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array:23 [ "pii" => "S2254887415001022" "issn" => "22548874" "doi" => "10.1016/j.rceng.2015.10.003" "estado" => "S300" "fechaPublicacion" => "2016-03-01" "aid" => "1194" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "copyrightAnyo" => "2015" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Clin Esp. 2016;216:99-105" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3 "PDF" => 3 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0014256515002258" "issn" => "00142565" "doi" => "10.1016/j.rce.2015.08.007" "estado" => "S300" "fechaPublicacion" => "2016-03-01" "aid" => "1194" "copyright" => "Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Clin Esp. 2016;216:99-105" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 321 "formatos" => array:2 [ "HTML" => 11 "PDF" => 310 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Simposio: insuficiencia cardíaca</span>" "titulo" => "Lesión de órganos diana en la insuficiencia cardiaca aguda" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "99" "paginaFinal" => "105" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Target organ damage in acute heart failure" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2304 "Ancho" => 3339 "Tamanyo" => 321231 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Fisiopatología del síndrome cardiorrenal.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">BNP: péptido natriurético cerebral; NTproBNP: fragmento aminoterminal del péptido natriurético cerebral; SRAA: sistema renina angiotensina aldosterona.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Casado Cerrada, J.P. Zabaleta Camino, M. Fontecha Ortega" "autores" => array:3 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Casado Cerrada" ] 1 => array:2 [ "nombre" => "J.P." "apellidos" => "Zabaleta Camino" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Fontecha Ortega" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2254887415001022" "doi" => "10.1016/j.rceng.2015.10.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887415001022?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256515002258?idApp=WRCEE" "url" => "/00142565/0000021600000002/v1_201603010019/S0014256515002258/v1_201603010019/es/main.assets" ] ] "itemAnterior" => array:19 [ "pii" => "S2254887415000740" "issn" => "22548874" "doi" => "10.1016/j.rceng.2015.08.002" "estado" => "S300" "fechaPublicacion" => "2016-03-01" "aid" => "1173" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:92-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "PDF" => 2 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Treatment of hyperglycemia in patients with acute stroke" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "92" "paginaFinal" => "98" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento de la hiperglucemia en pacientes con ictus agudo" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Castilla-Guerra, M.C. Fernández-Moreno, J. Hewitt" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Castilla-Guerra" ] 1 => array:2 [ "nombre" => "M.C." "apellidos" => "Fernández-Moreno" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Hewitt" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256515001885" "doi" => "10.1016/j.rce.2015.06.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256515001885?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887415000740?idApp=WRCEE" "url" => "/22548874/0000021600000002/v1_201603010018/S2254887415000740/v1_201603010018/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Symposium. Heart Failure</span>" "titulo" => "Target organ damage in acute heart failure" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "99" "paginaFinal" => "105" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Casado Cerrada, J.P. Zabaleta Camino, M. Fontecha Ortega" "autores" => array:3 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Casado Cerrada" "email" => array:1 [ 0 => "casadocerrada@telefonica.net" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.P." "apellidos" => "Zabaleta Camino" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Fontecha Ortega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario de Getafe, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Urgencias, Hospital Universitario de Getafe, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Lesión de órganos diana en la insuficiencia cardiaca aguda" ] ] "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" => 1061 "Ancho" => 1618 "Tamanyo" => 134385 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of acute heart failure. <span class="elsevierStyleItalic">Abbreviations</span>: ALT, alanine aminotransferase; <span class="elsevierStyleItalic">AST</span>, aspartate aminotransferase.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The heterogeneity and complexity of heart failure</span><p id="par0005" class="elsevierStylePara elsevierViewall">Our current understanding of heart failure (HF) provides us with sufficient perspective to state that this condition involves a more complex, heterogeneous and systemic syndrome than had been assumed up until relatively recently.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The heterogeneity is obvious when we recognize that HF, in reality, encompasses 2 distinct phenotypes: the phenotype that presents with reduced ejection fraction (EF) and the other that presents with preserved EF. Although differing in their pathophysiology,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">3</span></a> the 2 phenotypes share etiological factors and pathogenic mechanisms that involve practically all organs and body systems. Our view of their heterogeneity sharpens when we focus on the syndrome's presentation forms and its natural history. In a large portion of patients, HF represents a continuum, with a chronic compensated phase, which, regardless of EF, can experience episodes of decompensation or acute HF (AHF). Although less frequent, AHF is the disease presentation in some patients.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In Europe, 2% of the population has AHF,<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">4</span></a> which is the leading cause of hospitalization in Spain for patients older than 65 years, representing approximately 113,000 hospitalizations per year, of which one-fourth die during the following year.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">A false sense of security</span><p id="par0020" class="elsevierStylePara elsevierViewall">The currently available therapeutic arsenal for treating patients with AHF only provides for the relief of congestive symptoms. Despite the low level of scientific evidence backing it, conventional drug treatment (consisting mainly of diuretics, vasodilators and inotropic agents) provides improvements for the majority of patients, even in the first 24–48<span class="elsevierStyleHsp" style=""></span>h. The treatment improves hemodynamic disorders and a significant portion of the signs and symptoms of decompensation.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">6</span></a> These results can lead to the false perception that AHF is relatively easy to treat and reverse, thereby minimizing the actual importance of this syndrome and its potentially severe consequences. However, a careful observation of the clinical scenario of AHF will give us a very different perspective. In fact, it is striking that in the last decade few advances have been achieved, beyond symptomatic relief, with no significant reduction in morbidity and mortality, despite all the research efforts and numerous clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">7–12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Hospital mortality for patients admitted for AHF is between 4% and 12%, according to a number of series.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">6,13–15</span></a> The risk of complications is especially high in the short term, given that 30–50% of deaths and readmissions occur in the first 60 days after a hospitalization.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">4</span></a> An additional 20–30% of patients die during the first year following an AHF episode.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The change in the pathophysiological paradigm</span><p id="par0030" class="elsevierStylePara elsevierViewall">In recent years, there has been growing support for the hypothesis that short- and long-term morbidity and mortality after an AHF episode is not solely due to hemodynamic changes caused during the exacerbation. In fact, the reactive hemodynamic changes to decompensation can be attenuated or even resolved within a few hours or days of starting the treatment. However, it is speculated that a certain degree of organ, cardiac, renal and hepatic damage (among others) can occur before, during and after an AHF episode.<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">17,18</span></a> Organ damage would be based on the activation and maintenance of inflammatory, neurohormonal and oxidative stress mechanisms, beyond the acute episode, whose outcome would be ischemia, fibrosis and cell death due to apoptosis or necrosis phenomena in various organs and systems (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">17,19,20</span></a> This impairment, which would last over time despite the hemodynamic and congestive disorders having been resolved, could accelerate the progression of cardiovascular disease and worsen the long-term prognosis.<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">21,22</span></a> Within this context, we can understand the search for therapeutic strategies aimed at stopping or attenuating the activation of adaptive response mechanisms to the exacerbation, beyond the episode itself.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">The importance of target organ damage in the prognosis of acute heart failure</span><p id="par0035" class="elsevierStylePara elsevierViewall">The view of HF (both in the chronic and exacerbation phases) as a continuum,<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">1,2</span></a> with pathophysiological mechanisms common to other cardiovascular disorders and systemic outcomes,<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">23</span></a> has focused the attention of clinicians and researchers on the impact of AHF on organs other than the heart.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In the last decade, cardiorenal syndrome (CRS) has aroused interest in the complexity of the relationship between the heart and kidneys. This syndrome involves a two-way relationship that is much closer and complex than previously thought. We now recognize that low cardiac output is not the only factor responsible for renal impairment that can occur during AHF episodes, a condition known as type 1 CRS.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">24</span></a> In addition to hypoperfusion, there are studies that indicate the special relevance of venous congestion,<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">25,26</span></a> along with neurohormonal activation,<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">27</span></a> inflammatory disorders and oxidative stress mechanisms,<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">28</span></a> in mediating organ damage in AHF (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">To identify acute renal damage, various standardized criteria have been proposed, none of which have been shown to be better than the others (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">29,30</span></a> Their applicability in clinical practice for patients with AHF has not been resolved.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">31</span></a> A broader concept of renal function impairment was considered when preparing these criteria, a concept that is extensively used in the literature, with varying definitions depending on the author. In general terms, however, renal function impairment is considered significant when creatinine levels increase by at least 0.3<span class="elsevierStyleHsp" style=""></span>mg/dL or the estimated glomerular filtration rate decreases by at least 25% with respect to baseline.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">32</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">There is currently no question that renal dysfunction and damage are relevant prognostic factors for patients with AHF.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">33,34</span></a> However, recent observations have helped qualify this statement.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">35</span></a> It has been shown that some patients with AHF who experience an increase in creatinine levels above 0.3<span class="elsevierStyleHsp" style=""></span>mg/dL have a poorer prognosis than others with similar increases.<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">36,37</span></a> Moreover, the titration of various drugs, such as renin–angiotensin–aldosterone system blockers and angiotensin <span class="elsevierStyleSmallCaps">II</span> blockers, can cause a certain degree of temporary renal function impairment, which is related to renal protection and improved prognosis.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">38</span></a> Two recent articles called attention to the risk of developing an excessively simplistic view when interpreting the variations in renal function during AHF episodes.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">31,32</span></a> The authors introduced a key element to interpret the variations: the evolution of the patient's clinical state in response to treatment. In this respect, there is evidence that renal impairment is a marker of poor prognosis in AHF when associated with persistent congestion but not when appropriate decongestion is achieved by means of the treatment.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">39</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Another issue related to target organ involvement is acute myocardial damage, which probably affects a large number of patients hospitalized for AHF and has repercussions on the prognosis.<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">40,41</span></a> As occurs with renal damage, the pathophysiological disorders that entail myocardial damage are not precisely known, although it is believed that they can have similar mechanisms: excessive neurohormonal activation, hemodynamic overload, reduced coronary perfusion as a consequence of pump function failure and the tachycardia itself.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">42</span></a> From the biochemical perspective, myocardial damage during AHF translates in some patients into increased troponin levels in the blood, which in this context does not mean that there is a myocardial infarction. The proportion of patients with AHF in whom troponin levels increase depends on the intensity of the decompensation, the therapy employed and the technique used to measure them.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">42</span></a> Up to 40% of patients treated with vasoactive therapies, such as dopamine, who have undetectable troponin levels at admission will increase those levels during hospitalization.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">43</span></a> In a number of series, up to 75% of patients experience increased troponin levels above the 99 percentile (although only 6.2% have values comparable to those of myocardial infarction).<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">40</span></a> If highly sensitive techniques are employed for measuring troponin, virtually all patients with AHF will have this concentration range.<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">40,44</span></a> High-sensitivity techniques provide prognostic information that is superior to conventional techniques. This is reflected in a study of 202 patients with AHF and no acute myocardial infarction, which detected an increase in high-sensitivity troponin in 98% of the participants, compared with 56% using the conventional measuring method. Regardless of the technique, a troponin concentration >20<span class="elsevierStyleHsp" style=""></span>pg/mL identifies a population at significantly greater risk of death.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">45</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Lastly, it is also relatively common to find a certain degree of change in the hepatic function parameters, both in outpatients with chronic HF and those with AHF.<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">22,46,47</span></a> The increase in transaminase levels and cholestasis markers is attributed to hepatic congestion. Hepatic damage is due to volume overload and pressure, along with reduced cardiac output, with the subsequent reduction in hepatic perfusion, hypoxic damage and triggering of inflammatory mechanisms, oxidative stress and apoptosis.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">46</span></a> The growing interest in organ dysfunction in HF is reflected by the recent publication of a study that specifically described the epidemiology and predictive value of hepatic function test abnormalities for patients with HF, both chronic and acute, regardless of its etiology and EF.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">47</span></a> This study included 2096 patients who underwent transaminase and bilirubin readings at least 60 days before the first diagnosis of HF, a quarter of which corresponded to AHF episodes. It became clear over the course of almost 4 years of follow-up that patients who showed higher AST or alkaline phosphatase levels, even within the normal range, as well as those with lower albumin levels, had a greater risk of mortality. The bilirubin concentration, however, showed no statistically significant association with the prognosis.</p><p id="par0065" class="elsevierStylePara elsevierViewall">It was probably the RELAX-AHF study<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">48</span></a> (which analyzed the role of serelaxin in AHF) that emphasized the prognostic importance of organ damage during exacerbation episodes. This study investigated the effect of intravenous serelaxin on dyspnea, renal function and a number of markers of myocardial damage in patients hospitalized for AHF, with mild to moderate renal dysfunction. Serelaxin is a recombinant polypeptide hormone of endogenous relaxin-2, whose plasma values increase in the first trimester of pregnancy. The interaction with its specific receptor determines a series of biochemical mechanisms that mainly affect collagen metabolism and the modulation of the genetic expression of numerous cell mediators. This process results in the main biological effects of serelaxin, which include reduced inflammation and fibrosis; increased vasodilation and renal blood flow; endothelial growth factor stimulation; and angiogenesis.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">20</span></a> The RELAX-AHF study has ventured the hypothesis that the pathophysiological mechanisms triggered during exacerbations could remain active beyond the exacerbations. Otherwise, it would be difficult to interpret its main result: improved renal function several weeks after completing the treatment and controlling the exacerbation. The study results also made it clear that those patients who, during the AHF episode, presented higher increases in plasma congestion markers (NT-proBNP), myocardial damage (ultrasensitive troponin T), renal damage (creatinine and cystatin C) or hepatic damage (transaminase) had as a whole higher mortality rates at 180 days (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Is it possible to protect the target organs in acute heart failure?</span><p id="par0070" class="elsevierStylePara elsevierViewall">If we assume that there are target organs especially sensitive to the consequences of HF exacerbations, the immediate question is, “Is it possible to protect them?” More importantly, “How do we protect them?” and, if we achieve this, “Will this translate into a reduction in morbidity and mortality?”</p><p id="par0075" class="elsevierStylePara elsevierViewall">Unfortunately, there has been much effort and many failures in finding answers to these questions. In recent years, a considerable number of compounds have been assessed, with potentially useful biological properties for acting on some of the mechanisms involved in organ damage (inotropism, vasodilation, renal function, neurohumoral activation, inflammation, fibrosis, etc.). To date, however, none of the compounds have been able to show objective and specific clinical benefits (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The RELAX-AHF study is the only one till date that has provided a certain optimism for the future of the hypothetical “organ protection”. The previously mentioned biological properties of serelaxin are especially appropriate for perfectly fitting the scenario of organ protection in AHF. In fact, the perfusion of 30<span class="elsevierStyleHsp" style=""></span>mg/kg/day of serelaxin for 48<span class="elsevierStyleHsp" style=""></span>h showed a favorable effect on the short-term concentrations of organ damage markers analyzed in the study. The treated patients had a lower incidence of acute renal function impairment at 48<span class="elsevierStyleHsp" style=""></span>h from admission, as exhibited by lower concentrations of creatinine, cystatin C and urea for the first 5 days of hospitalization. The serelaxin perfusion was also accompanied by a significant reduction in troponin T and transaminase levels at 48<span class="elsevierStyleHsp" style=""></span>h, and the proportion of patients who increased their levels of these markers over the course of their hospitalization was also lower. This study's safety analysis found a 38% reduction in cardiovascular mortality at 180 days of the therapy. This phenomenon has been interpreted as an indication that treatment of the acute phase of HF with serelaxin can have a beneficial effect on the vital prognosis, probably through protection of those organs whose biomarkers have shown a more favorable response profile.</p><p id="par0085" class="elsevierStylePara elsevierViewall">If this interpretation is correct, it will open a new therapeutic scenario for AHF: organ protection. For the first time, a therapeutic intervention in the exacerbation phase of HF will be accompanied by a substantive and favorable change in the vital prognosis of these patients. It would therefore be a quantitative and qualitative change.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres611138" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec625128" "titulo" => "Keyword" ] 2 => array:3 [ "identificador" => "xres611137" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec625127" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "The heterogeneity and complexity of heart failure" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "A false sense of security" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "The change in the pathophysiological paradigm" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "The importance of target organ damage in the prognosis of acute heart failure" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Is it possible to protect the target organs in acute heart failure?" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-08-29" "fechaAceptado" => "2015-08-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keyword" "identificador" => "xpalclavsec625128" "palabras" => array:1 [ 0 => "Target organs" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec625127" "palabras" => array:1 [ 0 => "Órganos diana" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute heart failure is a prognostic factor due to its high mortality during the acute phase and the increased frequency of medium- to long-term adverse events. The pathophysiological mechanisms triggered during these exacerbations can persist after reaching clinical stability, remaining even after the acute episode has ended. A certain degree of neurohormonal activation, oxidative stress, apoptosis, and inflammation (among other conditions) can therefore persist, resulting in organ damage, not just of the myocardium but also likely for the entire cardiovascular apparatus. This new insight into the persistence of harmful mechanisms that last beyond the exacerbations could be the start of a change in perspective for developing new therapeutic strategies that seek an overall control of hemodynamic and congestive changes that occur during acute decompensated heart failure and changes that remain after achieving clinical stability.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La insuficiencia cardiaca aguda es un condicionante pronóstico, tanto por su alta morbimortalidad durante el episodio agudo, como por el incremento de acontecimientos adversos a medio y largo plazo. Los mecanismos fisiopatológicos desencadenados durante la agudización podrían no cesar al alcanzarse la estabilidad clínica, manteniéndose una vez pasado el episodio agudo. De este modo, persistiría cierto grado de activación neurohormonal, estrés oxidativo, apoptosis e inflamación, entre otros, que conllevaría daño orgánico, no exclusivamente miocárdico, sino probablemente generalizado sobre el aparato cardiovascular. Esta nueva percepción de la persistencia de los mecanismos lesivos más allá de las agudizaciones puede ser el inicio de un cambio de perspectiva para el desarrollo de nuevas estrategias terapéuticas que persiguen un control global, tanto de los cambios hemodinámicos y congestivos que acontecen durante la descompensación cardiaca aguda, como de los remanentes tras alcanzarse la estabilidad clínica.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Casado Cerrada J, Zabaleta Camino JP, Fontecha Ortega M. Lesión de órganos diana en la insuficiencia cardiaca aguda. Rev Clin Esp. 2016;216:99–105.</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" => 1061 "Ancho" => 1618 "Tamanyo" => 134385 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of acute heart failure. <span class="elsevierStyleItalic">Abbreviations</span>: ALT, alanine aminotransferase; <span class="elsevierStyleItalic">AST</span>, aspartate aminotransferase.</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" => 2313 "Ancho" => 3339 "Tamanyo" => 313613 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of cardiorenal syndrome. <span class="elsevierStyleItalic">Abbreviations</span>: BNP, brain natriuretic peptide; NT-proBNP, amino-terminal fragment of the brain natriuretic peptide; RAAS, renin–angiotensin–aldosterone system.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: AKIN, Aquatic Kidney Injury Network; Cr, creatinine; eGFR, estimated glomerular filtration rate; KDIGO, kidney disease improving global outcomes; RIFLE, risk, injury, failure, loss and end-stage renal disease.</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">Definition \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">Criteria \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">Minimum period for renal damage to occur \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">RIFLE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Risk: increase in Cr ≥1.5 times the baseline value or reduction in eGFR ≥25%Damage: increase in Cr ≥2 times the baseline value or reduction in eGFR ≥50%Failure: increase in Cr ≥3 times the baseline value or reduction in eGFR ≥75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Changes in Cr over the course of 1–7 days, maintained for more than 24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AKIN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Stage 1: increase in Cr of 0.3<span class="elsevierStyleHsp" style=""></span>mg/dL or 1.5–1.9 times the baseline valueStage 2: increase in Cr ≥2–2.9 times the baseline valueStage 3: increase in Cr ≥4<span class="elsevierStyleHsp" style=""></span>mg/dL or ≥3 times the baseline value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute changes in Cr that occur during a 48-h period during hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">KDIGO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Stage 1: increase in Cr ≥1.5 times the baseline value or increase of 0.3<span class="elsevierStyleHsp" style=""></span>mg/dLStage 2: increase in Cr ≥2 times the baseline valueStage 3: increase in Cr ≥3 times the baseline value or increase of ≥4<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Changes in Cr at least 1.5-fold compared with baseline in 7 days or increase of 0.3<span class="elsevierStyleHsp" style=""></span>mg/dL in a 48-h period \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001162.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diagnosis and classification criteria for acute renal damage.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Data extracted from the RELAX-AHF study.<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">48</span></a></p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; NT-proBNP: amino-terminal fraction of the brain natriuretic peptide; HR, hazard ratio.</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 concentration during the first 48<span class="elsevierStyleHsp" style=""></span>h \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">HR (95% CI) \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"><span class="elsevierStyleItalic">p</span> value \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">≥0.3<span class="elsevierStyleHsp" style=""></span>mg/dL increase in creatinine levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.78 (1.11–2.82) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.016 \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">≥20% increase in troponin levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.80 (1.16–2.77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0076 \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">≥0.3<span class="elsevierStyleHsp" style=""></span>mg/dL increase in cystatin C levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.10 (1.38–3.20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0004 \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">≥20% increase in AST levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.66 (0.92–3.00) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.099 \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">≥20% increase in ALT levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.96 (1.13–3.40) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0015 \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">>30% decrease in NT-proBNP levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.47 (0.31–0.69) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001160.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Association between biomarker levels in the first 48<span class="elsevierStyleHsp" style=""></span>h of hospitalization for acute heart failure and mortality at 180 days.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: HF, heart failure; AHF, acute heart failure.</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">Clinical trial \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">Patients, <span class="elsevierStyleItalic">n</span> \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">Drug \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">Result \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">SURVIVE<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">7</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF, 1327 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Levosimendan vs. dobutamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tendency (nonsignificant) to lower mortality at 6 months with levosimendan compared with dobutamine \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">EVEREST<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">8</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF, 4133 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tolvaptan vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No change in overall mortality or readmissions for HF in the first year \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">ASCEND-HF<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">9</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF, 7141 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nesiritide vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nonsignificant reduction in dyspnea, no effect on mortality or readmissions at 30 days \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">ROSE-AHF<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF and renal dysfunction, 360 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dopamine (2<span class="elsevierStyleHsp" style=""></span>μg/kg/min) vs. placeboNesiritide vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neutral effect on decongestion and renal function \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">ASTRONAUT<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF, 1615 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aliskiren vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No effect on reducing mortality or readmissions at 6 months of follow-up \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">PROTECT<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">12</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHF and renal dysfunction, 2033 patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rolofylline vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No improvement in dyspnea or renal dysfunction, no effect on cardiovascular events at 60 days and increased risk of seizures with rolofylline \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001161.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical trials with potentially useful drugs for the organ protection mechanism in patients hospitalized for acute heart failure.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:48 [ 0 => array:3 [ "identificador" => "bib0245" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. 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