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array:23 [ "pii" => "S0014256516000254" "issn" => "00142565" "doi" => "10.1016/j.rce.2016.01.009" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1240" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "copyrightAnyo" => "2016" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Clin Esp. 2016;216:393-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 65 "formatos" => array:2 [ "HTML" => 47 "PDF" => 18 ] ] "itemSiguiente" => array:18 [ "pii" => "S0014256515002854" "issn" => "00142565" "doi" => "10.1016/j.rce.2015.11.011" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1224" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Rev Clin Esp. 2016;216:399" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 49 "formatos" => array:2 [ "HTML" => 34 "PDF" => 15 ] ] "es" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Medicina en imágenes</span>" "titulo" => "Hiperplasia gingival en paciente con granulomatosis y poliangeítis" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:1 [ "paginaInicial" => "399" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Gingival hyperplasia in a patient with granulomatosis and polyangiitis" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:6 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 731 "Ancho" => 975 "Tamanyo" => 120439 ] ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D. Palma-Sánchez, A.C. Haro-Martínez, E. Peñas-Martínez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "D." "apellidos" => "Palma-Sánchez" ] 1 => array:2 [ "nombre" => "A.C." "apellidos" => "Haro-Martínez" ] 2 => array:2 [ "nombre" => "E." "apellidos" => "Peñas-Martínez" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256515002854?idApp=WRCEE" "url" => "/00142565/0000021600000007/v1_201609280158/S0014256515002854/v1_201609280158/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0014256516300315" "issn" => "00142565" "doi" => "10.1016/j.rce.2016.04.010" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1267" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:384-92" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 146 "formatos" => array:2 [ "HTML" => 104 "PDF" => 42 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVISIÓN</span>" "titulo" => "Consideraciones clínicas sobre la posología de los anticoagulantes orales de acción directa" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "384" "paginaFinal" => "392" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Clinical considerations on the posology of direct oral anticoagulants" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Sáez-Peñataro, C. Avendaño-Solá, J.R. González-Juanatey" "autores" => array:3 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Sáez-Peñataro" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Avendaño-Solá" ] 2 => array:2 [ "nombre" => "J.R." "apellidos" => "González-Juanatey" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S225488741630042X" "doi" => "10.1016/j.rceng.2016.04.003" "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/S225488741630042X?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300315?idApp=WRCEE" "url" => "/00142565/0000021600000007/v1_201609280158/S0014256516300315/v1_201609280158/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Symposium: Heart Failure</span>" "titulo" => "B-type natriuretic peptide and acute heart failure: Fluid homeostasis, biomarker and therapeutics" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "393" "paginaFinal" => "398" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "I. Torres-Courchoud, H.H. Chen" "autores" => array:2 [ 0 => array:3 [ "nombre" => "I." "apellidos" => "Torres-Courchoud" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "H.H." "apellidos" => "Chen" "email" => array:1 [ 0 => "chen.horng@mayo.edu" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "University Clinic Hospital Lozano Blesa, Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, MN, United States" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Péptido natriurético de tipo B e insuficiencia cardiaca aguda: homeostasis de fluidos, biomarcadores y terapéutica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1522 "Ancho" => 1650 "Tamanyo" => 174887 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and urodilatin (URO) bind to NP receptors (NPR-A and NPR-B), leading to cGMP production and downstream effects via cGMP-dependent protein kinase G (PKG) like natriuresis, diuresis, vasodilation and more. ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide; CNP: C-type natriuretic peptide; NPR-A: A type natriuretic peptide receptor; NPR-B: B type natriuretic peptide receptor; GTP: guanosine triphosphate; GC: guanyl cyclise; cGMP: cyclic guanosine monophosphate; PKG: protein kinase G.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure (HF) is commonly defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate that meets the requirements of the metabolizing tissues. Acute heart failure (AHF) represents the acute changes in signs and symptoms of HF that require urgent medical assistance and therapy, which include, but is not limited to, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, rales and peripheral edema.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a> AHF is associated with significant morbidity and mortality, and is the most common cause of hospitalization of the elderly in the US and Europe.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a> The prognosis of patients admitted with AHF is poor, with a 20%–30% mortality or readmission rate within six months.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Natriuretic peptides are a family of peptides that are structurally similar but genetically distinct with different actions in cardiorenal and fluid homeostasis.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">4</span></a> The atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are of a myocardial cell origin; the C-type natriuretic peptide (CNP) is of an endothelial origin; and the urodilatin (Uro) is thought to be derived from the processing of the prohormone-ANP in the kidney.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As biomarkers, both BNP and NT-proBNP are available clinically to aid the diagnosis of HF, assessing the severity of HF and risk stratification.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> Nesiritide, a human recombinant BNP, was approved by the Federal Drug Administration (FDA) for the management of AHF in 2001.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> Human recombinant ANP (Carperitide) was approved for the same clinical indication in Japan in 1995, and human recombinant Urodilatin (Ularitide) is currently undergoing phase III clinical trial (TRUE AHF).<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This review provides an update on important issues regarding the role of BNP in fluid hemostasis as a biomarker and therapeutics in AHF (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Neurohumoral activation in acute heart failure</span><p id="par0025" class="elsevierStylePara elsevierViewall">In AHF, the decrease in effective arterial blood volume initiated by decreased cardiac output produces a series of compensatory mechanisms to try to maintain cardiac output and ensure vital organs blood perfusion. The compensatory mechanism includes the activation of two main counteracting neurohumoral systems: (1) vasoconstriction and sodium retention systems such as sympathetic nervous system (SNS), renin–angiotensin–aldosterone system (RAAS), vasopressin and endothelin, and (2) vasodilation and natriuretic systems such as natriuretic peptides, bradykinin, and adrenomedullin. A balance between these two systems is necessary to maintain fluid homeostasis and decongestion.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> For this review, we will focus on the role of the B-type natriuretic peptide system (BNP).</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Activation and release of BNP in AHF</span><p id="par0030" class="elsevierStylePara elsevierViewall">In response to volume expansion or pressure overload (atrial or ventricular wall stretch), the heart secretes natriuretic peptides. Wall stress initiates synthesis of pre–proBNP in the atrial and ventricular myocardium. Subsequently, the pre-propeptide is cleaved first to proBNP1–108, then to the biologically active BNP1–32 and the inactive amino-terminal fragment (NT-proBNP).<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> Natriuretic peptides mediate their physiological actions by binding to three specific receptors localized on the target cell surface. Type-A (NPR-A) and type-B (NPR-B) receptors have two extracellular domains binding the ligand, and two intracellular domains containing guanyl cyclase (GC) and kinase which determine the formation of cGMP (cyclic guanosine monophosphate). GCs are enzymes that convert guanosine 5′-triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate cGMP, the second messenger of the natriuretic peptides. BNP mainly produces its effects via Type-A receptors and stimulates the production of cGMP, which is responsible for the majority of known biological activities of natriuretic peptides. There is a third receptor, NPR-C, whose main function is believed to be the clearing of natriuretic peptides.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> However, recent studies have indicated that this receptor may have biological actions that are not mediated by cGMP. BNP is also degraded by neprilysin on endothelial cells, smooth muscle cells, cardiac myocytes, renal epithelium, pulmonary cells and fibroblasts.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Physiological role of endogenous BNP in fluid homeostasis and decongestion</span><p id="par0035" class="elsevierStylePara elsevierViewall">The release of BNP results in the relaxation of vascular smooth muscle and vasodilation. This reduces systemic and pulmonary vascular resistance and hence, decreases both ventricular preload and afterload. BNP also reduces the sympathetic and RAAS activities. It has central sympathetic inhibitory actions, suppresses the release of aldosterone from the adrenal glands and antagonizes sodium and water reabsorption induced by angiotensin II in the renal proximal tubules.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">13</span></a> In the kidneys, BNP increases the glomerular filtration rate (GFR), diuresis and urinary sodium excretion by afferent arteriolar vasodilatation and efferent arteriolar constriction, thereby ameliorating the volume overload caused by neurohormonal activation and directly inhibiting sodium reabsorption by the collecting duct. In the heart, BNP also counteracts the remodeling effects of RAAS activation by inhibiting hypertrophy and fibrosis.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a> These physiological actions of BNP were elucidated from experimental pharmacological studies antagonizing the NPR-A/B receptors, which demonstrated that endogenous natriuretic peptides have vasodilating, natriuretic, diuretic, lusitropic and renin inhibiting properties that are essential to maintaining fluid homeostasis in AHF.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a></p></span></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Role of BNP as biomarker in AHF</span><p id="par0040" class="elsevierStylePara elsevierViewall">As the plasma BNP level is elevated in HF, its diagnostic utility in HF has been thoroughly investigated. There are three different diagnostic tests for the measurement of BNP or NT-proBNP approved by the FDA for aiding in the diagnosis of HF (Triage BNP; Biosite Diagnostics, San Diego, CA; Shionogi BNP and Roche Diagnostics NT-proBNP). The plasma concentrations of BNP and NT-proBNP are alike in normal healthy individuals.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> In contrast, patients with cardiovascular diseases have a greater increase in plasma NT-proBNP as compared to BNP, with NT-proBNP concentrations approximately four-fold higher than BNP concentrations.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">16</span></a> Studies have identified various factors that may affect BNP or NT-proBNP levels; these include age, gender, obesity, concurrent medications and renal function. Both BNP and NT-proBNP are very specific and function much better as a “rule out” test than a “rule in” test for AHF. As with any other blood test, it should not be used as a stand-alone, but rather with clinical signs, symptoms and other investigations.</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Aid in diagnosis of AHF</span><p id="par0045" class="elsevierStylePara elsevierViewall">AHF is a clinical diagnosis based on signs and symptoms. However, there are many causes of dyspnea and it may be difficult to definitively diagnose AHF in patients presenting with dyspnea. The Breathing Not Properly (BNP) study established the utility of plasma BNP as an aid to the diagnosis of AHF.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a> The study demonstrated in 1586 patients who presented to the urgent care setting with acute dyspnea that plasma BNP was markedly higher in those with clinically diagnosed AHF compared to the ones without AHF. The New Zealand group compared BNP and NT-proBNP assays for the diagnosis of AHF and found that even though the scale of values for BNP and NT-proBNP were different, the levels correlated very well (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.902, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001) and the predictive characteristics were very similar with the area under the receiver-operating-characteristic curve being identical.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Prognostic marker in AHF</span><p id="par0050" class="elsevierStylePara elsevierViewall">In AHF, data from the ADHERE registry established a strong relationship between admission BNP levels and risk of in-hospital mortality.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">19,20</span></a> The pre-discharge plasma BNP level also has an important prognostic value with regard to mortality or rehospitalization. A meta-analysis demonstrated that every 100<span class="elsevierStyleHsp" style=""></span>pg/mL increase in plasma BNP was associated with a 35 percent increase in the relative risk of death. In multivariable models, plasma BNP was a better predictor of survival than traditional risk factors such as NYHA class and left ventricular ejection fraction.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">BNP as therapeutics in AHF</span><p id="par0055" class="elsevierStylePara elsevierViewall">Despite the high plasma levels of BNP in patients with AHF, those patients still exhibit sodium and water retention associated with increased systemic vascular resistance and high cardiac filling pressures. Therefore, a state of relative BNP insufficiency and/or resistance exists, supporting the rationale for the administration of exogenous BNP as a therapy for AHF.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">22</span></a> Studies have reported that the circulating forms of BNP present in the plasma of patients with AHF have decreased biological activity and that there is very little biologically active BNP 1–32 present. Specifically, using mass spectroscopy, Hawkridge et al. failed to detect biologically active BNP 1–32 in the plasma of patients with severe HF despite having high levels of immunoreactive BNP as measured by BNP assay.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">23</span></a> Furthermore, in severe HF, there is an attenuated biological response to endogenous and exogenous BNP. The mechanisms for the development of resistance to BNP include increased clearance by neprilysin or the clearance receptor, and down-regulation of receptor or post-receptor issues such as increased activity of cGMP phosphodiesterase (PDE) V, which metabolizes cGMP.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">24,25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Nesiritide (human recombinant BNP) was approved by the FDA for the management of AHF owing to its acute hemodynamic ability to lower systemic and atrial pressure as demonstrated in the multicenter Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> The approved recommended dose of nesiritide is a bolus of 2<span class="elsevierStyleHsp" style=""></span>μg/kg followed by the infusion of 0.01<span class="elsevierStyleHsp" style=""></span>μg/kg/min. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF (ASCEND-HF) randomized 7141 patients with AHF to the approved dose of nesiritide or placebo and demonstrated that while there was minimal improvement in dyspnea in patients who received nesiritide, there was no change in renal function and mortality.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> Importantly, hypotension occurred in approximately one quarter of nesiritide treated patients, significantly greater than those treated with placebo.</p><p id="par0065" class="elsevierStylePara elsevierViewall">While preclinical studies have demonstrated the renal enhancing effects of BNP, clinical studies have not been able to reproduce favorable renal effects with the approved nesiritide dosage. In experimental HF, favorable renal effects of natriuretic peptides are attenuated when there is hypotension resulting in the reduction of renal perfusion pressure. Chen et al. reported that intra-renal infusion of BNP to avoid systemic hypotension is associated with natriuresis, diuresis and increases in GFR.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">27</span></a> Based on the concept of preserving the renal protective effects of BNP by limiting systemic hypotension, the ROSE AHF trial tested nesiritide at a lower dose with the rationale that there would be less hypotension and more renal-specific therapeutic effects.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a> However, even at the reduced dose, systemic effects were still noted as evidenced by an increased risk of hypotension in the nesiritide treatment arm. The results of ROSE AHF provided no significant support for the routine use of low-dosage nesiritide infusion in the treatment of AHF patients with renal dysfunction to improve renal function. However, subgroup analyses suggest that there was a tendency toward different treatment outcomes, depending on the ejection fraction. Subjects with reduced ejection fraction tended to benefit from low dose nesiritide. For this reason, further studies are warranted to determine if subjects with AHF and reduced ejection fraction may benefit from the use of BNP as a therapeutic agent.</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ongoing and future research on natriuretic peptides as therapeutics</span><p id="par0070" class="elsevierStylePara elsevierViewall">Neprilysin (neutral endopeptidase 24·11) is the enzyme responsible for the degradation of natriuretic peptides in humans. LCZ696, a dual acting drug that inhibits the RAAS system by blocking the angiotensin receptor (via its valsartan molecular moiety) and enhances natriuretic peptide levels by inhibiting neprilysin (via AHU377 moiety), is FDA approved for the management of chronic HF with reduced ejection fraction. The role of LCZ696 in the management of AHF remains to be defined.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">29</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Urodilatin, which is produced by the differential processing of the pro-atrial natriuretic peptide in the kidney, is currently undergoing a pivotal AHF Phase III study (TRUE-AHF).<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a> Physiologically, urodilatin plays a key role in sodium homeostasis and exerts its effects via the NPR-A receptor, resulting in vasodilation, diuresis, and natriuresis. Pre- and early clinical studies have demonstrated that Ularitide, a human recombinant Urodilatin, has beneficial effects such as symptom relief and vasodilation, with the preservation of renal function.</p><p id="par0080" class="elsevierStylePara elsevierViewall">There are two unique classes of novel designer natriuretic peptides, based on the principle of alternative splicing and amino acid substitution. These novel natriuretic peptides have been designed with superior pharmacologic profiles as compared to native human natriuretic peptides.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Pan et al. identified an alternatively spliced transcript for BNP resulting from intronic retention.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a> The intron retained transcript generated a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. Given structural considerations, a carboxyl-terminal truncated form of alternative splicing BNP (ASBNP) was generated; ANX-042 was found to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells, but lacked similar effects in vascular cells. In a canine-pacing model of HF, systemic infusion of ANX-042 did not alter mean arterial pressure, but increased GFR, suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Thus, the biodesigner peptide ANX-042 enhances GFR associated with HF while lacking the vasoactive hypotensive properties of BNP. ANX-042 is currently undergoing early clinical studies.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Lisy et al. designed the chimeric natriuretic peptide CD-NP, which consists of the full-length 22-AA human CNP and the 15-AA C-terminus of <span class="elsevierStyleItalic">Dendroaspis</span> NP (DNP).<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a> CD-NP is the first dual activator of both the NPR-A and NPR-B receptors and has the biological properties of both the NPR-A receptor which includes natriuresis, diuresis, and arterial vasodilation, and that of the NPR-B receptor, which includes preload reduction via vasodilation, anti-hypertrophy and anti-fibrosis properties. CD-NP has moved on to the clinical trial stage and Lee et al. recently completed the first-in-human clinical trial and demonstrated the favorable renal and hemodynamic effects of CD-NP.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Summary</span><p id="par0095" class="elsevierStylePara elsevierViewall">BNP is central in maintaining fluid homeostasis and is clinically useful as a biomarker aiding diagnosis and also has prognostic value in AHF. However, the therapeutic role of BNP (nesiritide) in AHF since its FDA approval in 2001 remains to be defined and more studies are needed to fully determine its true therapeutic potential in this unique family of endogenous peptides in AHF. Ongoing research with angiotensin receptor blocker/neprilysin inhibitors and novel designer chimeric natriuretic peptides may result in new therapeutic strategies for AHF.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding</span><p id="par0100" class="elsevierStylePara elsevierViewall">This research was supported by grants <span class="elsevierStyleGrantNumber" refid="gs1">HL P01 HL76611</span> and <span class="elsevierStyleGrantNumber" refid="gs1">R01HL84155</span> from the <span class="elsevierStyleGrantSponsor" id="gs1">National Institutes of Health</span> and <span class="elsevierStyleGrantSponsor" id="gs2">Mayo Foundation</span> awarded to Dr Horng Chen.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">Dr. Chen received Research Grants from NIH, Scios Inc, Mayo Clinic and has filed patents for chimeric natriuretic peptides; Mayo Clinic has licensed patents to Capricor Therapeutics and Anexon with other patents pending at the U.S. patent office; Dr. Chen received royalties from Capricor Therapeutics, Anexon Inc and UpToDate; and is the Co-founder of Zumbro Discovery Inc.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres734863" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec738669" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres734862" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec738670" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Neurohumoral activation in acute heart failure" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Activation and release of BNP in AHF" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Physiological role of endogenous BNP in fluid homeostasis and decongestion" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Role of BNP as biomarker in AHF" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Aid in diagnosis of AHF" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Prognostic marker in AHF" ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "BNP as therapeutics in AHF" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Ongoing and future research on natriuretic peptides as therapeutics" ] ] ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Summary" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-01-11" "fechaAceptado" => "2016-01-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec738669" "palabras" => array:5 [ 0 => "Natriuretic peptide" 1 => "Brain natriuretic peptide" 2 => "Recombinant natriuretic peptides" 3 => "Heart failure" 4 => "Volume homeostasis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec738670" "palabras" => array:5 [ 0 => "Péptido natriurético" 1 => "Péptido natriurético cerebral" 2 => "Péptidos natriuréticos recombinantes" 3 => "Insuficiencia cardiaca" 4 => "Homeostasis del volumen" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Natriuretic peptides are a family of peptides with similar structures, but are genetically distinct with diverse actions in cardiovascular, renal and fluid homeostasis. The family consists of an atrial natriuretic peptide (ANP) and a brain natriuretic peptide (BNP) of myocardial cell origin, a C-type natriuretic peptide (CNP) of endothelial origin, and a urodilatin (Uro) which is processed from a prohormone ANP in the kidney. Nesiritide, a human recombinant BNP, was approved by the Federal Drug Administration (FDA) for the management of acute heart failure (AHF) in 2001. Human recombinant ANP (Carperitide) was approved for the same clinical indication in Japan in 1995, and human recombinant Urodilatin (Ularitide) is currently undergoing phase III clinical trial (TRUE AHF). This review will provide an update on important issues regarding the role of BNP in fluid hemostasis as a biomarker and therapeutics in AHF.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los péptidos natriuréticos son una familia de péptidos con estructura semejante, pero distintos genéticamente, con múltiples acciones en la homeostasis cardiovascular, renal y de fluidos. Esta familia está formada por un péptido natriurético auricular y un péptido natriurético cerebral que se originan en las células miocárdicas, un péptido natriurético de tipo C de origen endotelial y una urodilatina que se procesa de una prohormona del péptido natriurético auricular en el riñón. La nesitirida, un péptido natriurético cerebral recombinante humano, fue aprobada por la Administración de Medicamentos y Alimentos (FDA) en el año 2001 para el tratamiento de la insuficiencia cardiaca aguda. El péptido natriurético auricular recombinante humano (carperitida) fue aprobado con las mismas indicaciones clínicas en Japón en el año 1995, y la urodilatina recombinante humana (ularitida) forma parte ahora mismo de un ensayo de fase <span class="elsevierStyleSmallCaps">iii</span> (TRUE-AHF). Esta revisión permitirá actualizar aspectos importantes relativos al papel que desempeña el péptido natriurético cerebral en la homeostasis de fluidos como biomarcador y fármaco para las insuficiencias cardiacas agudas.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1093 "Ancho" => 1627 "Tamanyo" => 124771 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Amino acid sequence of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and urodilatin (URO). ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide.</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" => 1522 "Ancho" => 1650 "Tamanyo" => 174887 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and urodilatin (URO) bind to NP receptors (NPR-A and NPR-B), leading to cGMP production and downstream effects via cGMP-dependent protein kinase G (PKG) like natriuresis, diuresis, vasodilation and more. ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide; CNP: C-type natriuretic peptide; NPR-A: A type natriuretic peptide receptor; NPR-B: B type natriuretic peptide receptor; GTP: guanosine triphosphate; GC: guanyl cyclise; cGMP: cyclic guanosine monophosphate; PKG: protein kinase G.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0165" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An introduction to acute heart failure syndromes: definition and classification" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. Filippatos" 1 => "F. 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