Special article
Iron and heart failure
Hierro e insuficiencia cardiaca
M.Á. de las Nieves López
Instituto de Gestión Sanitaria (INGESA), Área Sanitaria de Melilla, Melilla, Spain
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En cuadrícula se detalla la captación del trazador en corazón y médula ósea.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">AH: adecuado en hierro; DH: déficit de hierro; MO: médula ósea; SH: sobrecarga de hierro.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Fuente: adaptada con permiso de Lopes et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a> (Prof. Jens Reich).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.Á. de las Nieves López" "autores" => array:1 [ 0 => array:2 [ "nombre" => "M.Á." 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The technique is simple: posterior, anterior and lateral face sweeps of both lungs. 1. Normal lung: characterized by the presence of A-lines. 2. Interstitial pattern: characterized by the presence of B-lines. 3. Pulmonary condensation (pneumonia). 4. Pleural effusion.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "G. García de Casasola, I. Casado López, J. Torres-Macho" "autores" => array:3 [ 0 => array:2 [ "nombre" => "G." "apellidos" => "García de Casasola" ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Casado López" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Torres-Macho" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256519301109" "doi" => "10.1016/j.rce.2019.04.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256519301109?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887419301250?idApp=WRCEE" "url" => "/22548874/0000022000000001/v1_202002130124/S2254887419301250/v1_202002130124/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2254887419302565" "issn" => "22548874" "doi" => "10.1016/j.rceng.2019.09.010" "estado" => "S300" "fechaPublicacion" => "2020-01-01" "aid" => "1736" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Clin Esp. 2020;220:31-42" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Management of iron deficiency in various clinical conditions and the role of intravenous iron: Recommendations of the Spanish erythropathology group of the Spanish society of hematology and hemotherapy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "31" "paginaFinal" => "42" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Manejo del déficit de hierro en distintas situaciones clínicas y papel del hierro intravenoso: recomendaciones del Grupo Español de Eritropatología de la SEHH" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2840 "Ancho" => 2500 "Tamanyo" => 376598 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0425" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithms for the diagnosis and treatment of iron-refractory iron-deficiency anemia (A) and for treatment with intravenous iron and its control (B). CRF: chronic renal failure; ESA: erythropoiesis-stimulating agents; Fe: iron; Ft: ferritin; IA: inflammatory anemia; IDA: iron-deficiency anemia; IRIDA: iron-refractory iron-deficiency anemia; IVFe: intravenous iron; TSAT: transferrin saturation index; WHO: World Health Organization.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.A. García Erce, A. Altés, M. López Rubio, Á.F. Remacha" "autores" => array:5 [ 0 => array:2 [ "nombre" => "J.A." "apellidos" => "García Erce" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Altés" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "López Rubio" ] 3 => array:2 [ "nombre" => "Á.F." "apellidos" => "Remacha" ] 4 => array:1 [ "colaborador" => "en representación del Grupo Español de Eritropatología de la Sociedad Española de Hematología y Hemoterapia" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256519302358" "doi" => "10.1016/j.rce.2019.09.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256519302358?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887419302565?idApp=WRCEE" "url" => "/22548874/0000022000000001/v1_202002130124/S2254887419302565/v1_202002130124/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Iron and heart failure" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "43" "paginaFinal" => "48" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "M.Á. de las Nieves López" "autores" => array:1 [ 0 => array:3 [ "nombre" => "M.Á." "apellidos" => "de las Nieves López" "email" => array:2 [ 0 => "manieves@ingesa.msssi.es" 1 => "marbelhem@telefonica.net" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Instituto de Gestión Sanitaria (INGESA), Área Sanitaria de Melilla, Melilla, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hierro e insuficiencia cardiaca" ] ] "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" => 1782 "Ancho" => 2167 "Tamanyo" => 167018 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Selection and identification of patients who would benefit the most from intravenous iron according to the meta-analysis by Anker et al.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> Results related to readmissions for cardiovascular cause and mortality of patients with irony deficiency treated with intravenous iron.</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: Ferrit, ferritin (expressed in ng/mL); TSAT, transferrin saturation.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Iron and oxygen are essential for hemoglobin synthesis and for oxidative phosphorylation in aerobic conditions, respectively. In clinical practice, iron deficiency (ID) and heart failure (HF) are frequently associated; ID is the leading cause of anemia worldwide. In developed countries, HF is predominantly the result of myocardial ischemia.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Anemia is associated with positive regulation of erythropoietin, transferrin and its tissue receptor (TfR) and with negative regulation of hepcidin, thereby enabling greater iron bioavailability.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">2</span></a> High hepcidin levels have been observed in HF, except in highly advanced phases of the disease, despite an inverse relationship with inflammatory mediators such as interleukin-6 and reactants such as C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">3</span></a> Other factors should determine the high hepcidin levels in HF, which could be related to oxidative stress in ischemic hearts or to increases in afterload,<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">4,5</span></a> as well as positive regulation of oxidases in response to hypoxia,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">6</span></a> conditions in which excess iron can be harmful to cells.</p><p id="par0015" class="elsevierStylePara elsevierViewall">ID is a therapeutic target for patients with systolic HF, and intravenous iron therapy is the recommended therapeutic option. There is abundant literature on the subject, including its consideration in clinical practice guidelines,<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">7,8</span></a> as well as in a consensus document of the Spanish Society of Internal Medicine and the Spanish Society of Cardiology.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">9</span></a> Nevertheless, this treatment does not provide a benefit for many patients who undergo it and might not be exempt from toxicity.</p><p id="par0020" class="elsevierStylePara elsevierViewall">It is therefore advisable to review the criteria diagnostic for ID and the pathways and doses for administering iron, as well as propose therapeutic objectives and identifying those patients who will receive an unequivocal benefit from this treatment.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Iron deficiency diagnosis</span><p id="par0025" class="elsevierStylePara elsevierViewall">The main indicator of body iron and the best guarantor of its appropriate transfer to tissues is the blood hemoglobin rate. In physiological conditions, 95% of the tissue's daily iron needs (25<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>mg) is provided by hemoglobin catabolism, and only a small fraction (1–2<span class="elsevierStyleHsp" style=""></span>mg/day) comes from the exterior through intestinal absorption to balance the physiological losses. This is the only regulated mechanism for controlling body iron.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">10</span></a> Transferrin and TfR are the main transport and cellular acquisition proteins for iron, respectively. In contrast, there are active mechanisms at the systemic level for the cellular exit of iron via ferroportin, the target of hepcidin. Both TfR and ferroportin are expressed in cardiomyocytes.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">All laboratory parameters that assess the transfer of iron to tissues, such as transferrin saturation (TSAT), or its requirements, such as the soluble traces of TfR and erythrocyte zinc protoporphyrin, necessarily reflect its cellular deficiency for hemoglobin synthesis, which requires up to 80% of circulating iron in healthy humans.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> The state of body iron in mammals can change the hierarchy of its tissue transfer (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Serum ferritin is correlated with biologically inactive iron, especially as a hepatic reserve, with each ng/mL of ferritin reflecting approximately 8<span class="elsevierStyleHsp" style=""></span>mg of reserve iron.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">14</span></a> Sex, age, ferric state, morbidity and other factors determine each individual's hemoglobin rate, whose normal mean in healthy individuals in developed countries is 13.5<span class="elsevierStyleHsp" style=""></span>g/dL in women and 15<span class="elsevierStyleHsp" style=""></span>g/dL in men<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">15</span></a>; similarly, iron reserves fluctuate from 300 to 1000<span class="elsevierStyleHsp" style=""></span>mg of iron, respectively.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> Anemia, as defined by the World Health Organization (<12<span class="elsevierStyleHsp" style=""></span>g/dL in women and <13<span class="elsevierStyleHsp" style=""></span>g/dL in men), is a late indicator of ID and is always associated with ferritin levels <30<span class="elsevierStyleHsp" style=""></span>ng/mL and TSAT <20%. The reactant character of ferritin and hepcidin-mediated hypoferremia associated with systemic inflammatory processes results in the loss of specificity for high serum ferritin levels and TSAT <20% for diagnosing ID.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The proposed levels for diagnosing ID in HF (TSAT<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>20% and ferritin levels<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>ng/mL or ferritin levels<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>ng/mL regardless of TSAT)<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">9,17</span></a> have considerable sensitivity but little specificity. These limits are those defined in intravenous iron trials, and their practical application is the result of the overall benefit observed from this treatment in the perception of wellbeing and general condition, as well as in the distance walked in 6<span class="elsevierStyleHsp" style=""></span>min as the primary objectives.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">18,19</span></a> These limits contrast with those typically employed for detecting ID in the context of anemia in inflammatory processes, in which other factors should be investigated when ferritin levels are >100<span class="elsevierStyleHsp" style=""></span>ng/mL.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">20,21</span></a> Not taking into account the hemoglobin rate and differences in sex, associated comorbidity (particularly renal) and the state of acute-phase reactants are relevant aspects that decrease the specificity of the ID diagnosis in HF. In fact, applying these diagnostic criteria can result in the administration of intravenous iron in up to 75% of the population with HF.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">9,17,22</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Treatment for iron deficiency</span><p id="par0045" class="elsevierStylePara elsevierViewall">The first therapeutic step is oral iron therapy, preferably with ferrous salts, in doses of 80–200<span class="elsevierStyleHsp" style=""></span>mg of elemental iron daily. The selection of dose and its absorbed fraction (10–20%) are determined by the deviation of hemoglobin (and consequently TSAT) from the normal mean, with an increase in hemoglobin within 2–4 weeks of starting treatment as a necessary response indicator. The maximum hemoglobin level for each individual is achieved with the total replacement by well-hemoglobinized red blood cells in 12–16 weeks, although the proper tissue distribution of iron by transferrin should start much earlier, particularly for nonmitotic cells such as cardiomyocytes. Nevertheless, the maximum benefit in the functional capacity of patients with HF treated with intravenous iron occurred at 12 weeks.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The option of oral iron appears to be ruled out for patients with HF, given the null effect of a polysaccharide–iron complex in improving functional capacity in the IRONOUT-HF trial.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a> A number of aspects of this trial deserve attention, such as the massive doses of iron administered separately from meals (300<span class="elsevierStyleHsp" style=""></span>mg daily in 2 doses of 150<span class="elsevierStyleHsp" style=""></span>mg) and the frequent use of antiplatelets and anticoagulants (67% and 50% of patients, respectively), indicative of a frequent use of antacids, as well as relevant differences in the laboratory parameters with the intravenous iron trials. Iron preparations have a more irregular absorption than ferrous salts. When combined with a polysaccharide, food can act as a booster for absorption,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a> and this absorption can be compromised by the inhibition of gastric acidity by preventing the reduction to the preparations’ ferrous form, a chemical state in which non-heme iron is absorbed. It is relevant that none of the patients in this trial presented moderate anemia or exhausted iron deposits (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Therefore, the evidence for not treating patients with HF, anemia and iron depletion (ferritin level<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ng) with an oral ferrous salt in a single dose or every 2 days is not persuasive.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">When opting for intravenous iron therapy, the dosage should be adjusted to each patient's needs. Except for patients with biologically recognized and predictable chronic bleeding and those included in a blood management program with severe anemia, there is no justification for administering dosages greater than 600<span class="elsevierStyleHsp" style=""></span>mg every 6 weeks, which represents an extra supply of 14.3<span class="elsevierStyleHsp" style=""></span>mg/day to recycled hemoglobin iron.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Benefits and risks of iron therapy</span><p id="par0060" class="elsevierStylePara elsevierViewall">Iron sufficiency results in reaching the individual's maximum hemoglobin level, which ensures the maximum tissue transfer of iron and oxygen and maintains an appropriate and not excessive iron reserve. The treatment's benefits are numerous and include greater physical performance and improved cognitive and affective aspects, especially at critical moments of development.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">25</span></a> ID and impaired hemoglobin synthesis, with or without anemia in the strict sense, are therefore targets for improving the health of the population in general and of patients with HF in particular.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Any increase in the hemoglobin rate in patients with HF improves their aerobic capacity, as reflected in changes in the functional tests for gas exchange during exercise (VO<span class="elsevierStyleInf">2 peak</span>/VO<span class="elsevierStyleInf">2 max</span>) and in the 6-min walk distance, as indicated by the deterioration of these parameters in patients with HF and anemia compared with patients with the same ejection fraction but without anemia<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">26</span></a> or its improvement with the increase in hemoglobin in response to treatment with erythropoietin.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">27</span></a> Increasing the hemoglobin rate is probably the first therapeutic target for iron therapy in these patients, given that the simple increase in TSAT and ferritin levels does not lead to an improvement in their functional capacity, as reflected by an a posteriori analysis of the IRONOUT-HF trial on the few patients who absorbed oral iron.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Erythroid expansion mediated by endogenous erythropoietin should not be overlooked in patients with advanced systolic HF, which can lead to the depletion of iron reserves due to an increase in erythrocyte mass (polycythemia) and blood volume,<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">29,30</span></a> which could explain the low hepcidin levels in advanced HF, separate from the coexistent anemia. Most of the patients included in intravenous iron trials presented hemoglobin levels <13.5<span class="elsevierStyleHsp" style=""></span>g/dL,<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">18</span></a> which subsequently increased to <15<span class="elsevierStyleHsp" style=""></span>g/dL with no lower limit in only 151 patients, except when transfusion was required, with a mean hemoglobin level (±1<span class="elsevierStyleHsp" style=""></span>SD) of 12.37<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.41<span class="elsevierStyleHsp" style=""></span>g/dL.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a> There were therefore too few included patients with hemoglobin levels >14<span class="elsevierStyleHsp" style=""></span>g/dL to reach conclusions for recommending this treatment for this patient group, particularly without discriminating by sex. The ischemic etiology of HF, a lower ejection fraction, renal function impairment, diabetes and hemoglobin levels <12<span class="elsevierStyleHsp" style=""></span>g/dL were the factors clearly associated with improvement in the 6-min walk distance.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The benefit of intravenous iron in experimental models of selective abolition of the genetic expression of TfR and iron regulatory proteins in cardiomyocytes,<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">31,32</span></a> as well as the observation of frequent myocardial iron deficiency in hearts explanted for HF,<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">33</span></a> could serve as an argument for boosting the transfer of iron to cardiomyocytes, with a dynamic similarity to the hypersaturation model shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, for improving energy production and cardiac contractility. However, these experimental models were not performed with humans, and the ejection fraction of hearts with iron deficiency did not differ from that of hearts with no iron deficiency (% left ventricular ejection fraction of 23<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7 for iron deficiency vs. 22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.8).<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">33</span></a> From the mechanistic standpoint, the importance of myocardial iron should be contrasted with its potential cell toxicity in conditions of hypoxia, ischemia and chemotherapy damage, as clinical examples of the myocardial toxicity of iron.<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">34,35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Patients with systolic HF treated with intravenous iron can present lower readmission rates and cardiovascular mortality than those treated with placebo, according to a meta-analysis of these trials.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> Among 504 treated patients, only 56 (11%) showed ferritin levels >100<span class="elsevierStyleHsp" style=""></span>ng/mL, 178 (35%) had depleted iron reserves according to conventional criteria (ferritin levels<span class="elsevierStyleHsp" style=""></span><28<span class="elsevierStyleHsp" style=""></span>ng/mL), and 162 (32%) were diagnosed with ID based on ferritin levels <100<span class="elsevierStyleHsp" style=""></span>ng/mL, given that the TSAT was >20%. There is a notable benefit of placebo for these results in patients with ferritin levels <28<span class="elsevierStyleHsp" style=""></span>ng/mL, who are thereby eligible for oral iron, as well as for those with TSAT >20% and therefore diagnosed with ID exclusively due to ferritin levels <100<span class="elsevierStyleHsp" style=""></span>ng/mL (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="par0085" class="elsevierStylePara elsevierViewall">Iron sufficiency can improve patients’ wellbeing and functional capacity, especially those with HF, and helps decrease hospital admissions, readmissions and mortality. A state of iron sufficiency should be achieved in the most physiological manner possible and should be adapted to each patient's needs, establishing temporary goals based on the incorporation of iron into erythrocytes, until each patient's maximum hemoglobin level is reached, according to sex and comorbidity. Massive doses of intravenous iron that can lead to transferrin hypersaturation not neutralizable by TfR should be avoided, except in patients with unresolved chronic bleeding.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1306141" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1206266" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1306140" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1206267" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Iron deficiency diagnosis" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Treatment for iron deficiency" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Benefits and risks of iron therapy" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-04-11" "fechaAceptado" => "2019-06-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1206266" "palabras" => array:5 [ 0 => "Oral iron" 1 => "Anemia" 2 => "Oxidative stress" 3 => "Heart failure" 4 => "Hierro oral" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1206267" "palabras" => array:4 [ 0 => "Hierro oral" 1 => "Anemia" 2 => "Estrés oxidativo" 3 => "Insuficiencia cardiaca" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Iron deficiency has become a new target to improve functional outcomes in patients with heart failure, and intravenous preparations seem to be the only effective treatment for that purpose. However, the relation among iron and oxygen in this population is far from understood as hepcidin is generally upregulated, potentially avoiding iron availability and harm in the context of excess oxidative stress.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Laboratory markers used to detect tissue iron deficiency are highly dependent on needs for hemoglobin synthesis, so that reaching peak hemoglobin for each individual should rationally be the first goal of any attempt with therapeutic iron. A subset of patients receiving intravenous iron may have a worse outcome related to admissions and mortality compared to placebo, suggesting that the laboratory thresholds used to detect iron deficiency in heart failure are highly sensitive but less specific to identify patients that would not benefit of this therapy. A gradual delivery of iron over time with parallel measurement of its uptake for hemoglobin synthesis could therefore be recommended to fulfill tissue needs. Standard oral iron therapy should not be dismissed in heart failure patients with anemia and depleted iron stores (ferritin<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ng/mL) as, contrary to intravenous iron trials, these patients were not included in a trial resulting in neglectable effect of oral iron on exercise capacity.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">La deficiencia de hierro se ha convertido en un nuevo objetivo para mejorar los resultados funcionales en pacientes con insuficiencia cardiaca, y las preparaciones intravenosas parecen ser el único tratamiento eficaz para ese propósito. Sin embargo, está lejos de entenderse la relación existente entre el hierro y el oxígeno en esta población, ya que por lo general la hepcidina está regulada al alza, lo que evita posiblemente la disponibilidad de hierro y el daño en el contexto de un exceso de estrés oxidativo.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los marcadores empleados para detectar la deficiencia de hierro tisular en el laboratorio son altamente dependientes de las necesidades de síntesis de hemoglobina, por lo que el primer objetivo racional en cualquier intento de terapia con hierro es alcanzar el pico de hemoglobina para cada individuo. Un subgrupo de pacientes tratados con hierro intravenoso pueden mostrar un peor resultado en cuanto a ingresos hospitalarios y mortalidad cuando se comparan con un grupo placebo, lo que señala que los umbrales de laboratorio utilizados para detectar deficiencias de hierro en la insuficiencia cardiaca son altamente sensibles pero menos específicos en la identificación de los pacientes que no se beneficiarían de esta terapia. Por lo tanto, se podría recomendar un suministro gradual de hierro a lo largo del tiempo con una medición paralela de su incorporación para la síntesis de hemoglobina para satisfacer las necesidades de los tejidos. La terapia oral estándar con hierro no debe descartarse en pacientes con insuficiencia cardiaca con anemia y reservas de hierro agotado (ferritina<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ng/ml), ya que, contrariamente a los ensayos con hierro por vía intravenosa, estos pacientes no se incluyeron en un ensayo en el que el efecto del hierro oral en la capacidad de ejercicio resultó despreciable.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: de las Nieves López M. Hierro e insuficiencia cardiaca. Rev Clin Esp. 2020;220:43–48.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1030 "Ancho" => 3230 "Tamanyo" => 134806 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Tissue distribution (%) of transferrin iron in mice according to ferric state. The tracer uptake in the heart and bone marrow is shown in the grid.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: BM, bone marrow; ID, iron deficient; IS, iron sufficient; IO, iron overload.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Source: adapted with permission from Lopes et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a> (Prof. Jens Reich).</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" => 1782 "Ancho" => 2167 "Tamanyo" => 167018 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Selection and identification of patients who would benefit the most from intravenous iron according to the meta-analysis by Anker et al.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> Results related to readmissions for cardiovascular cause and mortality of patients with irony deficiency treated with intravenous iron.</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: Ferrit, ferritin (expressed in ng/mL); TSAT, transferrin saturation.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array: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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FAIR-HF<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">18</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CONFIRM-HF<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IRONOUT-HF<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n intervention (NI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">304 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">111 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">155 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">114 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Observation, weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean Hb, g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemoglobin range, g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.5–13.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8?-15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.7–13.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean ferritin, ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ferritin range, ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43–108 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">% NI ferritin <28<span class="elsevierStyleHsp" style=""></span>ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2237770.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Selected characteristics of the main trials of intravenous and oral iron in heart failure.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0185" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. 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