proADM in the diagnosis of acute HF, it should be borne in mind that this biomarker is also increased in other conditions, such as systemic and pulmonary hypertension, following myocardial infarction, kidney failure and sepsis.<a class="elsevierStyleCrossRefs" href="#bib0375">18,19</a> In order to determine the diagnostic value of MR-proADM, Dieplinger et al. measured its levels in patients who attended the ED with acute dyspnea.<a class="elsevierStyleCrossRef" href="#bib0400">23</a> It was concluded that MR-proADM had no statistically significant value in the diagnosis of acute HF and was clearly inferior to NT-proBNP.<a class="elsevierStyleCrossRef" href="#bib0400">23</a> Another study confirmed the lack of specificity of MR-proADM in the diagnosis of acute HF.<a class="elsevierStyleCrossRef" href="#bib0405">24</a> Therefore, MR-proADM appears to have no practical utility in the diagnosis of acute HF and its measurement has no advantage over the established natriuretic peptides.Prognostic value of MR-proADM in acute heart failureSeveral studies have shown that MR-proADM can be used in the prognostic assessment of patients with acute HF<a class="elsevierStyleCrossRef" href="#bib0380">19</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The BACH study by Maisel et al., involving a large number of patients presenting to the ED with acute dyspnea, analyzed whether MR-proADM was related to 90-day survival.<a class="elsevierStyleCrossRef" href="#bib0410">25</a> Survivors had lower MR-proADM levels than those who died.<a class="elsevierStyleCrossRef" href="#bib0410">25</a> Furthermore, for predicting 90-day survival, MR-proADM had an area under the curve (AUC) on receiver operating characteristic analysis of 0.67, which was slightly superior to BNP (AUC 0.61) and NT-proBNP (AUC 0.66).<a class="elsevierStyleCrossRef" href="#bib0410">25</a> The prognostic accuracy of MR-proADM levels, assessed in blood samples taken on admission to the ED, was 73%, which was higher than for BNP and NT-proBNP (62% and 64%, respectively).<a class="elsevierStyleCrossRef" href="#bib0410">25</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In a subsequent sub-analysis of the BACH study assessing the prognostic value of ADM in the shorter term,<a class="elsevierStyleCrossRef" href="#bib0415">26</a> MR-proADM was superior to natriuretic peptides in predicting 14-day mortality; the AUC for BNP and NT-proBNP was, respectively, 0.48 and 0.59, while MR-proADM had an AUC of 0.74.<a class="elsevierStyleCrossRef" href="#bib0415">26</a> As the latter value is considerably superior to the AUC observed for predicting 90-day mortality, this biomarker seems to be more useful in shorter-term prognostic assessment. It is important to note that in the above study treatment was similar in survivors and in those who died within 14 days; this shows the importance of identifying patients with worse prognosis, who may need more aggressive treatment and surveillance.<a class="elsevierStyleCrossRef" href="#bib0415">26</a> The Verifying Dyspnea study<a class="elsevierStyleCrossRef" href="#bib0420">27</a> also confirmed the prognostic value of MR-proADM. In the group of patients with acute HF, MR-proADM levels in the ED and at 72 hours after admission had an AUC for 90-day mortality of 0.76 (p<0.005) and 0.77 (p<0.05), respectively.<a class="elsevierStyleCrossRef" href="#bib0420">27</a> Moreover, reassessment of MR-proADM 72 hours after admission was superior to a single measurement.<a class="elsevierStyleCrossRef" href="#bib0420">27</a>These studies show that MR-proADM is a good prognostic marker in patients hospitalized due to acute HF and, in some reports, is even superior to natriuretic peptides. Hence, MR-proADM can be complementary to natriuretic peptides and its measurement may be useful. It is important to point out that MR-proADM levels vary according to certain patient characteristics. Women, older patients, and those with kidney failure and systolic dysfunction have higher MR-proADM levels, while like natriuretic peptides, levels decrease with higher body mass index.<a class="elsevierStyleCrossRefs" href="#bib0425">28,29</a>MR-proADM in follow-up and biomarker-guided therapyAssessment of MR-proADM appears to be useful in the follow-up of patients with stable chronic HF. Von Haehling et al.<a class="elsevierStyleCrossRef" href="#bib0425">28</a> measured MR-proADM and NT-proBNP in patients with chronic HF, under medication and clinically stable. Higher MR-proADM levels were seen in patients in more advanced NYHA classes and these higher levels were also associated with increased mortality (p<0.0001).<a class="elsevierStyleCrossRef" href="#bib0425">28</a> Concerning 12-month mortality, MR-proADM had a similar value to NT-proBNP; however, for three-month mortality MR-proADM was shown to be superior to NT-proBNP.<a class="elsevierStyleCrossRef" href="#bib0425">28</a> Once again MR-proADM appears to be more useful in short-term assessment. The use of MR-proADM together with clinical assessment and natriuretic peptides had a better prognostic value than the individual use of any of these variables (p<0.0009).<a class="elsevierStyleCrossRef" href="#bib0425">28</a> Masson et al., in the GISSI-HF study,<a class="elsevierStyleCrossRef" href="#bib0430">29</a> found that higher concentrations of MR-proADM were associated with an increased risk of mortality or hospitalization for cardiovascular causes (p<0.0001). In this study, NT-proBNP and MR-proADM had similar value in prognostic assessment.<a class="elsevierStyleCrossRef" href="#bib0430">29</a> Xue et al. recently confirmed these results, concluding that MR-proADM levels were strong predictors of mortality (p<0.0001).<a class="elsevierStyleCrossRef" href="#bib0435">30</a> Considering all these studies, MR-proADM is a good prognostic marker even in patients with stable chronic HF, and is useful as a follow-up tool.MR-proADM values change with some medications, and lower levels are observed in patients treated with diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and beta-blockers.<a class="elsevierStyleCrossRef" href="#bib0430">29</a> Richards et al. showed that patients with chronic HF who had higher MR-proADM levels particularly benefited from the use of carvedilol.<a class="elsevierStyleCrossRef" href="#bib0440">31</a> Nevertheless, there is no evidence that MR-proADM can be used in a biomarker-guided therapeutic strategy.ST2ST2 is a member of the IL-1 receptor family. There are two main isoforms: a transmembrane receptor (ST2L) and a soluble receptor (sST2). ST2L includes an extracellular domain, a transmembrane segment and an intracellular domain. sST2, which lacks the transmembrane and intracellular domains, is a circulating isoform that can be detected in serum. The ligand of ST2 is interleukin-33 (IL-33), an interleukin-1-like cytokine that is secreted by most cells in response to damage. IL-33 exerts its biological actions only when it binds to the ST2L isoform. However, circulating sST2 acts as a decoy receptor, binding to IL-33 and blocking the IL-33/ST2L interaction, which inhibits the action of IL-33<a class="elsevierStyleCrossRef" href="#bib0445">32</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The IL-33/ST2 complex participates in the immune response through the activation of Th2 effector cells and the release of Th2-related cytokines. IL-33/ST2 thus plays a role in various inflammatory diseases, including asthma and rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0445">32</a> Recently, it was discovered that IL-33/ST2 is also expressed in cardiac fibroblasts and cardiomyocytes.<a class="elsevierStyleCrossRef" href="#bib0445">32</a> Expression is increased in response to myocardial stress, and this appears to have a cardioprotective effect, reducing myocardial fibrosis, preventing cardiomyocyte hypertrophy, reducing apoptosis, and improving myocardial function.<a class="elsevierStyleCrossRef" href="#bib0445">32</a> The beneficial effects of IL-33 are exerted specifically through the ST2L receptor and are blocked when IL-33 binds to the decoy receptor sST2, which occurs when sST2 levels are increased.<a class="elsevierStyleCrossRefs" href="#bib0445">32,33</a> This explains why higher sST2 levels are associated with remodeling, fibrosis and hypertrophy in patients with cardiac disease, especially HF and ischemic heart disease.<a class="elsevierStyleCrossRef" href="#bib0445">32</a> In view of this, several studies have measured circulating sST2 levels in patients with HF, in order to determine the utility of this biomarker.Diagnostic value of ST2 in acute heart failureRegarding the diagnostic value of sST2 in acute HF, it is important to note that sST2 levels are increased in other cardiovascular diseases besides HF, such as hypertension, ischemic heart disease and valvular heart disease.<a class="elsevierStyleCrossRef" href="#bib0450">33</a> Higher concentrations of sST2 are also seen in several inflammatory diseases, including asthma, rheumatoid arthritis and systemic erythematous lupus, and in sepsis.<a class="elsevierStyleCrossRef" href="#bib0450">33</a> In the PRIDE study,<a class="elsevierStyleCrossRef" href="#bib0455">34</a> the sST2 levels of patients presenting to the ED with acute dyspnea were measured in order to determine its diagnostic value for acute HF. Although sST2 concentrations were higher in patients with acute HF than in those with non-cardiac dyspnea, sST2 was not found to have a statistically significant diagnostic value; likewise, it was clearly inferior to NT-proBNP in the diagnosis of acute HF.<a class="elsevierStyleCrossRef" href="#bib0455">34</a> Accordingly, it can be concluded that sST2 measurement is not useful for the diagnosis of acute HF and does not present advantages over the established natriuretic peptides, which has been confirmed in more recent studies.<a class="elsevierStyleCrossRefs" href="#bib0400">23,35</a>Prognostic value of ST2 in acute heart failuresST2 levels in patients hospitalized due to acute HF, measured at admission and discharge, can be used for prognostic assessment<a class="elsevierStyleCrossRef" href="#bib0465">36</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The PRIDE study<a class="elsevierStyleCrossRef" href="#bib0455">34</a> showed that high sST2 concentrations were clearly associated with increased one-year mortality. Likewise, patients with sST2 levels above the median value had 11-fold greater odds for death (p<0.0005).<a class="elsevierStyleCrossRef" href="#bib0455">34</a> sST2 was also superior to NT-proBNP in predicting one-year mortality risk (p<0.05), but the best value was obtained by using these two biomarkers together.<a class="elsevierStyleCrossRef" href="#bib0455">34</a> Rehman et al.<a class="elsevierStyleCrossRef" href="#bib0470">37</a> confirmed the correlation between higher sST2 and worse prognosis and also showed that sST2 levels increased with higher NYHA class.<a class="elsevierStyleCrossRef" href="#bib0470">37</a> More recently, Friões et al.<a class="elsevierStyleCrossRef" href="#bib0475">38</a> concluded that higher sST2 concentrations in patients with acute HF were associated with greater risk of six-month mortality or readmission. In this study, sST2 and BNP had similar values but, again, the best value was attained by using the two biomarkers together.<a class="elsevierStyleCrossRef" href="#bib0475">38</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Monitoring of sST2 values through serial measurements appears to be particularly useful, increasing the prognostic power of this biomarker.<a class="elsevierStyleCrossRef" href="#bib0480">39</a> Bayes-Genis et al.<a class="elsevierStyleCrossRef" href="#bib0485">40</a> studied a small group of patients with acute HF and measured their sST2 values at discharge and two weeks later. Patients with a greater decrease in sST2 two weeks after discharge had a better prognosis.<a class="elsevierStyleCrossRef" href="#bib0485">40</a> Another study measured sST2 at admission in the ED and 48 hours later, concluding that sST2 levels clearly separated those who survived from those who did not.<a class="elsevierStyleCrossRef" href="#bib0485">40</a> Likewise, the percentage of sST2 decrease predicted long term mortality.<a class="elsevierStyleCrossRef" href="#bib0490">41</a>It can be concluded that sST2 is a good prognostic marker, both short- and long-term, in patients hospitalized for acute HF. Also, the addition of sST2 to natriuretic peptides is superior to the use of natriuretic peptides alone. It is important to emphasize that repeated monitoring of sST2 levels is more useful than a single measurement, and its low biological variability increases its potential for serial testing and patient monitoring.<a class="elsevierStyleCrossRef" href="#bib0495">42</a> It has also recently been shown that the prognostic value of sST2 is not influenced by renal function.<a class="elsevierStyleCrossRef" href="#bib0500">43</a> It should be noted that higher sST2 levels are associated with decreased ejection fraction, left ventricular enlargement and hypokinesia, which suggests its potential for the assessment of ventricular remodeling.<a class="elsevierStyleCrossRef" href="#bib0505">44</a>ST2 in follow-up and biomarker-guided therapysST2 assessment may also be useful as a follow-up measure in patients with stable chronic HF.<a class="elsevierStyleCrossRef" href="#bib0510">45</a> The Penn Heart Failure study, which determined sST2 levels in patients with chronic HF, concluded that higher sST2 concentrations (>36.3 ng/ml) were associated with a higher risk of mortality or heart transplantation (p<0.0001).<a class="elsevierStyleCrossRef" href="#bib0515">46</a> Although the prognostic value of sST2 was similar to that of NT-proBNP, the combination of the two biomarkers was superior to their use individually,<a class="elsevierStyleCrossRef" href="#bib0515">46</a> and was a useful complement to conventional clinical assessment, enabling better classification of patients in appropriate risk categories.<a class="elsevierStyleCrossRef" href="#bib0515">46</a> Bayes-Genis et al.,<a class="elsevierStyleCrossRef" href="#bib0520">47</a> whose study showed comparable results, subsequently confirmed these findings. In the Val-HeFT trial, elevated sST2 levels in patients with chronic HF were significantly (p<0.0001) correlated with increased morbidity, mortality and hospitalization for decompensated HF,<a class="elsevierStyleCrossRef" href="#bib0525">48</a> while in the PROTECT study,<a class="elsevierStyleCrossRef" href="#bib0530">49</a> patients with increased sST2 during follow-up had earlier cardiovascular complications (p=0.009). This study reached another important conclusion: sST2 levels below a cutoff of 35 ng/ml were associated with lower left ventricular end-diastolic volume.<a class="elsevierStyleCrossRef" href="#bib0530">49</a> This links sST2 with left ventricular remodeling and suggests the potential of this biomarker in surveillance of structural heart changes.<a class="elsevierStyleCrossRef" href="#bib0530">49</a> Hence, sST2 has prognostic value in patients with chronic HF, as it identifies those at higher risk, particularly when used together with natriuretic peptides, and could thus be used as a follow-up strategy in these patients.Patients under HF treatment including ACEIs, ARBs, mineralocorticoid receptor antagonists and beta-blockers show lower concentrations of sST2.<a class="elsevierStyleCrossRef" href="#bib0535">50</a> This association has led to the hypothesis that this biomarker can be used as a treatment guide in HF. Beta-blockers have shown a substantial effect on sST2 levels.<a class="elsevierStyleCrossRef" href="#bib0525">48</a> Exploring this link, Gaggin et al.<a class="elsevierStyleCrossRef" href="#bib0540">51</a> observed that, in patients with elevated sST2 levels, those under higher beta-blocker doses had lower mortality, suggesting that high sST2 levels may identify patients who will benefit from higher treatment doses. In another study, spironolactone therapy was significantly beneficial for patients hospitalized with acute HF who had elevated sST2.<a class="elsevierStyleCrossRef" href="#bib0545">52</a> However, there is insufficient data to support the clinical use of sST2 in biomarker-tailored therapy.<a class="elsevierStyleCrossRef" href="#bib0535">50</a>Discussion and conclusionsNatriuretic peptides are a part of daily clinical practice, not only for the large number of patients hospitalized with decompensated HF, and their utility has been confirmed in various studies. They are an important tool in the diagnosis of acute HF, as well as in prognostic assessment. They have a promising role in biomarker-guided therapy, though this is still not recommended by clinical guidelines. Several other biomarkers that can complement natriuretic peptides have been studied. A multimarker strategy appears to be beneficial, which is another incentive for thorough investigation of new molecules.<a class="elsevierStyleCrossRefs" href="#bib0550">53,54</a>Considering the studies analyzed in this work, it can be concluded that measurement of MR-proADM and sST2 is not of significant help in the diagnostic assessment of patients hospitalized with HF.Regarding risk stratification, the best results can be found in the MOCA study,<a class="elsevierStyleCrossRef" href="#bib0560">55</a> in which these biomarkers were able to identify patients with higher mortality risk, who need enhanced surveillance and more aggressive therapeutic strategies. The addition of sST2 and MR-proADM to the natriuretic peptides helps to determine both short- and long-term prognosis. sST2 and MR-proADM can be used in the follow-up of patients with stable chronic HF. In these patients, MR-proADM and sST2 appear to be equivalent or, in some cases, superior to natriuretic peptides, and can be used in conjunction with them in follow-up. Unlike for natriuretic peptides, studies proving the clinical utility of sST2 and MR-proADM in biomarker-guided therapy are still lacking. These conclusions are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>sST2 appears to have some advantages compared to MR-proADM. Some studies on sST2 have shown that this biomarker is linked to ventricular remodeling: elevated sST2 levels are associated with an enlarged and hypokinetic left ventricle. This suggests that natriuretic peptides could be more useful when assessed in conjunction with sST2 than with MR-proADM.Despite the benefits of these two biomarkers, many questions remain to be answered. For instance, the cutoff values indicating good or bad prognosis are of considerable importance. Biomarker values usually reach their peak in the acute phase and then decrease during stabilization, reaching lower levels in patients with stable chronic HF.For sST2, 35 ng/ml is the cutoff validated in both acute and chronic HF. This biomarker is most widely used to classify patients with chronic HF.<a class="elsevierStyleCrossRefs" href="#bib0565">56,57</a> By contrast, there is no agreed threshold for MR-proADM in either acute or chronic HF patients. It is consequently a priority to define cutoff values that can be applied to the general population, enabling widespread clinical use of these biomarkers.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres859476" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec853585" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres859477" "titulo" => "Resumo" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec853584" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Adrenomedullin" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnostic value of MR-proADM in acute heart failure" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Prognostic value of MR-proADM in acute heart failure" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "MR-proADM in follow-up and biomarker-guided therapy" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "ST2" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Diagnostic value of ST2 in acute heart failure" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Prognostic value of ST2 in acute heart failure" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "ST2 in follow-up and biomarker-guided therapy" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion and conclusions" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-05" "fechaAceptado" => "2016-11-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec853585" "palabras" => array:6 [ 0 => "Heart failure" 1 => "Biomarkers" 2 => "NT-proBNP" 3 => "Mid-regional pro-adrenomedullin" 4 => "ST2" 5 => "sST2" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec853584" "palabras" => array:6 [ 0 => "Insuficiência cardíaca" 1 => "Biomarcadores" 2 => "NT-proBNP" 3 => "Adrenomedulina" 4 => "ST2" 5 => "sST2" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Heart failure has a high prevalence in developed countries. It is a frequent cause of hospital admission and has an important impact on morbidity, mortality and healthcare costs. Biomarkers have been widely studied in heart failure, as they improve diagnosis and prognostic assessment. Natriuretic peptides are already a part of daily clinical practice but several other biomarkers are being studied. This review focuses on mid-regional pro-adrenomedullin (MR-proADM) and ST2. Neither of these biomarkers is useful in the diagnosis of acute heart failure. However, both have considerable short- and long-term prognostic value in patients with acute and with stable chronic heart failure. The utility of these two biomarkers in guiding heart failure treatment is yet to be established. ST2 appears to have some advantages compared to MR-proADM, because it is more closely associated with ventricular remodeling and fibrosis." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "A insuficiência cardíaca tem uma elevada prevalência nos países desenvolvidos. Trata-se de uma causa frequente de internamento hospitalar com importante impacto na morbilidade, mortalidade e custos dos cuidados de saúde. Os biomarcadores têm contribuído para a avaliação diagnóstica e prognóstica na insuficiência cardíaca. Os péptidos natriuréticos fazem já parte da prática clínica diária, mas há vários outros biomarcadores que têm vindo a ser estudados. Este artigo pretende avaliar a importância da MR-proadrenomedulina e do ST2. Nenhum destes biomarcadores se tem revelado útil para o diagnóstico da insuficiência cardíaca aguda. Também não está estabelecida ainda a utilidade destes dois biomarcadores na terapêutica guiada da insuficiência cardíaca. Contudo, ambos têm importante valor prognóstico em doentes com insuficiência cardíaca aguda ou insuficiência cardíaca crónica. O uso combinado com os péptidos natriuréticos pode permitir uma melhor estratificação de risco na insuficiência cardíaca." ] ] "nomenclatura" => array:1 [ 0 => array:3 [ "identificador" => "nom0005" "titulo" => "List of abbreviations" "listaDefinicion" => array:1 [ 0 => array:1 [ "definicion" => array:13 [ 0 => array:2 [ "termino" => "ADM" "descripcion" => "adrenomedullin" ] 1 => array:2 [ "termino" => "ACEIs" "descripcion" => "angiotensin-converting enzyme inhibitors" ] 2 => array:2 [ "termino" => "ARBs" "descripcion" => "angiotensin receptor blockers" ] 3 => array:2 [ "termino" => "AUC" "descripcion" => "area under the curve" ] 4 => array:2 [ "termino" => "BNP" "descripcion" => "B-type natriuretic peptide" ] 5 => array:2 [ "termino" => "ED" "descripcion" => "emergency department" ] 6 => array:2 [ "termino" => "HF" "descripcion" => "heart failure" ] 7 => array:2 [ "termino" => "IL-1" "descripcion" => "interleukin-1" ] 8 => array:2 [ "termino" => "IL-33" "descripcion" => "interleukin-33" ] 9 => array:2 [ "termino" => "MR-proADM" "descripcion" => "mid-regional pro-adrenomedullin" ] 10 => array:2 [ "termino" => "NT-proBNP" "descripcion" => "N-terminal pro-B-type natriuretic peptide" ] 11 => array:2 [ "termino" => "ST2" "descripcion" => "suppression of tumorigenicity 2" ] 12 => array:2 [ "termino" => "sST2" "descripcion" => "soluble ST2" ] ] ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1050 "Ancho" => 2500 "Tamanyo" => 139993 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the production and actions of adrenomedullin (ADM) in heart failure (HF). The pressure/volume overload and ventricular wall stretching seen in HF lead to upregulation of the ADM gene. The preprohormone undergoes cleavage, forming pro-ADM, which is further processed to ADM. ADM causes natriuresis, diuresis, and vasodilation. It is also associated with reduced hypertrophy, ventricular remodeling and fibrosis. The actions of ADM thus have a cardioprotective effect. Due to its in vitro instability, ADM levels cannot be measured directly, but cleavage of pro-ADM also produces mid-regional pro-adrenomedullin, a stable fragment that is easily measured and whose concentrations reflect those of ADM. ADM: adrenomedullin; MR-proADM: mid-regional pro-adrenomedullin." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1016 "Ancho" => 2333 "Tamanyo" => 68545 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the interleukin-33 (IL-33)/ST2 pathway. IL-33 exerts its biological actions when it binds to the ST2L isoform. In situations of myocardial stress, the IL-33/ST2L interaction appears to have a cardioprotective effect. Soluble ST2 acts as a decoy receptor, preventing the beneficial effects of IL-33/ST2L signaling. IL-33: interleukin-33; sST2: soluble ST2." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AUC: area under the curve on receiver operating characteristic analysis; BNP: B-type natriuretic peptide; ED: emergency department; MR-proADM: mid-regional pro-adrenomedullin; NT-proBNP: N-terminal pro-B-type natriuretic peptide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Setting \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. of patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary endpoint \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main conclusions \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maisel et al.<a class="elsevierStyleCrossRef" href="#bib0410">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients presenting to the ED with dyspnea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1641 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">90-day mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MR-proADM had an AUC of 0.67, which was marginally superior to BNP (AUC 0.61) and NT-proBNP (AUC 0.66) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Peacock et al.<a class="elsevierStyleCrossRef" href="#bib0415">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients presenting to the ED with dyspnea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1641 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14-day mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">With an AUC of 0.72, MR-proADM was superior to both BNP (0.48) and NT-proBNP (0.59) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Travaglino et al.<a class="elsevierStyleCrossRef" href="#bib0420">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients presenting to the ED with dyspnea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">501 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30- and 90-day mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MR-proADM values at admission and at 72 hours significantly predicted 30-day mortality (p<0.001) and 90-day mortality (p<0.0001) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1452731.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies assessing the prognostic value of MR-proADM in acute heart failure." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ED: emergency department; HF: heart failure; NYHA: New York Heart Association." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Setting \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. of patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary endpoint \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main conclusions \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Januzzi et al.<a class="elsevierStyleCrossRef" href="#bib0455">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dyspneic patients in the ED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">599 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-year mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">High ST2 levels associated with increased 1-year mortality \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rehman et al.<a class="elsevierStyleCrossRef" href="#bib0470">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients in the ED with acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">346 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-year mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Higher ST2 levels are found in patients in higher NYHA class and correlate with worse prognosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Friões et al.<a class="elsevierStyleCrossRef" href="#bib0475">38</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients hospitalized with acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">195 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6-month mortality or readmission \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Higher ST2 concentrations associated with higher risk of 6-month mortality or readmission \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bayes-Genis et al.<a class="elsevierStyleCrossRef" href="#bib0485">40</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ambulatory patients with recent decompensated HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-year cardiovascular death, hospital admission for HF or heart transplantation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A greater decrease in ST2 levels two weeks after discharge associated with better outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Breidthardt et al.<a class="elsevierStyleCrossRef" href="#bib0490">41</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patients in the ED with acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">207 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-year mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ED and serial ST2 measurements are independent predictors of 1-year mortality in acute HF \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1452732.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies assessing the prognostic value of ST2 in acute heart failure." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "+ indicates utility; - indicates lack of data suggesting utility." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Biomarker \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prognosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapy guidance \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BNP/NT-proBNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MR-proADM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">sST2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1452730.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical usefulness of natriuretic peptides, adrenomedullin and ST2 in patients with heart failure." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:57 [ 0 => array:3 [ "identificador" => "bib0290" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P. Ponikowski" 1 => "A. Voors" 2 => "S. Anker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehw128" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2016" "volumen" => "37" "paginaInicial" => "2129" "paginaFinal" => "2200" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27206819" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0295" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "E. 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Review Article

Mid-regional pro-adrenomedullin and ST2 in heart failure: Contributions to diagnosis and prognosis

A MR-proadrenomedulina e o ST2 na insuficiência cardíaca: contribuição para o diagnóstico e prognóstico

Daniela Lopesa, Luiz Menezes Falcãob,

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luizmfalcao@sapo.pt

Corresponding author.

a University Hospital Santa Maria/CHLN, Lisbon, Portugal

b University Hospital Santa Maria/CHLN, Faculty of Medicine of Lisbon, Lisbon, Portugal

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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the production and actions of adrenomedullin &#40;ADM&#41; in heart failure &#40;HF&#41;&#46; The pressure&#47;volume overload and ventricular wall stretching seen in HF lead to upregulation of the ADM gene&#46; The preprohormone undergoes cleavage&#44; forming pro-ADM&#44; which is further processed to ADM&#46; ADM causes natriuresis&#44; diuresis&#44; and vasodilation&#46; It is also associated with reduced hypertrophy&#44; ventricular remodeling and fibrosis&#46; The actions of ADM thus have a cardioprotective effect&#46; Due to its in vitro instability&#44; ADM levels cannot be measured directly&#44; but cleavage of pro-ADM also produces mid-regional pro-adrenomedullin&#44; a stable fragment that is easily measured and whose concentrations reflect those of ADM&#46; ADM&#58; adrenomedullin&#59; MR-proADM&#58; mid-regional pro-adrenomedullin&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0060" class="elsevierStylePara elsevierViewall">In the most recent European Society of Cardiology &#40;ESC&#41; guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">1</span></a> heart failure &#40;HF&#41; is defined as a clinical syndrome characterized by typical symptoms &#40;e&#46;g&#46; breathlessness&#44; ankle swelling and fatigue&#41; that may be accompanied by signs &#40;e&#46;g&#46; elevated jugular venous pressure&#44; pulmonary crackles and peripheral edema&#41; caused by a structural and&#47;or functional cardiac abnormality&#44; resulting in a reduced cardiac output and&#47;or elevated intracardiac pressures at rest or during stress&#46; This definition of HF restricts itself to stages at which clinical symptoms are apparent&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">1</span></a> In recent decades&#44; there have been notable advances in the prevention&#44; diagnosis and treatment of cardiovascular disease&#46; However&#44; HF still has a significant impact&#44; as it results in frequent hospitalizations&#44; reduced life expectancy and high expenditure in healthcare systems&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">2</span></a> HF has an estimated prevalence of 1-2&#37; in the adult population of developed countries&#44; but the number of cases in the elderly is higher&#44; affecting at least 10&#37; of individuals aged 70 years or older&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">1</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Considering that the symptoms and signs described are non-specific&#44; the diagnosis of acute HF is not always easy and differential diagnosis can be complicated&#46; The presence of comorbidities such as pulmonary infection also complicates diagnosis due to overlapping symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">3</span></a> Therefore&#44; the use of biomarkers to provide more accurate diagnosis has been widely studied&#46; Ideally&#44; biomarkers should provide information that is not given by clinical assessment or routine exams&#44; thereby helping medical decisions&#46; They should also be highly sensitive and specific&#44; as well as easily measured&#44; with reasonable costs and rapidly available results&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">3</span></a> The part played by biomarkers is not limited to the diagnosis of HF&#44; as they may also be useful in prognostic assessment&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Natriuretic peptides&#44; especially B-type natriuretic peptide &#40;BNP&#41; and its precursor N-terminal pro-B-type natriuretic peptide &#40;NT-proBNP&#41;&#44; are currently used in clinical practice and their measurement is recommended by the ESC guidelines for the diagnosis and assessment of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">1</span></a> Their use in the diagnosis of acute HF in patients presenting with acute dyspnea in the emergency department &#40;ED&#41; has been validated by several studies&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">4</span></a> Both BNP and NT-proBNP are very precise in identifying acute HF and their addition to routine clinical assessment is clearly advantageous&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">5&#8211;7</span></a> In terms of diagnostic value&#44; there is no statistical difference between the two biomarkers&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">8</span></a> Natriuretic peptides are also useful in the prognostic assessment of patients hospitalized due to acute HF&#58; higher BNP and NT-proBNP concentrations are associated with higher mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">9&#8211;11</span></a> In patients with stable chronic HF&#44; measurement of natriuretic peptides is also an important follow-up tool&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">12&#44;13</span></a> Natriuretic peptide-guided therapy has been the subject of considerable study&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">14</span></a> Adjusting therapy in order to attain lower BNP and NT-proBNP levels has been found to be associated with lower hospitalization and mortality rates&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Despite their important role in HF&#44; natriuretic peptides show some limitations&#46; They are elevated in other conditions as well as HF&#44; such as valvular heart disease&#44; pulmonary hypertension&#44; pulmonary thromboembolism&#44; atrial fibrillation and sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">4&#44;17</span></a> Age and kidney failure increase natriuretic peptide levels&#44; while obesity is associated with lower levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">4&#44;17</span></a> These situations can give values in a gray area that requires particularly careful analysis&#46; The investigation of new biomarkers that can complement natriuretic peptides has been the subject of considerable attention&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">This review focuses on two interesting and promising biomarkers currently under study&#58; adrenomedullin &#40;ADM&#41;&#44; mainly a myocyte strain marker&#44; and ST2&#44; mainly a cardiac remodeling marker&#46; These biomarkers reflect different pathological pathways&#46; Their diagnostic and prognostic value will be examined&#44; as will their importance in monitoring of therapy and patient follow-up&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Adrenomedullin</span><p id="par0085" class="elsevierStylePara elsevierViewall">ADM is a 52-amino acid peptide belonging to the calcitonin gene-related peptide family&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">18&#44;19</span></a> The ADM gene encodes a 185-amino acid preprohormone&#44; which&#44; after cleavage&#44; generates a 164-amino acid prohormone&#44; pro-ADM&#59; pro-ADM is then processed&#44; forming ADM<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">18&#44;19</span></a> and mid-regional pro-adrenomedullin &#40;MR-proADM&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; ADM is secreted in various tissues&#44; including the heart&#44; lungs&#44; central nervous system&#44; kidneys and gastrointestinal organs&#59; it is also expressed in endothelial cells&#44; vascular smooth muscle cells&#44; fibroblasts and adipocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">18&#44;19</span></a> ADM has a hypotensive effect&#58; it stimulates diuresis and natriuresis and also causes vasodilation&#44; lowering blood pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">18</span></a> In HF&#44; as a consequence of pressure&#47;volume overload and ventricular wall stretching&#44; the ADM gene is upregulated in cardiac myocytes&#46; The resulting high ADM levels appear to have a protective effect in the myocardium&#44; as they lead to a decrease in preload and afterload&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a> Some studies suggest that ADM additionally inhibits cell growth and hypertrophy&#59; it has also been associated with reductions in remodeling and fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">19&#44;20</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">ADM&#44; like natriuretic peptides and many other vasoactive peptides&#44; is cleaved by neprilysin&#44; a ubiquitous enzyme that is mainly expressed in the proximal tubules of nephrons&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">21</span></a> Inhibition of neprilysin has been studied as a way to enhance endogenous neurohumoral systems that are diuretic and natriuretic and able to inhibit hypertrophy and fibrosis in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Clinical use of ADM was limited for some time because of the in vitro instability of this biomarker&#58; its half-life is short and it is quickly removed from the circulation&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a> This problem was solved by the use of MR-proADM&#44; a stable fragment of pro-ADM whose concentrations reflect those of ADM&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnostic value of MR-proADM in acute heart failure</span><p id="par0100" class="elsevierStylePara elsevierViewall">Regarding the use of MR-proADM in the diagnosis of acute HF&#44; it should be borne in mind that this biomarker is also increased in other conditions&#44; such as systemic and pulmonary hypertension&#44; following myocardial infarction&#44; kidney failure and sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">18&#44;19</span></a> In order to determine the diagnostic value of MR-proADM&#44; Dieplinger et al&#46; measured its levels in patients who attended the ED with acute dyspnea&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">23</span></a> It was concluded that MR-proADM had no statistically significant value in the diagnosis of acute HF and was clearly inferior to NT-proBNP&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">23</span></a> Another study confirmed the lack of specificity of MR-proADM in the diagnosis of acute HF&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">24</span></a> Therefore&#44; MR-proADM appears to have no practical utility in the diagnosis of acute HF and its measurement has no advantage over the established natriuretic peptides&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Prognostic value of MR-proADM in acute heart failure</span><p id="par0105" class="elsevierStylePara elsevierViewall">Several studies have shown that MR-proADM can be used in the prognostic assessment of patients with acute HF<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">19</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The BACH study by Maisel et al&#46;&#44; involving a large number of patients presenting to the ED with acute dyspnea&#44; analyzed whether MR-proADM was related to 90-day survival&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a> Survivors had lower MR-proADM levels than those who died&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a> Furthermore&#44; for predicting 90-day survival&#44; MR-proADM had an area under the curve &#40;AUC&#41; on receiver operating characteristic analysis of 0&#46;67&#44; which was slightly superior to BNP &#40;AUC 0&#46;61&#41; and NT-proBNP &#40;AUC 0&#46;66&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a> The prognostic accuracy of MR-proADM levels&#44; assessed in blood samples taken on admission to the ED&#44; was 73&#37;&#44; which was higher than for BNP and NT-proBNP &#40;62&#37; and 64&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">In a subsequent sub-analysis of the BACH study assessing the prognostic value of ADM in the shorter term&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">26</span></a> MR-proADM was superior to natriuretic peptides in predicting 14-day mortality&#59; the AUC for BNP and NT-proBNP was&#44; respectively&#44; 0&#46;48 and 0&#46;59&#44; while MR-proADM had an AUC of 0&#46;74&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">26</span></a> As the latter value is considerably superior to the AUC observed for predicting 90-day mortality&#44; this biomarker seems to be more useful in shorter-term prognostic assessment&#46; It is important to note that in the above study treatment was similar in survivors and in those who died within 14 days&#59; this shows the importance of identifying patients with worse prognosis&#44; who may need more aggressive treatment and surveillance&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">26</span></a> The Verifying Dyspnea study<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">27</span></a> also confirmed the prognostic value of MR-proADM&#46; In the group of patients with acute HF&#44; MR-proADM levels in the ED and at 72 hours after admission had an AUC for 90-day mortality of 0&#46;76 &#40;p&#60;0&#46;005&#41; and 0&#46;77 &#40;p&#60;0&#46;05&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">27</span></a> Moreover&#44; reassessment of MR-proADM 72 hours after admission was superior to a single measurement&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">27</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">These studies show that MR-proADM is a good prognostic marker in patients hospitalized due to acute HF and&#44; in some reports&#44; is even superior to natriuretic peptides&#46; Hence&#44; MR-proADM can be complementary to natriuretic peptides and its measurement may be useful&#46; It is important to point out that MR-proADM levels vary according to certain patient characteristics&#46; Women&#44; older patients&#44; and those with kidney failure and systolic dysfunction have higher MR-proADM levels&#44; while like natriuretic peptides&#44; levels decrease with higher body mass index&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">28&#44;29</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">MR-proADM in follow-up and biomarker-guided therapy</span><p id="par0120" class="elsevierStylePara elsevierViewall">Assessment of MR-proADM appears to be useful in the follow-up of patients with stable chronic HF&#46; Von Haehling et al&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">28</span></a> measured MR-proADM and NT-proBNP in patients with chronic HF&#44; under medication and clinically stable&#46; Higher MR-proADM levels were seen in patients in more advanced NYHA classes and these higher levels were also associated with increased mortality &#40;p&#60;0&#46;0001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">28</span></a> Concerning 12-month mortality&#44; MR-proADM had a similar value to NT-proBNP&#59; however&#44; for three-month mortality MR-proADM was shown to be superior to NT-proBNP&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">28</span></a> Once again MR-proADM appears to be more useful in short-term assessment&#46; The use of MR-proADM together with clinical assessment and natriuretic peptides had a better prognostic value than the individual use of any of these variables &#40;p&#60;0&#46;0009&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">28</span></a> Masson et al&#46;&#44; in the GISSI-HF study&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">29</span></a> found that higher concentrations of MR-proADM were associated with an increased risk of mortality or hospitalization for cardiovascular causes &#40;p&#60;0&#46;0001&#41;&#46; In this study&#44; NT-proBNP and MR-proADM had similar value in prognostic assessment&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">29</span></a> Xue et al&#46; recently confirmed these results&#44; concluding that MR-proADM levels were strong predictors of mortality &#40;p&#60;0&#46;0001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">30</span></a> Considering all these studies&#44; MR-proADM is a good prognostic marker even in patients with stable chronic HF&#44; and is useful as a follow-up tool&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">MR-proADM values change with some medications&#44; and lower levels are observed in patients treated with diuretics&#44; angiotensin-converting enzyme inhibitors &#40;ACEIs&#41;&#44; angiotensin receptor blockers &#40;ARBs&#41; and beta-blockers&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">29</span></a> Richards et al&#46; showed that patients with chronic HF who had higher MR-proADM levels particularly benefited from the use of carvedilol&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">31</span></a> Nevertheless&#44; there is no evidence that MR-proADM can be used in a biomarker-guided therapeutic strategy&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">ST2</span><p id="par0130" class="elsevierStylePara elsevierViewall">ST2 is a member of the IL-1 receptor family&#46; There are two main isoforms&#58; a transmembrane receptor &#40;ST2L&#41; and a soluble receptor &#40;sST2&#41;&#46; ST2L includes an extracellular domain&#44; a transmembrane segment and an intracellular domain&#46; sST2&#44; which lacks the transmembrane and intracellular domains&#44; is a circulating isoform that can be detected in serum&#46; The ligand of ST2 is interleukin-33 &#40;IL-33&#41;&#44; an interleukin-1-like cytokine that is secreted by most cells in response to damage&#46; IL-33 exerts its biological actions only when it binds to the ST2L isoform&#46; However&#44; circulating sST2 acts as a decoy receptor&#44; binding to IL-33 and blocking the IL-33&#47;ST2L interaction&#44; which inhibits the action of IL-33<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">The IL-33&#47;ST2 complex participates in the immune response through the activation of Th2 effector cells and the release of Th2-related cytokines&#46; IL-33&#47;ST2 thus plays a role in various inflammatory diseases&#44; including asthma and rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> Recently&#44; it was discovered that IL-33&#47;ST2 is also expressed in cardiac fibroblasts and cardiomyocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> Expression is increased in response to myocardial stress&#44; and this appears to have a cardioprotective effect&#44; reducing myocardial fibrosis&#44; preventing cardiomyocyte hypertrophy&#44; reducing apoptosis&#44; and improving myocardial function&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> The beneficial effects of IL-33 are exerted specifically through the ST2L receptor and are blocked when IL-33 binds to the decoy receptor sST2&#44; which occurs when sST2 levels are increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">32&#44;33</span></a> This explains why higher sST2 levels are associated with remodeling&#44; fibrosis and hypertrophy in patients with cardiac disease&#44; especially HF and ischemic heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">32</span></a> In view of this&#44; several studies have measured circulating sST2 levels in patients with HF&#44; in order to determine the utility of this biomarker&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diagnostic value of ST2 in acute heart failure</span><p id="par0140" class="elsevierStylePara elsevierViewall">Regarding the diagnostic value of sST2 in acute HF&#44; it is important to note that sST2 levels are increased in other cardiovascular diseases besides HF&#44; such as hypertension&#44; ischemic heart disease and valvular heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">33</span></a> Higher concentrations of sST2 are also seen in several inflammatory diseases&#44; including asthma&#44; rheumatoid arthritis and systemic erythematous lupus&#44; and in sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">33</span></a> In the PRIDE study&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> the sST2 levels of patients presenting to the ED with acute dyspnea were measured in order to determine its diagnostic value for acute HF&#46; Although sST2 concentrations were higher in patients with acute HF than in those with non-cardiac dyspnea&#44; sST2 was not found to have a statistically significant diagnostic value&#59; likewise&#44; it was clearly inferior to NT-proBNP in the diagnosis of acute HF&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> Accordingly&#44; it can be concluded that sST2 measurement is not useful for the diagnosis of acute HF and does not present advantages over the established natriuretic peptides&#44; which has been confirmed in more recent studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">23&#44;35</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Prognostic value of ST2 in acute heart failure</span><p id="par0145" class="elsevierStylePara elsevierViewall">sST2 levels in patients hospitalized due to acute HF&#44; measured at admission and discharge&#44; can be used for prognostic assessment<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">36</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The PRIDE study<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> showed that high sST2 concentrations were clearly associated with increased one-year mortality&#46; Likewise&#44; patients with sST2 levels above the median value had 11-fold greater odds for death &#40;p&#60;0&#46;0005&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> sST2 was also superior to NT-proBNP in predicting one-year mortality risk &#40;p&#60;0&#46;05&#41;&#44; but the best value was obtained by using these two biomarkers together&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a> Rehman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">37</span></a> confirmed the correlation between higher sST2 and worse prognosis and also showed that sST2 levels increased with higher NYHA class&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">37</span></a> More recently&#44; Fri&#245;es et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">38</span></a> concluded that higher sST2 concentrations in patients with acute HF were associated with greater risk of six-month mortality or readmission&#46; In this study&#44; sST2 and BNP had similar values but&#44; again&#44; the best value was attained by using the two biomarkers together&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">38</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Monitoring of sST2 values through serial measurements appears to be particularly useful&#44; increasing the prognostic power of this biomarker&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">39</span></a> Bayes-Genis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">40</span></a> studied a small group of patients with acute HF and measured their sST2 values at discharge and two weeks later&#46; Patients with a greater decrease in sST2 two weeks after discharge had a better prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">40</span></a> Another study measured sST2 at admission in the ED and 48 hours later&#44; concluding that sST2 levels clearly separated those who survived from those who did not&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">40</span></a> Likewise&#44; the percentage of sST2 decrease predicted long term mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">41</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">It can be concluded that sST2 is a good prognostic marker&#44; both short- and long-term&#44; in patients hospitalized for acute HF&#46; Also&#44; the addition of sST2 to natriuretic peptides is superior to the use of natriuretic peptides alone&#46; It is important to emphasize that repeated monitoring of sST2 levels is more useful than a single measurement&#44; and its low biological variability increases its potential for serial testing and patient monitoring&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">42</span></a> It has also recently been shown that the prognostic value of sST2 is not influenced by renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">43</span></a> It should be noted that higher sST2 levels are associated with decreased ejection fraction&#44; left ventricular enlargement and hypokinesia&#44; which suggests its potential for the assessment of ventricular remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">ST2 in follow-up and biomarker-guided therapy</span><p id="par0160" class="elsevierStylePara elsevierViewall">sST2 assessment may also be useful as a follow-up measure in patients with stable chronic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">45</span></a> The Penn Heart Failure study&#44; which determined sST2 levels in patients with chronic HF&#44; concluded that higher sST2 concentrations &#40;&#62;36&#46;3 ng&#47;ml&#41; were associated with a higher risk of mortality or heart transplantation &#40;p&#60;0&#46;0001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">46</span></a> Although the prognostic value of sST2 was similar to that of NT-proBNP&#44; the combination of the two biomarkers was superior to their use individually&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">46</span></a> and was a useful complement to conventional clinical assessment&#44; enabling better classification of patients in appropriate risk categories&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">46</span></a> Bayes-Genis et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">47</span></a> whose study showed comparable results&#44; subsequently confirmed these findings&#46; In the Val-HeFT trial&#44; elevated sST2 levels in patients with chronic HF were significantly &#40;p&#60;0&#46;0001&#41; correlated with increased morbidity&#44; mortality and hospitalization for decompensated HF&#44;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">48</span></a> while in the PROTECT study&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">49</span></a> patients with increased sST2 during follow-up had earlier cardiovascular complications &#40;p&#61;0&#46;009&#41;&#46; This study reached another important conclusion&#58; sST2 levels below a cutoff of 35 ng&#47;ml were associated with lower left ventricular end-diastolic volume&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">49</span></a> This links sST2 with left ventricular remodeling and suggests the potential of this biomarker in surveillance of structural heart changes&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">49</span></a> Hence&#44; sST2 has prognostic value in patients with chronic HF&#44; as it identifies those at higher risk&#44; particularly when used together with natriuretic peptides&#44; and could thus be used as a follow-up strategy in these patients&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Patients under HF treatment including ACEIs&#44; ARBs&#44; mineralocorticoid receptor antagonists and beta-blockers show lower concentrations of sST2&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">50</span></a> This association has led to the hypothesis that this biomarker can be used as a treatment guide in HF&#46; Beta-blockers have shown a substantial effect on sST2 levels&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">48</span></a> Exploring this link&#44; Gaggin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">51</span></a> observed that&#44; in patients with elevated sST2 levels&#44; those under higher beta-blocker doses had lower mortality&#44; suggesting that high sST2 levels may identify patients who will benefit from higher treatment doses&#46; In another study&#44; spironolactone therapy was significantly beneficial for patients hospitalized with acute HF who had elevated sST2&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">52</span></a> However&#44; there is insufficient data to support the clinical use of sST2 in biomarker-tailored therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">50</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion and conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">Natriuretic peptides are a part of daily clinical practice&#44; not only for the large number of patients hospitalized with decompensated HF&#44; and their utility has been confirmed in various studies&#46; They are an important tool in the diagnosis of acute HF&#44; as well as in prognostic assessment&#46; They have a promising role in biomarker-guided therapy&#44; though this is still not recommended by clinical guidelines&#46; Several other biomarkers that can complement natriuretic peptides have been studied&#46; A multimarker strategy appears to be beneficial&#44; which is another incentive for thorough investigation of new molecules&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">53&#44;54</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Considering the studies analyzed in this work&#44; it can be concluded that measurement of MR-proADM and sST2 is not of significant help in the diagnostic assessment of patients hospitalized with HF&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Regarding risk stratification&#44; the best results can be found in the MOCA study&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">55</span></a> in which these biomarkers were able to identify patients with higher mortality risk&#44; who need enhanced surveillance and more aggressive therapeutic strategies&#46; The addition of sST2 and MR-proADM to the natriuretic peptides helps to determine both short- and long-term prognosis&#46; sST2 and MR-proADM can be used in the follow-up of patients with stable chronic HF&#46; In these patients&#44; MR-proADM and sST2 appear to be equivalent or&#44; in some cases&#44; superior to natriuretic peptides&#44; and can be used in conjunction with them in follow-up&#46; Unlike for natriuretic peptides&#44; studies proving the clinical utility of sST2 and MR-proADM in biomarker-guided therapy are still lacking&#46; These conclusions are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">sST2 appears to have some advantages compared to MR-proADM&#46; Some studies on sST2 have shown that this biomarker is linked to ventricular remodeling&#58; elevated sST2 levels are associated with an enlarged and hypokinetic left ventricle&#46; This suggests that natriuretic peptides could be more useful when assessed in conjunction with sST2 than with MR-proADM&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Despite the benefits of these two biomarkers&#44; many questions remain to be answered&#46; For instance&#44; the cutoff values indicating good or bad prognosis are of considerable importance&#46; Biomarker values usually reach their peak in the acute phase and then decrease during stabilization&#44; reaching lower levels in patients with stable chronic HF&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">For sST2&#44; 35 ng&#47;ml is the cutoff validated in both acute and chronic HF&#46; This biomarker is most widely used to classify patients with chronic HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">56&#44;57</span></a> By contrast&#44; there is no agreed threshold for MR-proADM in either acute or chronic HF patients&#46; It is consequently a priority to define cutoff values that can be applied to the general population&#44; enabling widespread clinical use of these biomarkers&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Adrenomedullin"
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              "titulo" => "Diagnostic value of MR-proADM in acute heart failure"
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              "titulo" => "Prognostic value of MR-proADM in acute heart failure"
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              "titulo" => "MR-proADM in follow-up and biomarker-guided therapy"
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          "titulo" => "ST2"
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              "titulo" => "Diagnostic value of ST2 in acute heart failure"
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              "titulo" => "Prognostic value of ST2 in acute heart failure"
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            2 => array:2 [
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              "titulo" => "ST2 in follow-up and biomarker-guided therapy"
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            0 => "Heart failure"
            1 => "Biomarkers"
            2 => "NT-proBNP"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Heart failure has a high prevalence in developed countries&#46; It is a frequent cause of hospital admission and has an important impact on morbidity&#44; mortality and healthcare costs&#46; Biomarkers have been widely studied in heart failure&#44; as they improve diagnosis and prognostic assessment&#46; Natriuretic peptides are already a part of daily clinical practice but several other biomarkers are being studied&#46; This review focuses on mid-regional pro-adrenomedullin &#40;MR-proADM&#41; and ST2&#46; Neither of these biomarkers is useful in the diagnosis of acute heart failure&#46; However&#44; both have considerable short- and long-term prognostic value in patients with acute and with stable chronic heart failure&#46; The utility of these two biomarkers in guiding heart failure treatment is yet to be established&#46; ST2 appears to have some advantages compared to MR-proADM&#44; because it is more closely associated with ventricular remodeling and fibrosis&#46;</p></span>"
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      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A insufici&#234;ncia card&#237;aca tem uma elevada preval&#234;ncia nos pa&#237;ses desenvolvidos&#46; Trata-se de uma causa frequente de internamento hospitalar com importante impacto na morbilidade&#44; mortalidade e custos dos cuidados de sa&#250;de&#46; Os biomarcadores t&#234;m contribu&#237;do para a avalia&#231;&#227;o diagn&#243;stica e progn&#243;stica na insufici&#234;ncia card&#237;aca&#46; Os p&#233;ptidos natriur&#233;ticos fazem j&#225; parte da pr&#225;tica cl&#237;nica di&#225;ria&#44; mas h&#225; v&#225;rios outros biomarcadores que t&#234;m vindo a ser estudados&#46; Este artigo pretende avaliar a import&#226;ncia da MR-proadrenomedulina e do ST2&#46; Nenhum destes biomarcadores se tem revelado &#250;til para o diagn&#243;stico da insufici&#234;ncia card&#237;aca aguda&#46; Tamb&#233;m n&#227;o est&#225; estabelecida ainda a utilidade destes dois biomarcadores na terap&#234;utica guiada da insufici&#234;ncia card&#237;aca&#46; Contudo&#44; ambos t&#234;m importante valor progn&#243;stico em doentes com insufici&#234;ncia card&#237;aca aguda ou insufici&#234;ncia card&#237;aca cr&#243;nica&#46; O uso combinado com os p&#233;ptidos natriur&#233;ticos pode permitir uma melhor estratifica&#231;&#227;o de risco na insufici&#234;ncia card&#237;aca&#46;</p></span>"
      ]
    ]
    "nomenclatura" => array:1 [
      0 => array:3 [
        "identificador" => "nom0005"
        "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0025">List of abbreviations</span>"
        "listaDefinicion" => array:1 [
          0 => array:1 [
            "definicion" => array:13 [
              0 => array:2 [
                "termino" => "ADM"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">adrenomedullin</p>"
              ]
              1 => array:2 [
                "termino" => "ACEIs"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">angiotensin-converting enzyme inhibitors</p>"
              ]
              2 => array:2 [
                "termino" => "ARBs"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">angiotensin receptor blockers</p>"
              ]
              3 => array:2 [
                "termino" => "AUC"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">area under the curve</p>"
              ]
              4 => array:2 [
                "termino" => "BNP"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide</p>"
              ]
              5 => array:2 [
                "termino" => "ED"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">emergency department</p>"
              ]
              6 => array:2 [
                "termino" => "HF"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">heart failure</p>"
              ]
              7 => array:2 [
                "termino" => "IL-1"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">interleukin-1</p>"
              ]
              8 => array:2 [
                "termino" => "IL-33"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">interleukin-33</p>"
              ]
              9 => array:2 [
                "termino" => "MR-proADM"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">mid-regional pro-adrenomedullin</p>"
              ]
              10 => array:2 [
                "termino" => "NT-proBNP"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">N-terminal pro-B-type natriuretic peptide</p>"
              ]
              11 => array:2 [
                "termino" => "ST2"
                "descripcion" => "<p id="par0205" class="elsevierStylePara elsevierViewall">suppression of tumorigenicity 2</p>"
              ]
              12 => array:2 [
                "termino" => "sST2"
                "descripcion" => "<p id="par0210" class="elsevierStylePara elsevierViewall">soluble ST2</p>"
              ]
            ]
          ]
        ]
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1050
            "Ancho" => 2500
            "Tamanyo" => 139993
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the production and actions of adrenomedullin &#40;ADM&#41; in heart failure &#40;HF&#41;&#46; The pressure&#47;volume overload and ventricular wall stretching seen in HF lead to upregulation of the ADM gene&#46; The preprohormone undergoes cleavage&#44; forming pro-ADM&#44; which is further processed to ADM&#46; ADM causes natriuresis&#44; diuresis&#44; and vasodilation&#46; It is also associated with reduced hypertrophy&#44; ventricular remodeling and fibrosis&#46; The actions of ADM thus have a cardioprotective effect&#46; Due to its in vitro instability&#44; ADM levels cannot be measured directly&#44; but cleavage of pro-ADM also produces mid-regional pro-adrenomedullin&#44; a stable fragment that is easily measured and whose concentrations reflect those of ADM&#46; ADM&#58; adrenomedullin&#59; MR-proADM&#58; mid-regional pro-adrenomedullin&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1016
            "Ancho" => 2333
            "Tamanyo" => 68545
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the interleukin-33 &#40;IL-33&#41;&#47;ST2 pathway&#46; IL-33 exerts its biological actions when it binds to the ST2L isoform&#46; In situations of myocardial stress&#44; the IL-33&#47;ST2L interaction appears to have a cardioprotective effect&#46; Soluble ST2 acts as a decoy receptor&#44; preventing the beneficial effects of IL-33&#47;ST2L signaling&#46; IL-33&#58; interleukin-33&#59; sST2&#58; soluble ST2&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">AUC&#58; area under the curve on receiver operating characteristic analysis&#59; BNP&#58; B-type natriuretic peptide&#59; ED&#58; emergency department&#59; MR-proADM&#58; mid-regional pro-adrenomedullin&#59; NT-proBNP&#58; N-terminal pro-B-type natriuretic peptide&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Setting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary endpoint&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main conclusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Maisel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients presenting to the ED with dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1641&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90-day mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MR-proADM had an AUC of 0&#46;67&#44; which was marginally superior to BNP &#40;AUC 0&#46;61&#41; and NT-proBNP &#40;AUC 0&#46;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Peacock et al&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients presenting to the ED with dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1641&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14-day mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">With an AUC of 0&#46;72&#44; MR-proADM was superior to both BNP &#40;0&#46;48&#41; and NT-proBNP &#40;0&#46;59&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Travaglino et al&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients presenting to the ED with dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">501&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30- and 90-day mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MR-proADM values at admission and at 72 hours significantly predicted 30-day mortality &#40;p&#60;0&#46;001&#41; and 90-day mortality &#40;p&#60;0&#46;0001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1452731.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Studies assessing the prognostic value of MR-proADM in acute heart failure&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ED&#58; emergency department&#59; HF&#58; heart failure&#59; NYHA&#58; New York Heart Association&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Setting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary endpoint&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main conclusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Januzzi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dyspneic patients in the ED&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">599&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-year mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High ST2 levels associated with increased 1-year mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rehman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients in the ED with acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">346&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-year mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Higher ST2 levels are found in patients in higher NYHA class and correlate with worse prognosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fri&#245;es et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients hospitalized with acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">195&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6-month mortality or readmission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Higher ST2 concentrations associated with higher risk of 6-month mortality or readmission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bayes-Genis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ambulatory patients with recent decompensated HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-year cardiovascular death&#44; hospital admission for HF or heart transplantation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A greater decrease in ST2 levels two weeks after discharge associated with better outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Breidthardt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">41</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patients in the ED with acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">207&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-year mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ED and serial ST2 measurements are independent predictors of 1-year mortality in acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1452732.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Studies assessing the prognostic value of ST2 in acute heart failure&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">&#43; indicates utility&#59; - indicates lack of data suggesting utility&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Biomarker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prognosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapy guidance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BNP&#47;NT-proBNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MR-proADM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">sST2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2016.11.012

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	7	6	13
2024 October	31	37	68
2024 September	35	23	58
2024 August	37	29	66
2024 July	30	26	56
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2023 December	33	19	52
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2023 October	26	57	83
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2022 December	36	28	64
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2021 December	30	30	60
2021 November	50	28	78
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2021 August	41	26	67
2021 July	53	17	70
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2021 April	44	40	84
2021 March	87	17	104
2021 February	73	22	95
2021 January	57	9	66
2020 December	37	7	44
2020 November	51	19	70
2020 October	22	18	40
2020 September	51	12	63
2020 August	29	7	36
2020 July	56	9	65
2020 June	49	14	63
2020 May	51	3	54
2020 April	44	11	55
2020 March	56	12	68
2020 February	103	25	128
2020 January	33	8	41
2019 December	57	9	66
2019 November	38	10	48
2019 October	35	9	44
2019 September	100	17	117
2019 August	41	15	56
2019 July	35	12	47
2019 June	43	27	70
2019 May	44	11	55
2019 April	48	24	72
2019 March	98	8	106
2019 February	58	10	68
2019 January	98	6	104
2018 December	53	9	62
2018 November	131	15	146
2018 October	355	17	372
2018 September	160	13	173
2018 August	166	10	176
2018 July	34	3	37
2018 June	28	5	33
2018 May	60	11	71
2018 April	103	8	111
2018 March	135	17	152
2018 February	101	11	112
2018 January	144	31	175
2017 December	237	13	250
2017 November	88	26	114
2017 October	41	11	52
2017 September	32	17	49
2017 August	47	14	61
2017 July	54	28	82

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