Organ protection possibilities in acute heart failure

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Heart Failure" "titulo" => "Organ protection possibilities in acute heart failure" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "157" "paginaFinal" => "164" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Montero-Pérez-Barquero, J.L. Morales-Rull" "autores" => array:2 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Montero-Pérez-Barquero" "email" => array:1 [ 0 => "fm1mopem@uco.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.L." "apellidos" => "Morales-Rull" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Reina Sofía, Universidad de Córdoba, Córdoba, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Insuficiencia Cardiaca, Servicio de Medicina Interna, Hospital Universitario Arnau de Vilanova, Región Sanitaria de Lleida, Lleida, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Posibilidades de organoprotección en la insuficiencia cardiaca aguda" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Metra et al.<a class="elsevierStyleCrossRef" href="#bib0415">20</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1807 "Ancho" => 2916 "Tamanyo" => 207276 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of renal function impairment in heart failure." ] ] ] "textoCompleto" => "BackgroundHeart failure (HF) is a significant health problem that affects 15 million patients in Europe and 5 million in the United States.<a class="elsevierStyleCrossRefs" href="#bib0320">1,2</a> HF results in an extremely high consumption of healthcare resources,<a class="elsevierStyleCrossRefs" href="#bib0320">1,3</a> which is mainly due to the high rate of hospitalizations for acute HF (AHF). More than a million patients each year in the United States are hospitalized for HF, with a mean cost per hospitalization of $19,000.<a class="elsevierStyleCrossRef" href="#bib0335">4</a> In addition to the significant and constantly rising rate of annual readmissions, AHF has high mortality. The predictions are far from optimistic, with an even greater increase in the coming years, due to the aging of the population and an increase in predisposing factors for HF, such as arterial hypertension and ischemic heart disease.<a class="elsevierStyleCrossRefs" href="#bib0320">1,5–7</a>The treatment for AHF has essentially remained unchanged in recent decades. Most clinical trials performed with new drugs have failed to reduce morbidity and mortality, probably because of insufficient understanding of the pathophysiology and pharmaceutical mechanisms of action.<a class="elsevierStyleCrossRef" href="#bib0355">8</a>Pathophysiology of acute heart failureThe pathophysiology of AHF syndrome is complex and difficult to interpret, partly due to the lack of experimental models. Given the diversity of the clinical presentations, there are probably various pathophysiological mechanisms involved in the disease.<a class="elsevierStyleCrossRef" href="#bib0360">9</a> During episodes of AHF, cardiac dysfunction occurs, which includes acute damage to the myocardium, with subsequent remodeling, along with systemic and pulmonary circulation dysfunction. In addition to hemodynamic impairment and neurohormonal activation, there is inflammation and oxidative stress in the genesis of the myocardial, renal and hepatic injury, as well as myocardial remodeling.<a class="elsevierStyleCrossRefs" href="#bib0365">10–12</a>Neurohormonal activation involves various systems and signaling pathways, such as the renin–angiotensin–aldosterone system (RAAS), the sympathetic nervous system, endothelin-1, the adrenomedullin and natriuretic peptides.<a class="elsevierStyleCrossRef" href="#bib0380">13</a>The inflammatory reaction mainly includes the immune response activation, the increase in inflammatory mediators (e.g., tumor necrosis factor, interleukin-1, interleukin-6 and a new HF biomarker of the family of interleukin-1 receptors known as ST2), complement system activation, antibody production and overexpression of histocompatibility and adhesion compounds.<a class="elsevierStyleCrossRefs" href="#bib0385">14,15</a>Oxidative stress results from an excess of molecules that react with nitric oxide and that lead to the production of toxic substances (e.g., peroxynitrite and isoprostane), which increase purine catabolism, with a subsequent increase in serum uric acid and the release of myeloperoxidases by the activated neutrophils and monocytes.<a class="elsevierStyleCrossRef" href="#bib0395">16</a>The abnormalities observed in the myocardium during AHF are related to the progression of myocardial dysfunction and structural abnormalities, such as myocardial hypertrophy, cardiomyocyte apoptosis, depression of myocardial contractility with inhibition of the response capacity of the cardiomyocytes to beta-adrenergic stimulation, growth of fibroblasts, fibrosis and remodeling. It has been proposed that a significant loss of cardiomyocytes occurs during AHF episodes (by necrosis), as well as abnormalities in the architecture of the extracellular myocardial matrix (remodeling). Evidence of the loss of cardiomyocytes includes the increase in plasma troponin, which takes place during exacerbation episodes, in the absence of acute coronary syndrome.<a class="elsevierStyleCrossRefs" href="#bib0400">17–19</a>Renal dysfunction has an important role in the pathophysiology of AHF. The following mechanisms have been proposed to explain the relationship between the 2 conditions (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>):<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">(1)Hemodynamic abnormalities. The kidneys are sensitive to hemodynamic changes, such as increased venous pressure and reduced cardiac output. In patients with AHF, the increase in central venous pressure and intraabdominal pressure are important determinants of the increase in creatinine levels. The reduction in cardiac output is another determinant of renal impairment in HF.<a class="elsevierStyleCrossRef" href="#bib0415">20</a></li><li class="elsevierStyleListItem" id="lsti0010">(2)Sympathetic hyperactivity. The kidneys are richly innervated by sympathetic efferent nerve fibers, and the sympathetic renal impulses are markedly increased in HF. The sympathetic stimulation decreases renal blood flow, through vasoconstriction of the renal artery, and stimulates the release of renin by juxtaglomerular cells.<a class="elsevierStyleCrossRef" href="#bib0420">21</a></li><li class="elsevierStyleListItem" id="lsti0015">(3)RAAS. Angiotensin II can initially cause vasoconstriction of the efferent arteriole, boosting glomerular filtration despite the low renal blood flow during AHF. However, RAAS activation has long-term adverse effects on the kidneys, including the induction of inflammatory phenomena, fibrosis, increased oxidative stress and endothelial dysfunction. Antagonism of these pathogenic mechanisms is the basis of the protective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.<a class="elsevierStyleCrossRef" href="#bib0425">22</a>.</li><li class="elsevierStyleListItem" id="lsti0020">(4)Adenosine release. The release of adenosine can contribute to renal dysfunction, as occurs when high doses of furosemide are administered.<a class="elsevierStyleCrossRef" href="#bib0430">23</a></li><li class="elsevierStyleListItem" id="lsti0025">(5)Inflammation and oxidative stress. Inflammation can play an important role in cardiorenal interaction. Volume overload and venous congestion generate inflammatory activity in HF.<a class="elsevierStyleCrossRef" href="#bib0435">24</a></li></ul><elsevierMultimedia ident="fig0005"></elsevierMultimedia>As a whole, renal and multiple-organ damage can speed the progression of heart disease, negatively affecting the long-term prognosis.<a class="elsevierStyleCrossRef" href="#bib0440">25</a> Many of the existing or emerging biomarkers of cardiac and extra-cardiac injury provide confirmation that this damage is associated with poorer long-term outcomes after the AHF episode.<a class="elsevierStyleCrossRefs" href="#bib0445">26–33</a> Markers of renal dysfunction, such as ureic nitrogen, creatinine and cystatin C, and markers of myocardial injury, such as troponin, are important prognostic predictors in AHF. The resolution of congestion has classically been considered the main therapeutic objective. However, current evidence suggests that the early prevention of myocardial and renal damage should be the main treatment objective.<a class="elsevierStyleCrossRef" href="#bib0415">20</a>Opportunities for organ protectionCurrent knowledge of the pathophysiology of AHF suggests that the treatment strategy should be directed not only toward correcting the hemodynamic disorders but also, in particular, preventing organ damage, acting on the cardiac and extracardiac injury and counteracting myocardial remodeling in order to improve the long-term prognosis.In fact, various compounds with mainly vasodilatory properties have not been able to demonstrate an improvement in the long-term prognosis or in renal organ protection. This outcome has led to the hypothesis that inflammation and oxidative stress, resulting from hemodynamic disorders during AHF, can be more important therapeutic targets.<a class="elsevierStyleCrossRef" href="#bib0485">34</a>NesiritideThe administration of nesiritide, the recombinant form of the human brain natriuretic peptide (BNP), has not improved the short-term prognosis, despite its vasodilatory properties. The compound has also been incapable of achieving better symptomatic relief than standard treatment, as shown in the ASCEND study.<a class="elsevierStyleCrossRefs" href="#bib0490">35,36</a> Its main adverse effect, arterial hypotension, can also have negative consequences for the prognosis and glomerular filtration rate, which could have affected the study's results. Other trials such as the Renal Optimization Strategies Evaluation study have also failed to demonstrate a nephroprotective effect for nesiritide in AHF when added to conventional diuretic therapy.<a class="elsevierStyleCrossRef" href="#bib0500">37</a>RolofyllineAdenosine is an intrarenal mediator responsible for renal function impairment and resistance to diuretics. The hydrolysis of adenosine triphosphate (ATP) releases adenosine 1A into the extracellular space, which, through its specific receptors in the afferent arterioles of the glomerulus, reduces the blood flow and glomerular filtration rate, which in turn boosts the RAAS. Another effect of adenosine 1A receptor activation is sodium reabsorption in the proximal tubule. The PROTECT study (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) was designed to assess whether rolofylline, an adenosine A1 receptor antagonist, could have a nephroprotective role. Once again, no clinical benefits were achieved nor improvements in the prognosis at 60 days of treatment.<a class="elsevierStyleCrossRef" href="#bib0505">38</a>BosentanBosentan is an endothelin-1 antagonistic whose beneficial effects include reducing vasoconstriction, decreasing endothelial dysfunction and diminishing cardiovascular remodeling. Drugs such as bosentan, however, have failed to reduce long-term morbidity and mortality and have also been associated with excessive adverse effects.<a class="elsevierStyleCrossRefs" href="#bib0510">39,40</a>It is therefore important that therapeutic strategies for AHF include in their objectives the reduction of apoptosis and necrosis of the cardiomyocytes, the 2 fundamental mechanisms involved in myocardial dysfunction.<a class="elsevierStyleCrossRef" href="#bib0520">41</a> To date, only 2 drugs employed for treating AHF (levosimendan and serelaxin) have shown certain organ-protective properties, beyond their ability to improve hemodynamics and decompensation-associated symptoms.LevosimendanAlthough the hemodynamic improvement in AHF is associated with reducing myocardial enzymes, the inotropic drugs that act by increasing intracellular calcium levels (e.g., dobutamine and milrinone) can stimulate apoptosis and loss of cardiomyocytes. Thus, the beneficial effects on hemodynamics can be outweighed by the drug's long-term deleterious effects.<a class="elsevierStyleCrossRefs" href="#bib0525">42,43</a> Levosimendan is an inotropic agent with a distinct profile because it also has a vasodilator effect. Unlike other inotropic agents, levosimendan does not increase intracellular calcium levels. Its contractile effect is achieved through the sensitization of myocardial contractile proteins and the stabilization of the calcium–troponin C complex.<a class="elsevierStyleCrossRef" href="#bib0535">44</a> Thanks to phosphodiesterase III inhibition and the consequent opening of the ATP-dependent potassium channels in the plasma membrane, levosimendan achieves potent peripheral vasodilation that protects against myocardial ischemia.<a class="elsevierStyleCrossRef" href="#bib0540">45</a> The opening of the ATP channels not only has been associated in in vitro studies with reduced ischemia but also reduced myocardial apoptosis mediated by inflammation and oxidative stress (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0545">46,47</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Five randomized clinical trials have assessed the short-term effects of levosimendan on patients with AHF and depressed ejection fraction.<a class="elsevierStyleCrossRefs" href="#bib0555">48–52</a> In the first two (the Levosimendan Infusion versus Dobutamine [LIDO]<a class="elsevierStyleCrossRef" href="#bib0555">48</a> study, conducted with patients with AHF, and the Randomized Study on Safety and Effectiveness of Levosimendan [RUSSLAN]<a class="elsevierStyleCrossRef" href="#bib0560">49</a> of patients with acute myocardial infarction who required inotropic support), levosimendan showed clinical efficacy superior to dobutamine and placebo, respectively. In the analysis of the secondary objectives, longer survival was observed at 6 months of follow-up in the LIDO study<a class="elsevierStyleCrossRef" href="#bib0555">48</a> and at 14 days in the RUSSLAN study.<a class="elsevierStyleCrossRef" href="#bib0560">49</a> However, 2 subsequent studies (Randomized Evaluation of Intravenous Levosimendan Efficacy [REVIVE] I and II<a class="elsevierStyleCrossRef" href="#bib0565">50</a>) found no benefits in survival and even observed a nonsignificant tendency toward greater mortality in the group treated with levosimendan.<a class="elsevierStyleCrossRef" href="#bib0570">51</a> Nevertheless, it should be noted that the mortality analysis in the REVIVE studies<a class="elsevierStyleCrossRef" href="#bib0565">50</a> was a secondary objective. The primary objective was the combination of patient-perceived symptom improvement, reduction in BNP levels and mean hospital stay. Levosimendan showed improvements in these 3 parameters compared with conventional treatment along with placebo. The excess mortality in the REVIVE program has been related to the higher rate of hypotension and arrhythmias in the levosimendan group, which could be attributed to the use of loading doses, something that is no longer used in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0575">52</a> Another explanation for this adverse result could be the presence of synergies between drug groups, given that the patients could be treated with dobutamine or milrinone as part of the standard treatment.<a class="elsevierStyleCrossRefs" href="#bib0555">48,49</a>The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study<a class="elsevierStyleCrossRef" href="#bib0575">52</a> was the only one designed to determine the effect of levosimendan on survival at 180 days compared with dobutamine in patients with AHF and depressed ejection fraction who did not respond to diuretic treatment. The study also showed no reduction in mortality attributable to levosimendan. There were no differences in the primary objective between the 2 treatment groups, although the reduction in BNP levels was greater in the levosimendan group, and the number of patients whose AHF worsened during hospitalization was greater in the dobutamine group. In the 2 treatment arms, the mortality increased in the patients who had hypotension prior to the administration of the drug. Nevertheless, in the analysis of the patient subgroup with already diagnosed HF and undergoing beta-blocker treatment, a favorable tendency in terms of survival was observed compared with the dobutamine group, which was attributable to the antagonism caused by the beta-blockers on the hemodynamic effect of dobutamine.<a class="elsevierStyleCrossRef" href="#bib0575">52</a>In short, despite the theoretical advantages of levosimendan due to its anti-inflammatory, pleiotropic, antioxidant and antiapoptotic effects, these benefits have not been demonstrated in the main clinical trials in clinical practice. This is likely due, at least partly, to the studies’ design or the method in which the drug was employed. As was demonstrated by a recent meta-analysis,<a class="elsevierStyleCrossRef" href="#bib0580">53</a> however, there is a specific profile of patients who could benefit, in terms of mortality, from treatment with levosimendan: patients with AHF following cardiac surgery, patients with AHF secondary to myocardial ischemia and patients who are undergoing beta-blocker treatment. In any case, special attention should be paid to correct dosages to minimize the adverse effects.SerelaxinSerelaxin is the recombinant form of endogenous relaxin-2, a natural hormone that mediates the adaptive physiological changes in the gestation process. Its main effects consist of reducing systemic and renal vascular resistances and increasing cardiac output. Serelaxin acts by binding to a specific receptor group (the relaxin family peptide receptor) located in cardiac tissue, blood vessels and kidneys.<a class="elsevierStyleCrossRefs" href="#bib0585">54,55</a> The interaction with receptors not only translates into hemodynamic effects but also activates numerous intracellular signaling pathways that result in additional effects on the cardiovascular system, such as reducing cell damage and cell death, inflammation and fibrosis and the stimulation of angiogenesis.<a class="elsevierStyleCrossRef" href="#bib0595">56</a> Information on these properties comes from studies that employed animal models of ischemia-reperfusion, which observed a reduction in apoptosis mediated by oxidative stress and a reduction in myocardial inflammatory infiltrates. These studies also observed a proliferation in immature myocytes, increased angiogenesis and collagen synthesis inhibition associated with an increased degradation of the extracellular matrix.<a class="elsevierStyleCrossRefs" href="#bib0595">56–58</a> The organ-protective properties of serelaxin are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The RELAX-AHF study,<a class="elsevierStyleCrossRef" href="#bib0610">59</a> a randomized, double-blind, phase 3 clinical trial, compared the efficacy of serelaxin compared with placebo in AHF. The patients had to have a specific profile, lacking arterial hypotension and with mild-moderate renal function impairment (glomerular filtration rate of 30–75mL/min/1.73m2). Serelaxin showed efficacy in the primary objective of reducing dyspnea in the first 5days of treatment, with an appropriate safety profile. Furthermore, a greater reduction in the concentrations of the amino-terminal fragment of the brain natriuretic peptide (NT-proBNP) occurred in the patients treated with serelaxin, as well as a shorter hospital stay and lower susceptibility to worsening AHF during the hospitalization. One of the most interesting results of the study was the up to 37% reduction in deaths by vascular causes at 180 days of follow-up, a drop that was not observed at 60 days of follow-up as set in the secondary objectives.<a class="elsevierStyleCrossRef" href="#bib0610">59</a> These results are consistent with those obtained in the previous phase 2 study (pre-RELAX-HF study).<a class="elsevierStyleCrossRef" href="#bib0615">60</a> The explanation for this reduction in medium-term mortality, after an infusion of the drug for only 48h, is attributed to its nonhemodynamic effects. The drug is believed to interrupt the cascade of pathophysiological processes triggered by the exacerbation, which shows its benefits once the AHF episode has been overcome.<a class="elsevierStyleCrossRef" href="#bib0485">34</a> The greater reduction in high-sensitivity troponin T and NT-proBNP concentrations in patients treated with serelaxin<a class="elsevierStyleCrossRefs" href="#bib0445">26,61</a> reflect these cardioprotective properties. It should be noted that mortality was lowered as a result of fewer cardiovascular events and sudden death. Mortality related to worsening of the HF itself, however, was not reduced. This suggests a relationship between the benefits obtained and the profile of the patients selected for the study (high vascular risk, normal or high blood pressure, without excluding those with preserved ejection fraction).<a class="elsevierStyleCrossRef" href="#bib0620">61</a> The RELAX-AHF-2 study is currently underway<a class="elsevierStyleCrossRef" href="#bib0625">62</a> and is specifically designed to verify whether serelaxin administered during the AHF period is accompanied by reduced cardiovascular mortality at 180 days of follow-up, which would help confirm the previously proposed hypotheses.The positive results of the RELAX-HF study have been received with caution. Both the Food and Drug Administration and the European Medicines Agency refused to authorize the use of serelaxin in AHF, alleging that the results of the study showed no clear benefit for the immediate relief of dyspnea during the first 24h and that, despite the benefits at 5days, its clinical relevance was unclear. Therefore, serelaxin is currently in a similar position as other already known vasodilators.<a class="elsevierStyleCrossRef" href="#bib0630">63</a> We will have to wait for the results of the RELAX-HF-2 study to clear up some of the uncertainties.ConclusionsAlthough the pathophysiology of AHF is complex and not fully understood, there is increasing evidence that hemodynamic dysfunction is only a part of the syndrome. The activation of various neurohormonal and inflammatory mechanisms causes myocardial and renal lesions that persist once the acute episode has passed, which accelerate the disease progression, determining its medium to long-term prognosis. It is likely that early identification and treatment of AHF episodes will improve the long-term prognosis.Although drugs with allegedly organ-protective properties have been developed in recent years, drugs that are able to interfere with the pathophysiology of AHF, the results of the main clinical trials have been conflicting. A clear benefit has not been demonstrated in terms of long-term mortality, which would allow for the daily use of these new drugs. It is important to recognize that most of the trials lack information as to whether the predicted dose for these drugs was reached, as well as that of the treatments undergone at discharge, an issue that could have considerable relevance for understanding the results.More studies are needed, with specific designs aimed at confirming whether the organ-protective capabilities demonstrated in vitro by a number of these drugs translate into reduced long-term morbidity and mortality and whether the hypothetical benefit extends to all patients with AHF or is limited to certain subgroups." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres624519" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec637923" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres624520" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec637922" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pathophysiology of acute heart failure" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Opportunities for organ protection" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Nesiritide" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Rolofylline" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Bosentan" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Levosimendan" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Serelaxin" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec637923" "palabras" => array:3 [ 0 => "Acute heart failure" 1 => "Organ damage" 2 => "Cardiac preservation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec637922" "palabras" => array:3 [ 0 => "Insuficiencia cardiaca aguda" 1 => "Daño orgánico" 2 => "Organoprotección" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Unlike chronic heart failure (HF), the treatment for acute HF has not changed over the last decade. The drugs employed have shown their ability to control symptoms but have not achieved organ protection or managed to reduce medium to long-term morbidity and mortality. Advances in our understanding of the pathophysiology of acute HF suggest that treatment should be directed not only toward correcting the hemodynamic disorders and achieving symptomatic relief but also toward preventing organ damage, thereby counteracting myocardial remodeling and cardiac and extracardiac disorders. Compounds that exert vasodilatory and anti-inflammatory action in the acute phase of HF and can stop cell death, thereby boosting repair mechanisms, could have an essential role in organ protection." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "A diferencia de la insuficiencia cardiaca (IC) crónica, el tratamiento de la IC aguda no ha cambiado en la última década. Los fármacos empleados han demostrado controlar los síntomas, pero no han conseguido una protección orgánica ni una reducción de la morbimortalidad a medio y largo plazo. Los avances en el conocimiento de la fisiopatología de la IC aguda sugieren que el tratamiento debe dirigirse no solo a corregir las alteraciones hemodinámicas y a conseguir un alivio sintomático, sino sobre todo a prevenir el daño orgánico, contrarrestando el remodelado miocárdico y las alteraciones cardiacas y extracardiacas. Las moléculas que en la fase aguda de la IC puedan ejercer acciones vasodilatadoras y antiinflamatorias —y que sean capaces de detener la muerte celular, favoreciendo los mecanismos de reparación— podrían tener un papel esencial en la protección orgánica." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Montero-Pérez-Barquero M, Morales-Rull J.L. Posibilidades de organoprotección en la insuficiencia cardiaca aguda. Rev Clin Esp. 2016;216:157–164." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Metra et al.<a class="elsevierStyleCrossRef" href="#bib0415">20</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1807 "Ancho" => 2916 "Tamanyo" => 207276 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of renal function impairment in heart failure." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Maytin et al.<a class="elsevierStyleCrossRef" href="#bib0545">46</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1717 "Ancho" => 1634 "Tamanyo" => 135457 ] ] "descripcion" => array:1 [ "en" => "Action of levosimendan on myocyte loss. Abbreviation: K-ATP, adenosine triphosphate-sensitive potassium channels." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Du et al.<a class="elsevierStyleCrossRef" href="#bib0595">56</a>" "tabla" => array:2 [ "leyenda" => "Abbreviations: ANP, atrial natriuretic peptide; ET-1, endothelin 1." "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">Properties \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">Mechanisms involved \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">Vasorelaxation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased nitric oxide production Reduced vasoconstriction via ET-1 Increase in angiogenic growth factors \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">Inflammatory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction in the inflammatory infiltrates in cells Reduced oxidative stress \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">Antihypertrophic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced protein synthesis stimulated by cardiomyocytes Increased ANP \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">Antifibrotic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced differentiation of fibroblasts to myofibroblasts Reduced collagen synthesis Increased collagen disruption \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">Repair after aggression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased angiogenesis Maturing of cardiomyocytes \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">Reduced cell death/damage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced intracellular calcium overloading Increased integrity of plasmatic and mitochondrial membranes Reduced cardiomyocyte apoptosis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1024406.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Cardioprotective effects of serelaxin/relaxin-2." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:63 [ 0 => array:3 [ "identificador" => "bib0320" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 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Symposium. Heart Failure

Organ protection possibilities in acute heart failure

Posibilidades de organoprotección en la insuficiencia cardiaca aguda

M. Montero-Pérez-Barqueroa,

Corresponding author

fm1mopem@uco.es

Corresponding author.

, J.L. Morales-Rullb

a Servicio de Medicina Interna, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Reina Sofía, Universidad de Córdoba, Córdoba, Spain

b Unidad de Insuficiencia Cardiaca, Servicio de Medicina Interna, Hospital Universitario Arnau de Vilanova, Región Sanitaria de Lleida, Lleida, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure &#40;HF&#41; is a significant health problem that affects 15 million patients in Europe and 5 million in the United States&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">1&#44;2</span></a> HF results in an extremely high consumption of healthcare resources&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">1&#44;3</span></a> which is mainly due to the high rate of hospitalizations for acute HF &#40;AHF&#41;&#46; More than a million patients each year in the United States are hospitalized for HF&#44; with a mean cost per hospitalization of &#36;19&#44;000&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">4</span></a> In addition to the significant and constantly rising rate of annual readmissions&#44; AHF has high mortality&#46; The predictions are far from optimistic&#44; with an even greater increase in the coming years&#44; due to the aging of the population and an increase in predisposing factors for HF&#44; such as arterial hypertension and ischemic heart disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">1&#44;5&#8211;7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The treatment for AHF has essentially remained unchanged in recent decades&#46; Most clinical trials performed with new drugs have failed to reduce morbidity and mortality&#44; probably because of insufficient understanding of the pathophysiology and pharmaceutical mechanisms of action&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathophysiology of acute heart failure</span><p id="par0015" class="elsevierStylePara elsevierViewall">The pathophysiology of AHF syndrome is complex and difficult to interpret&#44; partly due to the lack of experimental models&#46; Given the diversity of the clinical presentations&#44; there are probably various pathophysiological mechanisms involved in the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">9</span></a> During episodes of AHF&#44; cardiac dysfunction occurs&#44; which includes acute damage to the myocardium&#44; with subsequent remodeling&#44; along with systemic and pulmonary circulation dysfunction&#46; In addition to hemodynamic impairment and neurohormonal activation&#44; there is inflammation and oxidative stress in the genesis of the myocardial&#44; renal and hepatic injury&#44; as well as myocardial remodeling&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">10&#8211;12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Neurohormonal activation involves various systems and signaling pathways&#44; such as the renin&#8211;angiotensin&#8211;aldosterone system &#40;RAAS&#41;&#44; the sympathetic nervous system&#44; endothelin-1&#44; the adrenomedullin and natriuretic peptides&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The inflammatory reaction mainly includes the immune response activation&#44; the increase in inflammatory mediators &#40;e&#46;g&#46;&#44; tumor necrosis factor&#44; interleukin-1&#44; interleukin-6 and a new HF biomarker of the family of interleukin-1 receptors known as ST2&#41;&#44; complement system activation&#44; antibody production and overexpression of histocompatibility and adhesion compounds&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Oxidative stress results from an excess of molecules that react with nitric oxide and that lead to the production of toxic substances &#40;e&#46;g&#46;&#44; peroxynitrite and isoprostane&#41;&#44; which increase purine catabolism&#44; with a subsequent increase in serum uric acid and the release of myeloperoxidases by the activated neutrophils and monocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">16</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The abnormalities observed in the myocardium during AHF are related to the progression of myocardial dysfunction and structural abnormalities&#44; such as myocardial hypertrophy&#44; cardiomyocyte apoptosis&#44; depression of myocardial contractility with inhibition of the response capacity of the cardiomyocytes to beta-adrenergic stimulation&#44; growth of fibroblasts&#44; fibrosis and remodeling&#46; It has been proposed that a significant loss of cardiomyocytes occurs during AHF episodes &#40;by necrosis&#41;&#44; as well as abnormalities in the architecture of the extracellular myocardial matrix &#40;remodeling&#41;&#46; Evidence of the loss of cardiomyocytes includes the increase in plasma troponin&#44; which takes place during exacerbation episodes&#44; in the absence of acute coronary syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">17&#8211;19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Renal dysfunction has an important role in the pathophysiology of AHF&#46; The following mechanisms have been proposed to explain the relationship between the 2 conditions &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#40;1&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hemodynamic abnormalities</span>&#46; The kidneys are sensitive to hemodynamic changes&#44; such as increased venous pressure and reduced cardiac output&#46; In patients with AHF&#44; the increase in central venous pressure and intraabdominal pressure are important determinants of the increase in creatinine levels&#46; The reduction in cardiac output is another determinant of renal impairment in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">20</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#40;2&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Sympathetic hyperactivity</span>&#46; The kidneys are richly innervated by sympathetic efferent nerve fibers&#44; and the sympathetic renal impulses are markedly increased in HF&#46; The sympathetic stimulation decreases renal blood flow&#44; through vasoconstriction of the renal artery&#44; and stimulates the release of renin by juxtaglomerular cells&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#40;3&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RAAS</span>&#46; Angiotensin II can initially cause vasoconstriction of the efferent arteriole&#44; boosting glomerular filtration despite the low renal blood flow during AHF&#46; However&#44; RAAS activation has long-term adverse effects on the kidneys&#44; including the induction of inflammatory phenomena&#44; fibrosis&#44; increased oxidative stress and endothelial dysfunction&#46; Antagonism of these pathogenic mechanisms is the basis of the protective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">22</span></a>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;4&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Adenosine release</span>&#46; The release of adenosine can contribute to renal dysfunction&#44; as occurs when high doses of furosemide are administered&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">23</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#40;5&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Inflammation and oxidative stress</span>&#46; Inflammation can play an important role in cardiorenal interaction&#46; Volume overload and venous congestion generate inflammatory activity in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">24</span></a></p></li></ul></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">As a whole&#44; renal and multiple-organ damage can speed the progression of heart disease&#44; negatively affecting the long-term prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">25</span></a> Many of the existing or emerging biomarkers of cardiac and extra-cardiac injury provide confirmation that this damage is associated with poorer long-term outcomes after the AHF episode&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">26&#8211;33</span></a> Markers of renal dysfunction&#44; such as ureic nitrogen&#44; creatinine and cystatin C&#44; and markers of myocardial injury&#44; such as troponin&#44; are important prognostic predictors in AHF&#46; The resolution of congestion has classically been considered the main therapeutic objective&#46; However&#44; current evidence suggests that the early prevention of myocardial and renal damage should be the main treatment objective&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Opportunities for organ protection</span><p id="par0075" class="elsevierStylePara elsevierViewall">Current knowledge of the pathophysiology of AHF suggests that the treatment strategy should be directed not only toward correcting the hemodynamic disorders but also&#44; in particular&#44; preventing organ damage&#44; acting on the cardiac and extracardiac injury and counteracting myocardial remodeling in order to improve the long-term prognosis&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In fact&#44; various compounds with mainly vasodilatory properties have not been able to demonstrate an improvement in the long-term prognosis or in renal organ protection&#46; This outcome has led to the hypothesis that inflammation and oxidative stress&#44; resulting from hemodynamic disorders during AHF&#44; can be more important therapeutic targets&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">34</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Nesiritide</span><p id="par0085" class="elsevierStylePara elsevierViewall">The administration of nesiritide&#44; the recombinant form of the human brain natriuretic peptide &#40;BNP&#41;&#44; has not improved the short-term prognosis&#44; despite its vasodilatory properties&#46; The compound has also been incapable of achieving better symptomatic relief than standard treatment&#44; as shown in the ASCEND study&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">35&#44;36</span></a> Its main adverse effect&#44; arterial hypotension&#44; can also have negative consequences for the prognosis and glomerular filtration rate&#44; which could have affected the study&#39;s results&#46; Other trials such as the Renal Optimization Strategies Evaluation study have also failed to demonstrate a nephroprotective effect for nesiritide in AHF when added to conventional diuretic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Rolofylline</span><p id="par0090" class="elsevierStylePara elsevierViewall">Adenosine is an intrarenal mediator responsible for renal function impairment and resistance to diuretics&#46; The hydrolysis of adenosine triphosphate &#40;ATP&#41; releases adenosine 1A into the extracellular space&#44; which&#44; through its specific receptors in the afferent arterioles of the glomerulus&#44; reduces the blood flow and glomerular filtration rate&#44; which in turn boosts the RAAS&#46; Another effect of adenosine 1A receptor activation is sodium reabsorption in the proximal tubule&#46; The PROTECT study &#40;Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function&#41; was designed to assess whether rolofylline&#44; an adenosine A1 receptor antagonist&#44; could have a nephroprotective role&#46; Once again&#44; no clinical benefits were achieved nor improvements in the prognosis at 60 days of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Bosentan</span><p id="par0095" class="elsevierStylePara elsevierViewall">Bosentan is an endothelin-1 antagonistic whose beneficial effects include reducing vasoconstriction&#44; decreasing endothelial dysfunction and diminishing cardiovascular remodeling&#46; Drugs such as bosentan&#44; however&#44; have failed to reduce long-term morbidity and mortality and have also been associated with excessive adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">39&#44;40</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It is therefore important that therapeutic strategies for AHF include in their objectives the reduction of apoptosis and necrosis of the cardiomyocytes&#44; the 2 fundamental mechanisms involved in myocardial dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">41</span></a> To date&#44; only 2 drugs employed for treating AHF &#40;levosimendan and serelaxin&#41; have shown certain organ-protective properties&#44; beyond their ability to improve hemodynamics and decompensation-associated symptoms&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Levosimendan</span><p id="par0105" class="elsevierStylePara elsevierViewall">Although the hemodynamic improvement in AHF is associated with reducing myocardial enzymes&#44; the inotropic drugs that act by increasing intracellular calcium levels &#40;e&#46;g&#46;&#44; dobutamine and milrinone&#41; can stimulate apoptosis and loss of cardiomyocytes&#46; Thus&#44; the beneficial effects on hemodynamics can be outweighed by the drug&#39;s long-term deleterious effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">42&#44;43</span></a> Levosimendan is an inotropic agent with a distinct profile because it also has a vasodilator effect&#46; Unlike other inotropic agents&#44; levosimendan does not increase intracellular calcium levels&#46; Its contractile effect is achieved through the sensitization of myocardial contractile proteins and the stabilization of the calcium&#8211;troponin C complex&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">44</span></a> Thanks to phosphodiesterase III inhibition and the consequent opening of the ATP-dependent potassium channels in the plasma membrane&#44; levosimendan achieves potent peripheral vasodilation that protects against myocardial ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">45</span></a> The opening of the ATP channels not only has been associated in in vitro studies with reduced ischemia but also reduced myocardial apoptosis mediated by inflammation and oxidative stress &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">46&#44;47</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Five randomized clinical trials have assessed the short-term effects of levosimendan on patients with AHF and depressed ejection fraction&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">48&#8211;52</span></a> In the first two &#40;the Levosimendan Infusion versus Dobutamine &#91;LIDO&#93;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">48</span></a> study&#44; conducted with patients with AHF&#44; and the Randomized Study on Safety and Effectiveness of Levosimendan &#91;RUSSLAN&#93;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">49</span></a> of patients with acute myocardial infarction who required inotropic support&#41;&#44; levosimendan showed clinical efficacy superior to dobutamine and placebo&#44; respectively&#46; In the analysis of the secondary objectives&#44; longer survival was observed at 6 months of follow-up in the LIDO study<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">48</span></a> and at 14 days in the RUSSLAN study&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">49</span></a> However&#44; 2 subsequent studies &#40;Randomized Evaluation of Intravenous Levosimendan Efficacy &#91;REVIVE&#93; I and II<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">50</span></a>&#41; found no benefits in survival and even observed a nonsignificant tendency toward greater mortality in the group treated with levosimendan&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">51</span></a> Nevertheless&#44; it should be noted that the mortality analysis in the REVIVE studies<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">50</span></a> was a secondary objective&#46; The primary objective was the combination of patient-perceived symptom improvement&#44; reduction in BNP levels and mean hospital stay&#46; Levosimendan showed improvements in these 3 parameters compared with conventional treatment along with placebo&#46; The excess mortality in the REVIVE program has been related to the higher rate of hypotension and arrhythmias in the levosimendan group&#44; which could be attributed to the use of loading doses&#44; something that is no longer used in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">52</span></a> Another explanation for this adverse result could be the presence of synergies between drug groups&#44; given that the patients could be treated with dobutamine or milrinone as part of the standard treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support &#40;SURVIVE&#41; study<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">52</span></a> was the only one designed to determine the effect of levosimendan on survival at 180 days compared with dobutamine in patients with AHF and depressed ejection fraction who did not respond to diuretic treatment&#46; The study also showed no reduction in mortality attributable to levosimendan&#46; There were no differences in the primary objective between the 2 treatment groups&#44; although the reduction in BNP levels was greater in the levosimendan group&#44; and the number of patients whose AHF worsened during hospitalization was greater in the dobutamine group&#46; In the 2 treatment arms&#44; the mortality increased in the patients who had hypotension prior to the administration of the drug&#46; Nevertheless&#44; in the analysis of the patient subgroup with already diagnosed HF and undergoing beta-blocker treatment&#44; a favorable tendency in terms of survival was observed compared with the dobutamine group&#44; which was attributable to the antagonism caused by the beta-blockers on the hemodynamic effect of dobutamine&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">52</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In short&#44; despite the theoretical advantages of levosimendan due to its anti-inflammatory&#44; pleiotropic&#44; antioxidant and antiapoptotic effects&#44; these benefits have not been demonstrated in the main clinical trials in clinical practice&#46; This is likely due&#44; at least partly&#44; to the studies&#8217; design or the method in which the drug was employed&#46; As was demonstrated by a recent meta-analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">53</span></a> however&#44; there is a specific profile of patients who could benefit&#44; in terms of mortality&#44; from treatment with levosimendan&#58; patients with AHF following cardiac surgery&#44; patients with AHF secondary to myocardial ischemia and patients who are undergoing beta-blocker treatment&#46; In any case&#44; special attention should be paid to correct dosages to minimize the adverse effects&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Serelaxin</span><p id="par0125" class="elsevierStylePara elsevierViewall">Serelaxin is the recombinant form of endogenous relaxin-2&#44; a natural hormone that mediates the adaptive physiological changes in the gestation process&#46; Its main effects consist of reducing systemic and renal vascular resistances and increasing cardiac output&#46; Serelaxin acts by binding to a specific receptor group &#40;the relaxin family peptide receptor&#41; located in cardiac tissue&#44; blood vessels and kidneys&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">54&#44;55</span></a> The interaction with receptors not only translates into hemodynamic effects but also activates numerous intracellular signaling pathways that result in additional effects on the cardiovascular system&#44; such as reducing cell damage and cell death&#44; inflammation and fibrosis and the stimulation of angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">56</span></a> Information on these properties comes from studies that employed animal models of ischemia-reperfusion&#44; which observed a reduction in apoptosis mediated by oxidative stress and a reduction in myocardial inflammatory infiltrates&#46; These studies also observed a proliferation in immature myocytes&#44; increased angiogenesis and collagen synthesis inhibition associated with an increased degradation of the extracellular matrix&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">56&#8211;58</span></a> The organ-protective properties of serelaxin are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The RELAX-AHF study&#44;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">59</span></a> a randomized&#44; double-blind&#44; phase 3 clinical trial&#44; compared the efficacy of serelaxin compared with placebo in AHF&#46; The patients had to have a specific profile&#44; lacking arterial hypotension and with mild-moderate renal function impairment &#40;glomerular filtration rate of 30&#8211;75<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46; Serelaxin showed efficacy in the primary objective of reducing dyspnea in the first 5<span class="elsevierStyleHsp" style=""></span>days of treatment&#44; with an appropriate safety profile&#46; Furthermore&#44; a greater reduction in the concentrations of the amino-terminal fragment of the brain natriuretic peptide &#40;NT-proBNP&#41; occurred in the patients treated with serelaxin&#44; as well as a shorter hospital stay and lower susceptibility to worsening AHF during the hospitalization&#46; One of the most interesting results of the study was the up to 37&#37; reduction in deaths by vascular causes at 180 days of follow-up&#44; a drop that was not observed at 60 days of follow-up as set in the secondary objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">59</span></a> These results are consistent with those obtained in the previous phase 2 study &#40;pre-RELAX-HF study&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">60</span></a> The explanation for this reduction in medium-term mortality&#44; after an infusion of the drug for only 48<span class="elsevierStyleHsp" style=""></span>h&#44; is attributed to its nonhemodynamic effects&#46; The drug is believed to interrupt the cascade of pathophysiological processes triggered by the exacerbation&#44; which shows its benefits once the AHF episode has been overcome&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">34</span></a> The greater reduction in high-sensitivity troponin T and NT-proBNP concentrations in patients treated with serelaxin<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">26&#44;61</span></a> reflect these cardioprotective properties&#46; It should be noted that mortality was lowered as a result of fewer cardiovascular events and sudden death&#46; Mortality related to worsening of the HF itself&#44; however&#44; was not reduced&#46; This suggests a relationship between the benefits obtained and the profile of the patients selected for the study &#40;high vascular risk&#44; normal or high blood pressure&#44; without excluding those with preserved ejection fraction&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">61</span></a> The RELAX-AHF-2 study is currently underway<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">62</span></a> and is specifically designed to verify whether serelaxin administered during the AHF period is accompanied by reduced cardiovascular mortality at 180 days of follow-up&#44; which would help confirm the previously proposed hypotheses&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The positive results of the RELAX-HF study have been received with caution&#46; Both the Food and Drug Administration and the European Medicines Agency refused to authorize the use of serelaxin in AHF&#44; alleging that the results of the study showed no clear benefit for the immediate relief of dyspnea during the first 24<span class="elsevierStyleHsp" style=""></span>h and that&#44; despite the benefits at 5<span class="elsevierStyleHsp" style=""></span>days&#44; its clinical relevance was unclear&#46; Therefore&#44; serelaxin is currently in a similar position as other already known vasodilators&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">63</span></a> We will have to wait for the results of the RELAX-HF-2 study to clear up some of the uncertainties&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">Although the pathophysiology of AHF is complex and not fully understood&#44; there is increasing evidence that hemodynamic dysfunction is only a part of the syndrome&#46; The activation of various neurohormonal and inflammatory mechanisms causes myocardial and renal lesions that persist once the acute episode has passed&#44; which accelerate the disease progression&#44; determining its medium to long-term prognosis&#46; It is likely that early identification and treatment of AHF episodes will improve the long-term prognosis&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Although drugs with allegedly organ-protective properties have been developed in recent years&#44; drugs that are able to interfere with the pathophysiology of AHF&#44; the results of the main clinical trials have been conflicting&#46; A clear benefit has not been demonstrated in terms of long-term mortality&#44; which would allow for the daily use of these new drugs&#46; It is important to recognize that most of the trials lack information as to whether the predicted dose for these drugs was reached&#44; as well as that of the treatments undergone at discharge&#44; an issue that could have considerable relevance for understanding the results&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">More studies are needed&#44; with specific designs aimed at confirming whether the organ-protective capabilities demonstrated in vitro by a number of these drugs translate into reduced long-term morbidity and mortality and whether the hypothetical benefit extends to all patients with AHF or is limited to certain subgroups&#46;</p></span></span>"
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          "titulo" => "Background"
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          "titulo" => "Pathophysiology of acute heart failure"
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            0 => "Acute heart failure"
            1 => "Organ damage"
            2 => "Cardiac preservation"
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            0 => "Insuficiencia cardiaca aguda"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Unlike chronic heart failure &#40;HF&#41;&#44; the treatment for acute HF has not changed over the last decade&#46; The drugs employed have shown their ability to control symptoms but have not achieved organ protection or managed to reduce medium to long-term morbidity and mortality&#46; Advances in our understanding of the pathophysiology of acute HF suggest that treatment should be directed not only toward correcting the hemodynamic disorders and achieving symptomatic relief but also toward preventing organ damage&#44; thereby counteracting myocardial remodeling and cardiac and extracardiac disorders&#46; Compounds that exert vasodilatory and anti-inflammatory action in the acute phase of HF and can stop cell death&#44; thereby boosting repair mechanisms&#44; could have an essential role in organ protection&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A diferencia de la insuficiencia cardiaca &#40;IC&#41; cr&#243;nica&#44; el tratamiento de la IC aguda no ha cambiado en la &#250;ltima d&#233;cada&#46; Los f&#225;rmacos empleados han demostrado controlar los s&#237;ntomas&#44; pero no han conseguido una protecci&#243;n org&#225;nica ni una reducci&#243;n de la morbimortalidad a medio y largo plazo&#46; Los avances en el conocimiento de la fisiopatolog&#237;a de la IC aguda sugieren que el tratamiento debe dirigirse no solo a corregir las alteraciones hemodin&#225;micas y a conseguir un alivio sintom&#225;tico&#44; sino sobre todo a prevenir el da&#241;o org&#225;nico&#44; contrarrestando el remodelado mioc&#225;rdico y las alteraciones cardiacas y extracardiacas&#46; Las mol&#233;culas que en la fase aguda de la IC puedan ejercer acciones vasodilatadoras y antiinflamatorias &#8212;y que sean capaces de detener la muerte celular&#44; favoreciendo los mecanismos de reparaci&#243;n&#8212; podr&#237;an tener un papel esencial en la protecci&#243;n org&#225;nica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Montero-P&#233;rez-Barquero M&#44; Morales-Rull J&#46;L&#46; Posibilidades de organoprotecci&#243;n en la insuficiencia cardiaca aguda&#46; Rev Clin Esp&#46; 2016&#59;216&#58;157&#8211;164&#46;</p>"
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        "fuente" => "Adapted from Metra et al&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">20</span></a>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of renal function impairment in heart failure&#46;</p>"
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        "etiqueta" => "Figure 2"
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        "fuente" => "Adapted from Maytin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">46</span></a>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Action of levosimendan on myocyte loss&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviation</span>&#58; K-ATP&#44; adenosine triphosphate-sensitive potassium channels&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; ANP&#44; atrial natriuretic peptide&#59; ET-1&#44; endothelin 1&#46;</p>"
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                  \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">Properties&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">Mechanisms involved&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">Vasorelaxation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased nitric oxide production<br>Reduced vasoconstriction via ET-1<br>Increase in angiogenic growth factors&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">Inflammatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction in the inflammatory infiltrates in cells<br>Reduced oxidative stress&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">Antihypertrophic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced protein synthesis stimulated by cardiomyocytes<br>Increased ANP&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">Antifibrotic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced differentiation of fibroblasts to myofibroblasts<br>Reduced collagen synthesis<br>Increased collagen disruption&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">Repair after aggression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased angiogenesis<br>Maturing of cardiomyocytes&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">Reduced cell death&#47;damage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced intracellular calcium overloading<br>Increased integrity of plasmatic and mitochondrial membranes<br>Reduced cardiomyocyte apoptosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Cardioprotective effects of serelaxin&#47;relaxin-2&#46;</p>"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.01.002

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