Anthracycline-mediated cardiomyopathy: Basic molecular knowledge for the cardiologist

array:24 ["pii" => "S1405994014000688" "issn" => "14059940" "doi" => "10.1016/j.acmx.2013.08.006" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "136" "copyright" => "Instituto Nacional de Cardiología Ignacio Chávez" "copyrightAnyo" => "2013" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Arch Cardiol Mex. 2014;84:218-23" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4062 "formatos" => array:3 [ "EPUB" => 73 "HTML" => 2883 "PDF" => 1106 ] ] "itemSiguiente" => array:19 [ "pii" => "S1405994014000329" "issn" => "14059940" "doi" => "10.1016/j.acmx.2013.10.011" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "119" "copyright" => "Instituto Nacional de Cardiología Ignacio Chávez" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Arch Cardiol Mex. 2014;84:224-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4514 "formatos" => array:3 [ "EPUB" => 41 "HTML" => 2808 "PDF" => 1665 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Artículo especial" "titulo" => "El conocimiento de la respiración animal como un fenómeno de combustión" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "224" "paginaFinal" => "228" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "The knowledge of animal respiration as a combustion phenomenon" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figura 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2513 "Ancho" => 1250 "Tamanyo" => 219685 ] ] "descripcion" => array:1 [ "es" => "Traité élémentaire de chimie, de A.L. Lavoisier (París, 1789)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alfredo de Micheli" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Alfredo" "apellidos" => "de Micheli" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000329?idApp=UINPBA00004N" "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000329/v1_201408290019/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1405994014000676" "issn" => "14059940" "doi" => "10.1016/j.acmx.2014.02.002" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "135" "copyright" => "Instituto Nacional de Cardiología Ignacio Chávez" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "ssu" "cita" => "Arch Cardiol Mex. 2014;84:211-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 2876 "formatos" => array:3 [ "EPUB" => 48 "HTML" => 2230 "PDF" => 598 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Artículo de revisión" "titulo" => "Papel de la inflamación renal en la fisiopatología de la hipertensión sensible a sal" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "211" "paginaFinal" => "217" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Role of renal inflammation in the physiopathology of salt-sensitive hypertension" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2030 "Ancho" => 1650 "Tamanyo" => 133707 ] ] "descripcion" => array:1 [ "es" => "Mecanismos que explican la relación entre inflamación renal y el desarrollo de HSS. La figura muestra cómo la formación de RL inicia la producción de citocinas proinflamatorias que favorecen la infiltración renal de linfocitos T y otras células del sistema inmunológico, como los macrófagos. Este proceso estimula la síntesis y liberación de angiotensina ii a este nivel, que incrementa la retención de sodio y agua y lleva finalmente a la HSS. Las flechas indican cómo el proceso se perpetúa, pues la inflamación renal incrementa los niveles de angiotensina ii, y esta a su vez acrecienta la producción de citocinas que aumentan el proceso inflamatorio, desencadenando un ciclo que explica la continuidad de la inflamación renal observada en estos pacientes. FNT α: factor de necrosis tumoral α; HSS: hipertensión sensible a sal, IL-1: interleucina-1; IL-6: Interleucina-6." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Yaniel Castro Torres, Alejandro Emilio Santos Portela, Ildiko María Garrido Bősze" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Yaniel" "apellidos" => "Castro Torres" ] 1 => array:2 [ "nombre" => "Alejandro Emilio" "apellidos" => "Santos Portela" ] 2 => array:2 [ "nombre" => "Ildiko María" "apellidos" => "Garrido Bősze" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000676?idApp=UINPBA00004N" "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000676/v1_201408290019/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Anthracycline-mediated cardiomyopathy: Basic molecular knowledge for the cardiologist" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "218" "paginaFinal" => "223" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Joel Salazar-Mendiguchía, José González-Costello, Josep Roca, Albert Ariza-Solé, Nicolás Manito, Ángel Cequier" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Joel" "apellidos" => "Salazar-Mendiguchía" "email" => array:1 [ 0 => "jsalazar@bellvitgehospital.cat" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "José" "apellidos" => "González-Costello" ] 2 => array:2 [ "nombre" => "Josep" "apellidos" => "Roca" ] 3 => array:2 [ "nombre" => "Albert" "apellidos" => "Ariza-Solé" ] 4 => array:2 [ "nombre" => "Nicolás" "apellidos" => "Manito" ] 5 => array:2 [ "nombre" => "Ángel" "apellidos" => "Cequier" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Miocardiopatías, Insuficiencia Cardíaca y Trasplante, Área de Enfermedades del Corazón, Hospital Universitari de Bellvitge, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Área de Enfermedades del Corazón, Hospital Universitari de Bellvitge, Av Feixa Llarga s/n, L’Hospitalet de Llobregat, 08904 Barcelona, Spain." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Miocardiopatía inducida por antraciclinas: conocimientos moleculares básicos para el cardiólogo" ] ] "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" => 1570 "Ancho" => 2167 "Tamanyo" => 197733 ] ] "descripcion" => array:1 [ "en" => "Role of DOX, doxorubicinol and ROS in cardiomyopathy." ] ] ] "textoCompleto" => "IntroductionAnthracyclines are cytostatic antibiotics discovered almost half a century ago that exert their action through inhibition of topoisomerase II.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> The two most representative drugs of this group are doxorubicin (active against some hematologic cancers and solid tumors)<a class="elsevierStyleCrossRef" href="#bib0015">3</a> and daunorubicin (used mainly in acute hematologic cancer),<a class="elsevierStyleCrossRef" href="#bib0020">4</a> although other drugs have been developed within this family (e.g. epirubicin, idarubicin and mitoxantrone).These drugs have been proven as useful antineoplastics and are amongst the most widely prescribed oncologic medication. Unfortunately, cardiotoxicity secondary to anthracyclines still remains a limiting factor when used,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> being generally related to dose–response (although there are several reports of cardiotoxicity associated with lower doses, probably secondary to individual susceptibility)<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a>and manifesting mainly as heart failure usually within a year after completion of treatment, although it is widely accepted that it can manifest itself several years after treatment.Recently, groups have been created in Europe and the United States for the study of this toxicity, highlighting its importance.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a>Scope of the problemChemotherapy-induced cardiotoxicity is usually classified in two groups according to the cellular damage induced by these drugs. Type I cardiotoxicity implies cellular death (either via necrosis or apoptosis) and thus, is not reversible, whereas type II cardiotoxicity is caused by cellular dysfunction (not death) and is usually described as reversible. Type I is characteristic of anthracycline damage, while type II is more frequent with monoclonal antibodies (namely, trastuzumab).<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Gianni et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> reported some of the several limitations that have emerged in terms of describing the current situation of anthracycline-mediated cardiotoxicity; these problems come from a lack of uniformity in reporting or detecting events in these patients and the different forms of presentation (acute vs. delayed, reversible vs. irreversible). At the same time, the wide difference in the treated populations (adults vs. children) makes it difficult to unify criteria. Nevertheless, recent statistics regarding survival of oncologic patients give us an overview of the problem.At the moment, in the US there are more than 300,000 survivors of childhood cancer, of whom 50% could potentially have been treated with anthracyclines,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and the probability of accumulated death due to cardiac cause (including sudden death likely to be cardiac in origin) is greater than the observed in control groups.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a>Likewise, survival of breast cancer (one of the clinical scenarios where these drugs have been used extensively) has increased dramatically in the last decades, translating into approximately two million women in the US with high likelihood of previous anthracycline exposure.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Despite several efforts to diminish this adverse effect (mainly by reducing the cumulative dose under 400–450mg/m2 for doxorubicin) and considering the previously mentioned caveats, studies estimate heart failure rates between 5 and 10%<a class="elsevierStyleCrossRefs" href="#bib0025">5,8</a> with the modern regimens of treatment, depending on age, cumulative dose, individual susceptibility or even past medical history (e.g. hypertension, coronary heart disease, etc.), among other factors.Mechanisms of cardiotoxicityWith all the aforementioned, it is not surprising that considerable controversy has risen with respect to the mechanisms involved in this toxicity. Anthracycline-induced cardiotoxicity seems to be a multi-step condition, with several pathways involved. Many research groups have tried to elucidate the processes associated; of these, we will focus in this review on those that have been most extensively studied.It is important to acknowledge the fact that these pathways are not necessarily independent from each other or exclusive, as each of them may play a role in causing cardiotoxicity via different mechanisms, by themselves or in cooperation with other pathways. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> depicts some of the mechanisms generating cardiotoxicity.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>We will not review in the present work the rare, but existent, acute presentation of anthracycline toxicity or the involvement of the pericardium.Oxidative stressOxidative stress is the most widely studied mechanism and it involves a highly complex pathophysiology, which is a matter of permanent debate.The myocardium is extremely prone to oxidative damage and this is, at least in part, due to its lower levels of catalase activity and superoxide dismutase (an enzyme that catalyses the dismutation of superoxide, one of the main reactive oxygen species [ROS])<a class="elsevierStyleCrossRef" href="#bib0070">14</a> compared with other tissues.The metabolism of anthracyclines involves the reduction of the quinone fraction of its formula to semiquinone, which can rapidly transfer its unpaired electron to an electron acceptor (usually molecular oxygen), returning to its original quinone form, therefore completing the redox cycle and leading to the formation of more ROS.Other mechanisms involved include the formation of DNA adducts by semiquinone or the generation of superoxide anions by anthracycline metabolism, with subsequent cellular damage by degradation of the sarcomere, mitochondrial dysfunction and DNA damage.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a>A recent paper by Octavia et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>elegantly describes the different pathways by which anthracyclines cause ROS, including mitochondrial, nitric oxide synthase (NOS), and nicotinamide adenine dinucleotide phosphate (NADPH) pathways.Even though the evidence for myocardial damage induced by ROS is vast, oxidative stress as the sole cause of cardiotoxicity is increasingly questioned and more research is dedicated to alternative pathways. Part of the reason for this came from earlier studies that failed to prove the protective role of certain antioxidants in the long term,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> especially when interventions that resembled the ones used in clinical practice were tested.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> It is noteworthy that some of the drugs that might have a protective role (e.g. dexrazoxane and carvedilol) probably exert their defensive mechanism through alternative molecular routes, besides their antioxidant activity. <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows the relationships between DOX, doxorubicinol and ROS in cardiotoxicity.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Accumulation of toxic metabolitesAnthracyclines metabolism generates toxic molecules at the myocardium level through a reduction of their carbonyl group (producing doxorubicinol in case of doxorubicin, being up to 50 times more potent than the original compound, or daunorubinicol and idarubicinol in case of daunorubicin and idarubicin, respectively),<a class="elsevierStyleCrossRef" href="#bib0085">17</a> capable of inhibiting the ion exchange pumps of calcium and sodium, even at the mitochondrial level, causing an imbalance in the energetics of the myocardium and a diminished systolic function.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Moreover, these secondary alcohol metabolites are more difficult to eliminate from the cardiomyocyte than the parent drug, accumulating inside them.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>All the anthracyclines have shown to have similar mechanisms of bioactivation, making them toxic from the cardiac standpoint,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> but the role of toxic metabolites has been challenged by the fact that both daunorubicin and idarubicin generate higher plasma levels of alcohol metabolites compared with doxorubicin<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and they tend to generate less cardiotoxicity.A more detailed description of the molecular damage induced by each drug is beyond the scope of this paper.Iron metabolismIron has a major role in cell metabolism and is under control by several regulatory systems.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Its functions go far beyond the oxygen transport complex, being part of different processes like bioenergetics, enzymatic coordination or even immune system physiology.Traditionally, it has been considered that anthracyclines are capable of altering iron homeostasis through the creation of Fe–anthracycline complexes and the posterior production of ROS,<a class="elsevierStyleCrossRef" href="#bib0105">21</a> even in the absence of a reduction system (through intramolecular redox reactions) and some researchers have suggested that the toxicity of the combination of iron and some anthracyclines (doxorubicin) is not a simple additive effect.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>At the same time, iron is capable of catalyzing diverse molecular reactions that create ROS, independently of the abovementioned Fe–anthracycline complex, generating hydroxyl radicals, and it is well known that this reaction is accelerated under the influence of iron itself in the cellular environment.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Iron regulatory proteins or IRPs (also known as iron responsive element binding proteins) are important elements in regulating iron metabolism and the interactions between doxorubicin and the human iron regulatory system have been studied by some researchers. Studies have found that the conversion of IRP1 to a null protein via doxorubicin metabolites yields a metabolic cellular impairment that may account to a certain degree for myocardial dysfunction, opening new paths towards a better understanding of the role of iron metabolism.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>Likewise, animal models have shown that iron overload is capable of potentiating doxorubicin cardiotoxicity by mechanisms other than ROS production.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Recently, human studies have confirmed this finding, showing that even cumulative doses of doxorubicin in the “safe” range are capable of inducing higher iron levels in cardiac tissue, specially at the intracellular level, opening the possibility of cardiotoxicity related with iron deposits as a new pathophysiologic mechanism<a class="elsevierStyleCrossRef" href="#bib0130">26</a> and raising the question of whether a real “safe” dose exists in terms of preventing long term cardiomyopathy.Disruption of energetic mechanismsThe integrity of mitochondrial function is of cornerstone importance in the physiology of myocardial cells, as ATP production is highly dependent on this organelle (almost all of the ATP used by cardiac cells is produced by the electron transport chain).<a class="elsevierStyleCrossRef" href="#bib0135">27</a>Several studies have suggested that disruptions in the mitochondrial membrane potential and respiratory chain are capable of inducing loss of architectural integrity, loss of energy production capability and difficulties in maintaining metabolic demands.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a>Recently, cadiolipin, a phospholipid of utmost importance in energy metabolism and a component of the inner mitochondrial membrane, has been suggested as having a major role in anthracycline-mediated cardiomyopathy.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Doxorubicin, by its ability to bind cardiolipin would modify membrane properties, environment and function, leading to disruption of several energetic mechanisms.As mentioned before, no pathway by itself justifies the complete clinical picture, and the disruption of mitochondrial functions mediated by cardiolipin-doxorubicin interactions are also mediated by oxidative stress,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> in fact, the disturbance in mitochondrial permeability has been related to a direct opening of the permeability transition pore by substances formed during de redox cycling of some anthracyclines and its dysfunction could be an early indicator of doxorubicin-induced apoptosis.Sarcomeric structure alterationsCardiotoxicity is characterized at the sarcomere level by disarray and loss of myofilaments and studies have demonstrated that anthracyclines are capable of disrupting the contractile apparatus by direct mechanisms, moving further away from the cytotoxic effects mediated by ROS.Titin is a giant protein and integral part of the sarcomere structure, extending from the M-line to the Z-disk and has diverse functions, structural as well as dynamic and regulatory.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> The loss of integrity or function of titin has recently been shown to play an important role in the pathophysiology of dilated cardiomyopathy.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> Exposure to anthracyclines induces an accelerated degradation of titin through proteolytic pathways, leading to energetic compromise. In vitro studies have shown that such effect is also related with loss of structural integrity and disarray or even myocyte necrosis in a calpain-dependent way.<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a>Recently, a very interesting work by Chen et al.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> studied the role of cardiac ankyrin repeat protein (CARP or ANKRD1, a transcriptional regulatory protein that may act as a nuclear transcription factor negatively regulating the expression of cardiac genes) in the pathophysiology of anthracycline cardiomyopathy. His group found that CARP is extremely sensible to doxorubicin, leading to depletion of CARP protein levels (by inhibition of CARP transcription) and causing marked sarcomeric disarray. In their same study, doxorubicin induced cardiac transcription factor GATA4 (GATA Binding Protein 4, thought to regulate genes involved in myocardial differentiation and function, including CARP) depletion, suggesting a co-dependent role for both proteins in maintaining sarcomere structure.Inflammatory mediatorsAnthracyclines are capable of promoting proinflammatory cytokines release, which has been related to several manifestations ranging from cardiotoxicity to asthenia experienced by these patients.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Doxorubicin stimulates macrophages and monocytes with the subsequent histamine and tumoral necrosis factor alpha release; these substances have been related with architectural alterations and dilated cardiomyopathy through myocardial receptors binding.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Wong et al.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> tested the effects of doxorubicin on the mitogen-activated protein kinase (MAPK) pathway, which is essential in translating signals from the cellular surface (through cellular membrane receptors) to the nucleus and, among other functions, regulates inflammatory cytokines. By using clinically relevant doses of doxorubicin, they found an increased expression of inflammatory genes in macrophages as well as increased levels of IL-1β and IL-6 in treated cells, without changes in the expression of tumoral necrosis factor (TNF). The expression of these cytokines has been shown to have a relevant role in cardiotoxicity induced by anthracyclines, mainly by modulating apoptosis through TNF receptors, whose function is affected by doxorubicin.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>Genetics and cardiotoxicityThe study and approach of several cardiovascular diseases has changed dramatically with the advent of genomic medicine, and anthracycline-induced cardiotoxicity is not alien to these advances. Previous evidence exists in terms of the usefulness of the study of genetic polymorphisms related to certain drug toxicities<a class="elsevierStyleCrossRefs" href="#bib0010">2,5</a> and some groups have investigated the possible relationship between polymorphisms (e.g. V244M on the CBR3-carbonyl reductase 3 gene) and heart failure related to these drugs.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> At the same time, certain genotypes might be associated with intracellular iron accumulation<a class="elsevierStyleCrossRef" href="#bib0130">26</a> in patients treated with anthracycline regimens, possibly favouring cellular damage via the mechanisms above mentioned.Wojnowski et al.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> also reported that some genetic variants in doxorubicin transport and in free radical generating enzymes might be involved in the predisposition to present doxorubicin-induced cardiotoxicity, at least in certain lymphomas.While these observations are promising and provide new insights into different aspects of doxorubicin cardiotoxicity, with the current data, we are not able to define a clear genotype-response correlation and further investigation should try to clarify this and provide more information about the clinical usefulness of genotyping.ConclusionsWith the improvements in early diagnosis and anti-tumoral treatments, we are witnessing an increased survival in oncologic patients. In this context, cardiologists are faced with new tasks, like how to manage the toxic effects caused by chemotherapy agents.Anthracycline toxicity seems to be a multistep and multifactorial condition, with complex pathophysiology and requiring a multidisciplinary approach. A deep understanding of this toxicity and its mechanisms will possibly allow us to reduce its incidence, identify early markers of susceptibility or find more specific therapeutic targets. As we have reviewed in the present paper, no mechanism seems capable by itself of causing the whole clinical picture.Development of new anticancer therapies will surely bring further challenges to cardiologists in the next decade, as the advent of novel therapies in oncology will also change the current landscape of these toxicities. It seems obvious to us that the “specialty” of cardiooncology is much needed in the current context.FundingThere was no funding for this research.Conflict of interestAuthors do not have any conflict of interests regarding this work." "textoCompletoSecciones" => array:1 [ "secciones" => array:18 [ 0 => array:2 [ "identificador" => "xres365892" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec345521" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres365893" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec345520" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Scope of the problem" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Mechanisms of cardiotoxicity" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Oxidative stress" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Accumulation of toxic metabolites" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Iron metabolism" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Disruption of energetic mechanisms" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Sarcomeric structure alterations" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Inflammatory mediators" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Genetics and cardiotoxicity" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 15 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 16 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 17 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-04-25" "fechaAceptado" => "2013-08-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec345521" "palabras" => array:4 [ 0 => "Anthracycline cardiotoxicity" 1 => "Chemotherapy cardiomyopathy" 2 => "Doxorubicin cardiomyopathy" 3 => "Spain" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec345520" "palabras" => array:4 [ 0 => "Cardiotoxicidad de antraciclinas" 1 => "Miocardiopatía por quimioterapia" 2 => "Miocardiopatía por doxorrubicina" 3 => "España" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Anthracyclines are cytostatic antibiotics discovered almost half a century ago exerting their action through inhibition of topoisomerase II. The two most representative drugs are doxorubicin and daunorubicin and they have been proven as useful antineoplastics and are widely prescribed in daily oncology practice; unfortunately, cardiotoxicity has been a limiting factor when it comes to their use.Diverse mechanisms have been involved in anthracycline cardiotoxicity, none of which are capable of causing the whole clinical picture by itself. Traditionally, reactive oxygen species (ROS) have received more attention, although recently basic research has proven other factors to be as important as ROS. These factors mainly involve sarcomeric structure disruption, toxic accumulation of metabolites, iron metabolism, energetic alterations and inflammation.The role of genetics has been studied by some groups, although a clear genotype-response relationship is yet to be elucidated.With the improved survival from different oncologic diseases we are witnessing more cases of chemotherapy-induced cardiotoxicity and the advent of new anticancer drugs poses several challenges for the cardiologist, highlighting the importance of a deep knowledge of the main mechanisms inducing this toxicity." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Hace casi medio siglo se descubrieron las antraciclinas; estas son antibióticos citostáticos inhibidores de la topoisomerasa ii. Los 2 fármacos más representativos de este grupo son la doxorrubicina y la daunorrubicina. Estos fármacos han demostrado ser eficaces antineoplásicos y han sido ampliamente utilizados en la práctica oncológica. Desafortunadamente, la cardiotoxicidad sigue siendo un elemento limitante para su uso.Los mecanismos mediante los cuales estos fármacos ocasionan cardiotoxicidad son múltiples pero ninguno de ellos de forma individual es capaz de explicar el cuadro clínico por completo. Casi siempre se ha considerado que la formación de especies reactivas de oxígeno era responsable de gran parte de la toxicidad, sin embargo la experimentación básica reciente ha demostrado que hay otros factores, entre los que destacan las alteraciones en la estructura sarcomérica, la acumulación de metabolitos tóxicos, las alteraciones del metabolismo del hierro o de los mecanismos energéticos, y la liberación de mediadores de inflamación.Por otra parte, diversos grupos han investigado la intervención que la genética podría tener en el desarrollo de esta enfermedad, si bien no se puede definir aún una clara correlación genotipo-respuesta.Con el aumento de la supervivencia por el tratamiento de diversas enfermedades oncológicas, se están detectando más casos de cardiotoxicidad mediada por quimioterapia; y con la aparición de nuevos fármacos quimioterápicos se añaden nuevos retos, con lo que se demuestra la importancia del estudio profundo de los mecanismos causales." ] ] "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" => 1238 "Ancho" => 1578 "Tamanyo" => 87965 ] ] "descripcion" => array:1 [ "en" => "Causative mechanisms of anthracycline cardiomyopathy." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1570 "Ancho" => 2167 "Tamanyo" => 197733 ] ] "descripcion" => array:1 [ "en" => "Role of DOX, doxorubicinol and ROS in cardiomyopathy." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:41 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adriamycin (14-hydroxydaunomycin), a novel antitumor antibiotic" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "F. Arcamone" 1 => "G. Franceschi" 2 => "S. Penco" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Tetrahedron Lett" "fecha" => "1969" "volumen" => "13" "paginaInicial" => "1007" "paginaFinal" => "1010" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5794423" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthracycline cardiotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P. Menna" 1 => "O. González" 2 => "M. Chello" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/14740338.2011.589834" "Revista" => array:6 [ "tituloSerie" => "Expert Opin Drug Saf" "fecha" => "2012" "volumen" => "11" "paginaInicial" => "S21" "paginaFinal" => "S36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21635149" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "S. Aebi" 1 => "T. Davidson" 2 => "G. Gruber" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdq159" "Revista" => array:6 [ "tituloSerie" => "Ann Oncol" "fecha" => "2010" "volumen" => "21" "paginaInicial" => "v9" "paginaFinal" => "v14" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20555111" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "U. Creutzig" 1 => "M.M. van den Heuvel-Eibrink" 2 => "B. Gibson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-03-362608" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2012" "volumen" => "120" "paginaInicial" => "3187" "paginaFinal" => "3205" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22879540" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthraycline cardiotoxicity from bench to bedside" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "L. Gianni" 1 => "E. Herman" 2 => "S.E. Lipshultz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2007.14.9401" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2008" "volumen" => "26" "paginaInicial" => "3777" "paginaFinal" => "3784" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18669466" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.M. Swain" 1 => "F.S. Whaley" 2 => "M.S. Ewer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.11407" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "2003" "volumen" => "97" "paginaInicial" => "2869" "paginaFinal" => "2879" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12767102" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of anthracyclines in the era of targeted therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Cortés-Funes" 1 => "C. Coronado" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12012-007-0015-3" "Revista" => array:6 [ "tituloSerie" => "Cardiovasc Toxicol" "fecha" => "2007" "volumen" => "7" "paginaInicial" => "56" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17652804" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. Eschenhagen" 1 => "T. Force" 2 => "M.S. Ewer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurjhf/hfq213" "Revista" => array:6 [ "tituloSerie" => "Eur J Heart Fail" "fecha" => "2011" "volumen" => "13" "paginaInicial" => "1" "paginaFinal" => "10" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21169385" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "American Society of Clinical Oncology: clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.R. Carver" 1 => "C.L. Shapiro" 2 => "A. Ng" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2007.10.9777" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2007" "volumen" => "25" "paginaInicial" => "3991" "paginaFinal" => "4008" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17577017" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.P. Krischer" 1 => "S. Epstein" 2 => "D.D. Cuthbertson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/jco.1997.15.4.1544" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "1997" "volumen" => "15" "paginaInicial" => "1544" "paginaFinal" => "1552" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9193351" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Late mortality experience in five-year survivors of childhood and adolescent cancer: The Childhood Cancer Survivor Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "A.C. Mertens" 1 => "Y. Yasui" 2 => "J.P. Neglia" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/jco.2001.19.13.3163" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2001" "volumen" => "19" "paginaInicial" => "3163" "paginaFinal" => "3172" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11432882" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T.R. Möller" 1 => "S. Garwicz" 2 => "L. Barlow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/jco.2001.19.13.3173" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2001" "volumen" => "19" "paginaInicial" => "3173" "paginaFinal" => "3181" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11432883" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer statistics 2007" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "A. Jemal" 1 => "R. Siegel" 2 => "E. Ward" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "CA Cancer J Clin" "fecha" => "2006" "volumen" => "56" "paginaInicial" => "106" "paginaFinal" => "130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16514137" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiotoxicity of chemotherapeutic agents, incidence, treatment and prevention" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B.P. Pai" 1 => "M. Nahata" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Drug Saf" "fecha" => "2000" "volumen" => "22" "paginaInicial" => "263" "paginaFinal" => "302" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10789823" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G. Minotti" 1 => "P. Menna" 2 => "E. Salvatorelli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1124/pr.56.2.6" "Revista" => array:6 [ "tituloSerie" => "Pharmacol Rev" "fecha" => "2004" "volumen" => "56" "paginaInicial" => "185" "paginaFinal" => "229" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15169927" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "DNA damage is an early event in doxorubicin-induced cardiac myocyte death" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. L’Ecuyer" 1 => "S. Sanjeev" 2 => "R. Thomas" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Physiol Heart Circ Physiol" "fecha" => "2006" "volumen" => "291" "paginaInicial" => "H370" "paginaFinal" => "H378" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "y Octavia" 1 => "C. Tocchetti" 2 => "K. Gabrielson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.yjmcc.2012.03.006" "Revista" => array:6 [ "tituloSerie" => "J Mol Cell Cardiol" "fecha" => "2012" "volumen" => "52" "paginaInicial" => "1213" "paginaFinal" => "1225" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22465037" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new insight intro adriamycin-induced cardiotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.X. Fu" 1 => "F. Waagstein" 2 => "A. Hjalmarson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "1990" "volumen" => "29" "paginaInicial" => "15" "paginaFinal" => "20" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2262210" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthracycline cardiotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P. Menna" 1 => "E. Salvatorelli" 2 => "L. Gianni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/128_2007_11" "Revista" => array:6 [ "tituloSerie" => "Top Curr Chem" "fecha" => "2008" "volumen" => "283" "paginaInicial" => "21" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23605627" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron metabolism: current facts and future directions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. Tandara" 1 => "I. Salamunic" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Biochem Med" "fecha" => "2012" "volumen" => "22" "paginaInicial" => "311" "paginaFinal" => "328" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G. Minotti" 1 => "R. Ronchi" 2 => "E. Salvatorelli" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cancer Res" "fecha" => "2001" "volumen" => "61" "paginaInicial" => "8422" "paginaFinal" => "8428" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11731422" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthracycline-induced cardiotoxicity: overview of oxidative stress and free cellular iron" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. Simunek" 1 => "M. Sterba" 2 => "O. Popelová" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Pharm Rep" "fecha" => "2009" "volumen" => "61" "paginaInicial" => "154" "paginaFinal" => "171" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Free radicals in biology and medicine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B. Halliwell" 1 => "J. Gutteridge" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2007" "editorial" => "Oxford University Press" "editorialLocalizacion" => "Oxford, NY" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interactions between doxorubicin and the human iron regulatory system" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "X. Brazzolotto" 1 => "M. Andriollo" 2 => "P. Guiraud" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "2003" "volumen" => "17" "paginaInicial" => "209" "paginaFinal" => "218" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Potentiation of doxorubicin cardiotoxicity by iron loading in a rodent model" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G.S. Pantjrath" 1 => "V. Patel" 2 => "N. Valdiviezo Cl Narula" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2007.02.060" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2007" "volumen" => "49" "paginaInicial" => "2457" "paginaFinal" => "2464" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17599610" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "A. Cascales" 1 => "B. Sánchez-Vega" 2 => "N. Navarro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2010.09.046" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2012" "volumen" => "154" "paginaInicial" => "282" "paginaFinal" => "286" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20974500" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Energy metabolism in heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Ventura-Clapier" 1 => "A. Garnier" 2 => "V. Veksler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1113/jphysiol.2003.055095" "Revista" => array:6 [ "tituloSerie" => "J Physiol" "fecha" => "2004" "volumen" => "555" "paginaInicial" => "1" "paginaFinal" => "13" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14660709" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "In-vivo and in-vitro mitochondrial membrane damages induced in mice by adriamycin and derivatives" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Praet" 1 => "J.M. Ruysschaert" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "1993" "volumen" => "1149" "paginaInicial" => "79" "paginaFinal" => "85" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8391322" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Doxorubicin-induced cardiac mitochondrionopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K.B. Wallace" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pharmacol Toxicol" "fecha" => "2003" "volumen" => "93" "paginaInicial" => "105" "paginaFinal" => "115" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12969434" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "M. Tokarska-Schlattner" 1 => "M. Zaugg" 2 => "C. Zuppinger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.yjmcc.2006.06.009" "Revista" => array:6 [ "tituloSerie" => "J Mol Cell Cardiol" "fecha" => "2006" "volumen" => "41" "paginaInicial" => "389" "paginaFinal" => "405" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16879835" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The sarcomeric cytoskeleton: who picks up the strain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Gautel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ceb.2010.12.001" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Cell Biol" "fecha" => "2011" "volumen" => "23" "paginaInicial" => "39" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21190822" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Truncations of titin causing dilated cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "D.S. Herman" 1 => "L. Lam" 2 => "M.R. Taylor" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1110186" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2012" "volumen" => "366" "paginaInicial" => "619" "paginaFinal" => "628" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22335739" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetics: broken giant linked to heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "E.M. McNally" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nature" "fecha" => "2012" "volumen" => "14" "paginaInicial" => "281" "paginaFinal" => "282" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "C.C. Lim" 1 => "C. Zuppinger" 2 => "X. Guo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Biol Chem" "fecha" => "2004" "volumen" => "27" "paginaInicial" => "8290" "paginaFinal" => "8299" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms of anthracycline cardiac injury: can we identify strategies for cardio-protection" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "D. Sawyer" 1 => "X. Peng" 2 => "B. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pcad.2010.06.007" "Revista" => array:6 [ "tituloSerie" => "Prog Cardiovasc Dis" "fecha" => "2010" "volumen" => "53" "paginaInicial" => "105" "paginaFinal" => "113" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20728697" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disruption of GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "B. Chen" 1 => "L. Zhong" 2 => "S. Roush" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "PLoS ONE" "fecha" => "2012" "volumen" => "7" "paginaInicial" => "1" "paginaFinal" => "13" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "C. Schubert" 1 => "S. Hong" 2 => "L. Natarajan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbi.2006.11.004" "Revista" => array:6 [ "tituloSerie" => "Brain Behav Immun" "fecha" => "2007" "volumen" => "21" "paginaInicial" => "413" "paginaFinal" => "427" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17178209" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J. Wong" 1 => "L.B. Smith" 2 => "E.A. Magun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4161/cbt.22628" "Revista" => array:6 [ "tituloSerie" => "Cancer Biol Ther" "fecha" => "2013" "volumen" => "14" "paginaInicial" => "56" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23114643" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Change in TNF-alpha receptor expression is a relevant event in doxorubicin-induced H9c2 cardiomyocyte cell death" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "E. Chiosi" 1 => "A. Spina" 2 => "A. Sorrentino" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/jir.2006.0161" "Revista" => array:6 [ "tituloSerie" => "J Interferon Cytokine Res" "fecha" => "2007" "volumen" => "27" "paginaInicial" => "589" "paginaFinal" => "597" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17651020" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.G. Blanco" 1 => "W.M. Leisenring" 2 => "V.M. González-Covarrubias" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.23534" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "2008" "volumen" => "112" "paginaInicial" => "2789" "paginaFinal" => "2795" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18457324" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "L. Wojnowski" 1 => "B. Kulle" 2 => "M. Schirmer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.105.576850" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2005" "volumen" => "112" "paginaInicial" => "3754" "paginaFinal" => "3762" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16330681" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000688/v1_201408290019/en/main.assets" "Apartado" => array:4 [ "identificador" => "11606" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Artículos de revisión" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/14059940/0000008400000003/v1_201408290019/S1405994014000688/v1_201408290019/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000688?idApp=UINPBA00004N"]

Statistics

Review article

Miocardiopatía inducida por antraciclinas: conocimientos moleculares básicos para el cardiólogo

Joel Salazar-Mendiguchía

Corresponding author

jsalazar@bellvitgehospital.cat

Corresponding author at: Área de Enfermedades del Corazón, Hospital Universitari de Bellvitge, Av Feixa Llarga s/n, L’Hospitalet de Llobregat, 08904 Barcelona, Spain.

, José González-Costello, Josep Roca, Albert Ariza-Solé, Nicolás Manito, Ángel Cequier

Unidad de Miocardiopatías, Insuficiencia Cardíaca y Trasplante, Área de Enfermedades del Corazón, Hospital Universitari de Bellvitge, Barcelona, Spain

Read

7696

Times
was read the article

1650

Total PDF

6046

Total HTML

Share statistics

 array:24 [
  "pii" => "S1405994014000688"
  "issn" => "14059940"
  "doi" => "10.1016/j.acmx.2013.08.006"
  "estado" => "S300"
  "fechaPublicacion" => "2014-07-01"
  "aid" => "136"
  "copyright" => "Instituto Nacional de Cardiolog&#237;a Ignacio Ch&#225;vez"
  "copyrightAnyo" => "2013"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
  "subdocumento" => "ssu"
  "cita" => "Arch Cardiol Mex. 2014;84:218-23"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 4062
    "formatos" => array:3 [
      "EPUB" => 73
      "HTML" => 2883
      "PDF" => 1106
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1405994014000329"
    "issn" => "14059940"
    "doi" => "10.1016/j.acmx.2013.10.011"
    "estado" => "S300"
    "fechaPublicacion" => "2014-07-01"
    "aid" => "119"
    "copyright" => "Instituto Nacional de Cardiolog&#237;a Ignacio Ch&#225;vez"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Arch Cardiol Mex. 2014;84:224-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 4514
      "formatos" => array:3 [
        "EPUB" => 41
        "HTML" => 2808
        "PDF" => 1665
      ]
    ]
    "es" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Art&#237;culo especial</span>"
      "titulo" => "El conocimiento de la respiraci&#243;n animal como un fen&#243;meno de combusti&#243;n"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "224"
          "paginaFinal" => "228"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "The knowledge of animal respiration as a combustion phenomenon"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0015"
          "etiqueta" => "Figura 3"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr3.jpeg"
              "Alto" => 2513
              "Ancho" => 1250
              "Tamanyo" => 219685
            ]
          ]
          "descripcion" => array:1 [
            "es" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Trait&#233; &#233;l&#233;mentaire de chimie</span>&#44; de A&#46;L&#46; Lavoisier &#40;Par&#237;s&#44; 1789&#41;&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Alfredo de Micheli"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "Alfredo"
              "apellidos" => "de Micheli"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000329?idApp=UINPBA00004N"
    "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000329/v1_201408290019/es/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1405994014000676"
    "issn" => "14059940"
    "doi" => "10.1016/j.acmx.2014.02.002"
    "estado" => "S300"
    "fechaPublicacion" => "2014-07-01"
    "aid" => "135"
    "copyright" => "Instituto Nacional de Cardiolog&#237;a Ignacio Ch&#225;vez"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "ssu"
    "cita" => "Arch Cardiol Mex. 2014;84:211-7"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 2876
      "formatos" => array:3 [
        "EPUB" => 48
        "HTML" => 2230
        "PDF" => 598
      ]
    ]
    "es" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Art&#237;culo de revisi&#243;n</span>"
      "titulo" => "Papel de la inflamaci&#243;n renal en la fisiopatolog&#237;a de la hipertensi&#243;n sensible a sal"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "211"
          "paginaFinal" => "217"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Role of renal inflammation in the physiopathology of salt-sensitive hypertension"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0005"
          "etiqueta" => "Figura 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 2030
              "Ancho" => 1650
              "Tamanyo" => 133707
            ]
          ]
          "descripcion" => array:1 [
            "es" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mecanismos que explican la relaci&#243;n entre inflamaci&#243;n renal y el desarrollo de HSS&#46; La figura muestra c&#243;mo la formaci&#243;n de RL inicia la producci&#243;n de citocinas proinflamatorias que favorecen la infiltraci&#243;n renal de linfocitos T y otras c&#233;lulas del sistema inmunol&#243;gico&#44; como los macr&#243;fagos&#46; Este proceso estimula la s&#237;ntesis y liberaci&#243;n de angiotensina <span class="elsevierStyleSmallCaps">ii</span> a este nivel&#44; que incrementa la retenci&#243;n de sodio y agua y lleva finalmente a la HSS&#46; Las flechas indican c&#243;mo el proceso se perpet&#250;a&#44; pues la inflamaci&#243;n renal incrementa los niveles de angiotensina <span class="elsevierStyleSmallCaps">ii</span>&#44; y esta a su vez acrecienta la producci&#243;n de citocinas que aumentan el proceso inflamatorio&#44; desencadenando un ciclo que explica la continuidad de la inflamaci&#243;n renal observada en estos pacientes&#46; FNT &#945;&#58; factor de necrosis tumoral &#945;&#59; HSS&#58; hipertensi&#243;n sensible a sal&#44; IL-1&#58; interleucina-1&#59; IL-6&#58; Interleucina-6&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Yaniel Castro Torres, Alejandro Emilio Santos Portela, Ildiko Mar&#237;a Garrido B&#337;sze"
          "autores" => array:3 [
            0 => array:2 [
              "nombre" => "Yaniel"
              "apellidos" => "Castro Torres"
            ]
            1 => array:2 [
              "nombre" => "Alejandro Emilio"
              "apellidos" => "Santos Portela"
            ]
            2 => array:2 [
              "nombre" => "Ildiko Mar&#237;a"
              "apellidos" => "Garrido B&#337;sze"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000676?idApp=UINPBA00004N"
    "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000676/v1_201408290019/es/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
    "titulo" => "Anthracycline-mediated cardiomyopathy&#58; Basic molecular knowledge for the cardiologist"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "218"
        "paginaFinal" => "223"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Joel Salazar-Mendiguch&#237;a, Jos&#233; Gonz&#225;lez-Costello, Josep Roca, Albert Ariza-Sol&#233;, Nicol&#225;s Manito, &#193;ngel Cequier"
        "autores" => array:6 [
          0 => array:4 [
            "nombre" => "Joel"
            "apellidos" => "Salazar-Mendiguch&#237;a"
            "email" => array:1 [
              0 => "jsalazar&#64;bellvitgehospital&#46;cat"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:2 [
            "nombre" => "Jos&#233;"
            "apellidos" => "Gonz&#225;lez-Costello"
          ]
          2 => array:2 [
            "nombre" => "Josep"
            "apellidos" => "Roca"
          ]
          3 => array:2 [
            "nombre" => "Albert"
            "apellidos" => "Ariza-Sol&#233;"
          ]
          4 => array:2 [
            "nombre" => "Nicol&#225;s"
            "apellidos" => "Manito"
          ]
          5 => array:2 [
            "nombre" => "&#193;ngel"
            "apellidos" => "Cequier"
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Unidad de Miocardiopat&#237;as&#44; Insuficiencia Card&#237;aca y Trasplante&#44; &#193;rea de Enfermedades del Coraz&#243;n&#44; Hospital Universitari de Bellvitge&#44; Barcelona&#44; Spain"
            "identificador" => "aff0005"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author at&#58; &#193;rea de Enfermedades del Coraz&#243;n&#44; Hospital Universitari de Bellvitge&#44; Av Feixa Llarga s&#47;n&#44; L&#8217;Hospitalet de Llobregat&#44; 08904 Barcelona&#44; Spain&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Miocardiopat&#237;a inducida por antraciclinas&#58; conocimientos moleculares b&#225;sicos para el cardi&#243;logo"
      ]
    ]
    "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" => 1570
            "Ancho" => 2167
            "Tamanyo" => 197733
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Role of DOX&#44; doxorubicinol and ROS in cardiomyopathy&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anthracyclines are cytostatic antibiotics discovered almost half a century ago that exert their action through inhibition of topoisomerase II&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> The two most representative drugs of this group are doxorubicin &#40;active against some hematologic cancers and solid tumors&#41;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and daunorubicin &#40;used mainly in acute hematologic cancer&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> although other drugs have been developed within this family &#40;e&#46;g&#46; epirubicin&#44; idarubicin and mitoxantrone&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">These drugs have been proven as useful antineoplastics and are amongst the most widely prescribed oncologic medication&#46; Unfortunately&#44; cardiotoxicity secondary to anthracyclines still remains a limiting factor when used&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> being generally related to dose&#8211;response &#40;although there are several reports of cardiotoxicity associated with lower doses&#44; probably secondary to individual susceptibility&#41;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a>and manifesting mainly as heart failure usually within a year after completion of treatment&#44; although it is widely accepted that it can manifest itself several years after treatment&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Recently&#44; groups have been created in Europe and the United States for the study of this toxicity&#44; highlighting its importance&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Scope of the problem</span><p id="par0020" class="elsevierStylePara elsevierViewall">Chemotherapy-induced cardiotoxicity is usually classified in two groups according to the cellular damage induced by these drugs&#46; Type I cardiotoxicity implies cellular death &#40;either via necrosis or apoptosis&#41; and thus&#44; is not reversible&#44; whereas type II cardiotoxicity is caused by cellular dysfunction &#40;not death&#41; and is usually described as reversible&#46; Type I is characteristic of anthracycline damage&#44; while type II is more frequent with monoclonal antibodies &#40;namely&#44; trastuzumab&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Gianni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> reported some of the several limitations that have emerged in terms of describing the current situation of anthracycline-mediated cardiotoxicity&#59; these problems come from a lack of uniformity in reporting or detecting events in these patients and the different forms of presentation &#40;acute vs&#46; delayed&#44; reversible vs&#46; irreversible&#41;&#46; At the same time&#44; the wide difference in the treated populations &#40;adults vs&#46; children&#41; makes it difficult to unify criteria&#46; Nevertheless&#44; recent statistics regarding survival of oncologic patients give us an overview of the problem&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">At the moment&#44; in the US there are more than 300&#44;000 survivors of childhood cancer&#44; of whom 50&#37; could potentially have been treated with anthracyclines&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and the probability of accumulated death due to cardiac cause &#40;including sudden death likely to be cardiac in origin&#41; is greater than the observed in control groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Likewise&#44; survival of breast cancer &#40;one of the clinical scenarios where these drugs have been used extensively&#41; has increased dramatically in the last decades&#44; translating into approximately two million women in the US with high likelihood of previous anthracycline exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite several efforts to diminish this adverse effect &#40;mainly by reducing the cumulative dose under 400&#8211;450<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> for doxorubicin&#41; and considering the previously mentioned caveats&#44; studies estimate heart failure rates between 5 and 10&#37;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a> with the modern regimens of treatment&#44; depending on age&#44; cumulative dose&#44; individual susceptibility or even past medical history &#40;e&#46;g&#46; hypertension&#44; coronary heart disease&#44; etc&#46;&#41;&#44; among other factors&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Mechanisms of cardiotoxicity</span><p id="par0045" class="elsevierStylePara elsevierViewall">With all the aforementioned&#44; it is not surprising that considerable controversy has risen with respect to the mechanisms involved in this toxicity&#46; Anthracycline-induced cardiotoxicity seems to be a multi-step condition&#44; with several pathways involved&#46; Many research groups have tried to elucidate the processes associated&#59; of these&#44; we will focus in this review on those that have been most extensively studied&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is important to acknowledge the fact that these pathways are not necessarily independent from each other or exclusive&#44; as each of them may play a role in causing cardiotoxicity via different mechanisms&#44; by themselves or in cooperation with other pathways&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> depicts some of the mechanisms generating cardiotoxicity&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We will not review in the present work the rare&#44; but existent&#44; acute presentation of anthracycline toxicity or the involvement of the pericardium&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Oxidative stress</span><p id="par0060" class="elsevierStylePara elsevierViewall">Oxidative stress is the most widely studied mechanism and it involves a highly complex pathophysiology&#44; which is a matter of permanent debate&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The myocardium is extremely prone to oxidative damage and this is&#44; at least in part&#44; due to its lower levels of catalase activity and superoxide dismutase &#40;an enzyme that catalyses the dismutation of superoxide&#44; one of the main reactive oxygen species &#91;ROS&#93;&#41;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> compared with other tissues&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The metabolism of anthracyclines involves the reduction of the quinone fraction of its formula to semiquinone&#44; which can rapidly transfer its unpaired electron to an electron acceptor &#40;usually molecular oxygen&#41;&#44; returning to its original quinone form&#44; therefore completing the redox cycle and leading to the formation of more ROS&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Other mechanisms involved include the formation of DNA adducts by semiquinone or the generation of superoxide anions by anthracycline metabolism&#44; with subsequent cellular damage by degradation of the sarcomere&#44; mitochondrial dysfunction and DNA damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">A recent paper by Octavia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>elegantly describes the different pathways by which anthracyclines cause ROS&#44; including mitochondrial&#44; nitric oxide synthase &#40;NOS&#41;&#44; and nicotinamide adenine dinucleotide phosphate &#40;NADPH&#41; pathways&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Even though the evidence for myocardial damage induced by ROS is vast&#44; oxidative stress as the sole cause of cardiotoxicity is increasingly questioned and more research is dedicated to alternative pathways&#46; Part of the reason for this came from earlier studies that failed to prove the protective role of certain antioxidants in the long term&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> especially when interventions that resembled the ones used in clinical practice were tested&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> It is noteworthy that some of the drugs that might have a protective role &#40;e&#46;g&#46; dexrazoxane and carvedilol&#41; probably exert their defensive mechanism through alternative molecular routes&#44; besides their antioxidant activity&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the relationships between DOX&#44; doxorubicinol and ROS in cardiotoxicity&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Accumulation of toxic metabolites</span><p id="par0090" class="elsevierStylePara elsevierViewall">Anthracyclines metabolism generates toxic molecules at the myocardium level through a reduction of their carbonyl group &#40;producing doxorubicinol in case of doxorubicin&#44; being up to 50 times more potent than the original compound&#44; or daunorubinicol and idarubicinol in case of daunorubicin and idarubicin&#44; respectively&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> capable of inhibiting the ion exchange pumps of calcium and sodium&#44; even at the mitochondrial level&#44; causing an imbalance in the energetics of the myocardium and a diminished systolic function&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Moreover&#44; these secondary alcohol metabolites are more difficult to eliminate from the cardiomyocyte than the parent drug&#44; accumulating inside them&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">All the anthracyclines have shown to have similar mechanisms of bioactivation&#44; making them toxic from the cardiac standpoint&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> but the role of toxic metabolites has been challenged by the fact that both daunorubicin and idarubicin generate higher plasma levels of alcohol metabolites compared with doxorubicin<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and they tend to generate less cardiotoxicity&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">A more detailed description of the molecular damage induced by each drug is beyond the scope of this paper&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Iron metabolism</span><p id="par0105" class="elsevierStylePara elsevierViewall">Iron has a major role in cell metabolism and is under control by several regulatory systems&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Its functions go far beyond the oxygen transport complex&#44; being part of different processes like bioenergetics&#44; enzymatic coordination or even immune system physiology&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Traditionally&#44; it has been considered that anthracyclines are capable of altering iron homeostasis through the creation of Fe&#8211;anthracycline complexes and the posterior production of ROS&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> even in the absence of a reduction system &#40;through intramolecular redox reactions&#41; and some researchers have suggested that the toxicity of the combination of iron and some anthracyclines &#40;doxorubicin&#41; is not a simple additive effect&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">At the same time&#44; iron is capable of catalyzing diverse molecular reactions that create ROS&#44; independently of the abovementioned Fe&#8211;anthracycline complex&#44; generating hydroxyl radicals&#44; and it is well known that this reaction is accelerated under the influence of iron itself in the cellular environment&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Iron regulatory proteins or IRPs &#40;also known as iron responsive element binding proteins&#41; are important elements in regulating iron metabolism and the interactions between doxorubicin and the human iron regulatory system have been studied by some researchers&#46; Studies have found that the conversion of IRP1 to a null protein via doxorubicin metabolites yields a metabolic cellular impairment that may account to a certain degree for myocardial dysfunction&#44; opening new paths towards a better understanding of the role of iron metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Likewise&#44; animal models have shown that iron overload is capable of potentiating doxorubicin cardiotoxicity by mechanisms other than ROS production&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Recently&#44; human studies have confirmed this finding&#44; showing that even cumulative doses of doxorubicin in the &#8220;safe&#8221; range are capable of inducing higher iron levels in cardiac tissue&#44; specially at the intracellular level&#44; opening the possibility of cardiotoxicity related with iron deposits as a new pathophysiologic mechanism<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> and raising the question of whether a real &#8220;safe&#8221; dose exists in terms of preventing long term cardiomyopathy&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Disruption of energetic mechanisms</span><p id="par0130" class="elsevierStylePara elsevierViewall">The integrity of mitochondrial function is of cornerstone importance in the physiology of myocardial cells&#44; as ATP production is highly dependent on this organelle &#40;almost all of the ATP used by cardiac cells is produced by the electron transport chain&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Several studies have suggested that disruptions in the mitochondrial membrane potential and respiratory chain are capable of inducing loss of architectural integrity&#44; loss of energy production capability and difficulties in maintaining metabolic demands&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Recently&#44; cadiolipin&#44; a phospholipid of utmost importance in energy metabolism and a component of the inner mitochondrial membrane&#44; has been suggested as having a major role in anthracycline-mediated cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Doxorubicin&#44; by its ability to bind cardiolipin would modify membrane properties&#44; environment and function&#44; leading to disruption of several energetic mechanisms&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">As mentioned before&#44; no pathway by itself justifies the complete clinical picture&#44; and the disruption of mitochondrial functions mediated by cardiolipin-doxorubicin interactions are also mediated by oxidative stress&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> in fact&#44; the disturbance in mitochondrial permeability has been related to a direct opening of the permeability transition pore by substances formed during de redox cycling of some anthracyclines and its dysfunction could be an early indicator of doxorubicin-induced apoptosis&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Sarcomeric structure alterations</span><p id="par0150" class="elsevierStylePara elsevierViewall">Cardiotoxicity is characterized at the sarcomere level by disarray and loss of myofilaments and studies have demonstrated that anthracyclines are capable of disrupting the contractile apparatus by direct mechanisms&#44; moving further away from the cytotoxic effects mediated by ROS&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Titin is a giant protein and integral part of the sarcomere structure&#44; extending from the M-line to the Z-disk and has diverse functions&#44; structural as well as dynamic and regulatory&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The loss of integrity or function of titin has recently been shown to play an important role in the pathophysiology of dilated cardiomyopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Exposure to anthracyclines induces an accelerated degradation of titin through proteolytic pathways&#44; leading to energetic compromise&#46; In vitro studies have shown that such effect is also related with loss of structural integrity and disarray or even myocyte necrosis in a calpain-dependent way&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Recently&#44; a very interesting work by Chen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> studied the role of cardiac ankyrin repeat protein &#40;CARP or ANKRD1&#44; a transcriptional regulatory protein that may act as a nuclear transcription factor negatively regulating the expression of cardiac genes&#41; in the pathophysiology of anthracycline cardiomyopathy&#46; His group found that CARP is extremely sensible to doxorubicin&#44; leading to depletion of CARP protein levels &#40;by inhibition of CARP transcription&#41; and causing marked sarcomeric disarray&#46; In their same study&#44; doxorubicin induced cardiac transcription factor GATA4 &#40;GATA Binding Protein 4&#44; thought to regulate genes involved in myocardial differentiation and function&#44; including CARP&#41; depletion&#44; suggesting a co-dependent role for both proteins in maintaining sarcomere structure&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Inflammatory mediators</span><p id="par0165" class="elsevierStylePara elsevierViewall">Anthracyclines are capable of promoting proinflammatory cytokines release&#44; which has been related to several manifestations ranging from cardiotoxicity to asthenia experienced by these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Doxorubicin stimulates macrophages and monocytes with the subsequent histamine and tumoral necrosis factor alpha release&#59; these substances have been related with architectural alterations and dilated cardiomyopathy through myocardial receptors binding&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Wong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> tested the effects of doxorubicin on the mitogen-activated protein kinase &#40;MAPK&#41; pathway&#44; which is essential in translating signals from the cellular surface &#40;through cellular membrane receptors&#41; to the nucleus and&#44; among other functions&#44; regulates inflammatory cytokines&#46; By using clinically relevant doses of doxorubicin&#44; they found an increased expression of inflammatory genes in macrophages as well as increased levels of IL-1&#946; and IL-6 in treated cells&#44; without changes in the expression of tumoral necrosis factor &#40;TNF&#41;&#46; The expression of these cytokines has been shown to have a relevant role in cardiotoxicity induced by anthracyclines&#44; mainly by modulating apoptosis through TNF receptors&#44; whose function is affected by doxorubicin&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Genetics and cardiotoxicity</span><p id="par0180" class="elsevierStylePara elsevierViewall">The study and approach of several cardiovascular diseases has changed dramatically with the advent of genomic medicine&#44; and anthracycline-induced cardiotoxicity is not alien to these advances&#46; Previous evidence exists in terms of the usefulness of the study of genetic polymorphisms related to certain drug toxicities<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a> and some groups have investigated the possible relationship between polymorphisms &#40;e&#46;g&#46; V244M on the CBR3-carbonyl reductase 3 gene&#41; and heart failure related to these drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> At the same time&#44; certain genotypes might be associated with intracellular iron accumulation<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> in patients treated with anthracycline regimens&#44; possibly favouring cellular damage via the mechanisms above mentioned&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Wojnowski et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> also reported that some genetic variants in doxorubicin transport and in free radical generating enzymes might be involved in the predisposition to present doxorubicin-induced cardiotoxicity&#44; at least in certain lymphomas&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">While these observations are promising and provide new insights into different aspects of doxorubicin cardiotoxicity&#44; with the current data&#44; we are not able to define a clear genotype-response correlation and further investigation should try to clarify this and provide more information about the clinical usefulness of genotyping&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">With the improvements in early diagnosis and anti-tumoral treatments&#44; we are witnessing an increased survival in oncologic patients&#46; In this context&#44; cardiologists are faced with new tasks&#44; like how to manage the toxic effects caused by chemotherapy agents&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Anthracycline toxicity seems to be a multistep and multifactorial condition&#44; with complex pathophysiology and requiring a multidisciplinary approach&#46; A deep understanding of this toxicity and its mechanisms will possibly allow us to reduce its incidence&#44; identify early markers of susceptibility or find more specific therapeutic targets&#46; As we have reviewed in the present paper&#44; no mechanism seems capable by itself of causing the whole clinical picture&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Development of new anticancer therapies will surely bring further challenges to cardiologists in the next decade&#44; as the advent of novel therapies in oncology will also change the current landscape of these toxicities&#46; It seems obvious to us that the &#8220;specialty&#8221; of cardiooncology is much needed in the current context&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Funding</span><p id="par0210" class="elsevierStylePara elsevierViewall">There was no funding for this research&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">Authors do not have any conflict of interests regarding this work&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:18 [
        0 => array:2 [
          "identificador" => "xres365892"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec345521"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres365893"
          "titulo" => "Resumen"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec345520"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Scope of the problem"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Mechanisms of cardiotoxicity"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Oxidative stress"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Accumulation of toxic metabolites"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Iron metabolism"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Disruption of energetic mechanisms"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Sarcomeric structure alterations"
        ]
        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Inflammatory mediators"
        ]
        13 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Genetics and cardiotoxicity"
        ]
        14 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conclusions"
        ]
        15 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Funding"
        ]
        16 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conflict of interest"
        ]
        17 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-04-25"
    "fechaAceptado" => "2013-08-20"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec345521"
          "palabras" => array:4 [
            0 => "Anthracycline cardiotoxicity"
            1 => "Chemotherapy cardiomyopathy"
            2 => "Doxorubicin cardiomyopathy"
            3 => "Spain"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec345520"
          "palabras" => array:4 [
            0 => "Cardiotoxicidad de antraciclinas"
            1 => "Miocardiopat&#237;a por quimioterapia"
            2 => "Miocardiopat&#237;a por doxorrubicina"
            3 => "Espa&#241;a"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Anthracyclines are cytostatic antibiotics discovered almost half a century ago exerting their action through inhibition of topoisomerase II&#46; The two most representative drugs are doxorubicin and daunorubicin and they have been proven as useful antineoplastics and are widely prescribed in daily oncology practice&#59; unfortunately&#44; cardiotoxicity has been a limiting factor when it comes to their use&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diverse mechanisms have been involved in anthracycline cardiotoxicity&#44; none of which are capable of causing the whole clinical picture by itself&#46; Traditionally&#44; reactive oxygen species &#40;ROS&#41; have received more attention&#44; although recently basic research has proven other factors to be as important as ROS&#46; These factors mainly involve sarcomeric structure disruption&#44; toxic accumulation of metabolites&#44; iron metabolism&#44; energetic alterations and inflammation&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The role of genetics has been studied by some groups&#44; although a clear genotype-response relationship is yet to be elucidated&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">With the improved survival from different oncologic diseases we are witnessing more cases of chemotherapy-induced cardiotoxicity and the advent of new anticancer drugs poses several challenges for the cardiologist&#44; highlighting the importance of a deep knowledge of the main mechanisms inducing this toxicity&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Hace casi medio siglo se descubrieron las antraciclinas&#59; estas son antibi&#243;ticos citost&#225;ticos inhibidores de la topoisomerasa <span class="elsevierStyleSmallCaps">ii</span>&#46; Los 2 f&#225;rmacos m&#225;s representativos de este grupo son la doxorrubicina y la daunorrubicina&#46; Estos f&#225;rmacos han demostrado ser eficaces antineopl&#225;sicos y han sido ampliamente utilizados en la pr&#225;ctica oncol&#243;gica&#46; Desafortunadamente&#44; la cardiotoxicidad sigue siendo un elemento limitante para su uso&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Los mecanismos mediante los cuales estos f&#225;rmacos ocasionan cardiotoxicidad son m&#250;ltiples pero ninguno de ellos de forma individual es capaz de explicar el cuadro cl&#237;nico por completo&#46; Casi siempre se ha considerado que la formaci&#243;n de especies reactivas de ox&#237;geno era responsable de gran parte de la toxicidad&#44; sin embargo la experimentaci&#243;n b&#225;sica reciente ha demostrado que hay otros factores&#44; entre los que destacan las alteraciones en la estructura sarcom&#233;rica&#44; la acumulaci&#243;n de metabolitos t&#243;xicos&#44; las alteraciones del metabolismo del hierro o de los mecanismos energ&#233;ticos&#44; y la liberaci&#243;n de mediadores de inflamaci&#243;n&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Por otra parte&#44; diversos grupos han investigado la intervenci&#243;n que la gen&#233;tica podr&#237;a tener en el desarrollo de esta enfermedad&#44; si bien no se puede definir a&#250;n una clara correlaci&#243;n genotipo-respuesta&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Con el aumento de la supervivencia por el tratamiento de diversas enfermedades oncol&#243;gicas&#44; se est&#225;n detectando m&#225;s casos de cardiotoxicidad mediada por quimioterapia&#59; y con la aparici&#243;n de nuevos f&#225;rmacos quimioter&#225;picos se a&#241;aden nuevos retos&#44; con lo que se demuestra la importancia del estudio profundo de los mecanismos causales&#46;</p>"
      ]
    ]
    "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" => 1238
            "Ancho" => 1578
            "Tamanyo" => 87965
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Causative mechanisms of anthracycline cardiomyopathy&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1570
            "Ancho" => 2167
            "Tamanyo" => 197733
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Role of DOX&#44; doxorubicinol and ROS in cardiomyopathy&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:41 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adriamycin &#40;14-hydroxydaunomycin&#41;&#44; a novel antitumor antibiotic"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "F&#46; Arcamone"
                            1 => "G&#46; Franceschi"
                            2 => "S&#46; Penco"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Tetrahedron Lett"
                        "fecha" => "1969"
                        "volumen" => "13"
                        "paginaInicial" => "1007"
                        "paginaFinal" => "1010"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5794423"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthracycline cardiotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "P&#46; Menna"
                            1 => "O&#46; Gonz&#225;lez"
                            2 => "M&#46; Chello"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1517/14740338.2011.589834"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Opin Drug Saf"
                        "fecha" => "2012"
                        "volumen" => "11"
                        "paginaInicial" => "S21"
                        "paginaFinal" => "S36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21635149"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ESMO Guidelines Working Group&#46; Primary breast cancer&#58; ESMO Clinical Practice Guidelines for diagnosis&#44; treatment and follow-up"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "S&#46; Aebi"
                            1 => "T&#46; Davidson"
                            2 => "G&#46; Gruber"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdq159"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2010"
                        "volumen" => "21"
                        "paginaInicial" => "v9"
                        "paginaFinal" => "v14"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20555111"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and management of acute myeloid leukemia in children and adolescents&#58; recommendations from an international expert panel"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "U&#46; Creutzig"
                            1 => "M&#46;M&#46; van den Heuvel-Eibrink"
                            2 => "B&#46; Gibson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2012-03-362608"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2012"
                        "volumen" => "120"
                        "paginaInicial" => "3187"
                        "paginaFinal" => "3205"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22879540"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthraycline cardiotoxicity from bench to bedside"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "L&#46; Gianni"
                            1 => "E&#46; Herman"
                            2 => "S&#46;E&#46; Lipshultz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2007.14.9401"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2008"
                        "volumen" => "26"
                        "paginaInicial" => "3777"
                        "paginaFinal" => "3784"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18669466"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Congestive heart failure in patients treated with doxorubicin&#58; a retrospective analysis of three trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46;M&#46; Swain"
                            1 => "F&#46;S&#46; Whaley"
                            2 => "M&#46;S&#46; Ewer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.11407"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "2003"
                        "volumen" => "97"
                        "paginaInicial" => "2869"
                        "paginaFinal" => "2879"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12767102"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of anthracyclines in the era of targeted therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Cort&#233;s-Funes"
                            1 => "C&#46; Coronado"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12012-007-0015-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cardiovasc Toxicol"
                        "fecha" => "2007"
                        "volumen" => "7"
                        "paginaInicial" => "56"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17652804"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiovascular side effects of cancer therapies&#58; a position statement from the Heart Failure Association of the European Society of Cardiology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46; Eschenhagen"
                            1 => "T&#46; Force"
                            2 => "M&#46;S&#46; Ewer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurjhf/hfq213"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Heart Fail"
                        "fecha" => "2011"
                        "volumen" => "13"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21169385"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "American Society of Clinical Oncology&#58; clinical evidence review on the ongoing care of adult cancer survivors&#58; cardiac and pulmonary late effects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;R&#46; Carver"
                            1 => "C&#46;L&#46; Shapiro"
                            2 => "A&#46; Ng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2007.10.9777"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2007"
                        "volumen" => "25"
                        "paginaInicial" => "3991"
                        "paginaFinal" => "4008"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17577017"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical cardiotoxicity following anthracycline treatment for childhood cancer&#58; The Pediatric Oncology Group experience"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;P&#46; Krischer"
                            1 => "S&#46; Epstein"
                            2 => "D&#46;D&#46; Cuthbertson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/jco.1997.15.4.1544"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1997"
                        "volumen" => "15"
                        "paginaInicial" => "1544"
                        "paginaFinal" => "1552"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9193351"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Late mortality experience in five-year survivors of childhood and adolescent cancer&#58; The Childhood Cancer Survivor Study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "A&#46;C&#46; Mertens"
                            1 => "Y&#46; Yasui"
                            2 => "J&#46;P&#46; Neglia"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/jco.2001.19.13.3163"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2001"
                        "volumen" => "19"
                        "paginaInicial" => "3163"
                        "paginaFinal" => "3172"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11432882"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Decreasing late mortality among five-year survivors of cancer in childhood and adolescence&#58; a population-based study in the Nordic countries"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46;R&#46; M&#246;ller"
                            1 => "S&#46; Garwicz"
                            2 => "L&#46; Barlow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/jco.2001.19.13.3173"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2001"
                        "volumen" => "19"
                        "paginaInicial" => "3173"
                        "paginaFinal" => "3181"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11432883"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer statistics 2007"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "A&#46; Jemal"
                            1 => "R&#46; Siegel"
                            2 => "E&#46; Ward"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "CA Cancer J Clin"
                        "fecha" => "2006"
                        "volumen" => "56"
                        "paginaInicial" => "106"
                        "paginaFinal" => "130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16514137"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiotoxicity of chemotherapeutic agents&#44; incidence&#44; treatment and prevention"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46;P&#46; Pai"
                            1 => "M&#46; Nahata"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Drug Saf"
                        "fecha" => "2000"
                        "volumen" => "22"
                        "paginaInicial" => "263"
                        "paginaFinal" => "302"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10789823"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthracyclines&#58; molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "G&#46; Minotti"
                            1 => "P&#46; Menna"
                            2 => "E&#46; Salvatorelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1124/pr.56.2.6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacol Rev"
                        "fecha" => "2004"
                        "volumen" => "56"
                        "paginaInicial" => "185"
                        "paginaFinal" => "229"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15169927"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA damage is an early event in doxorubicin-induced cardiac myocyte death"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46; L&#8217;Ecuyer"
                            1 => "S&#46; Sanjeev"
                            2 => "R&#46; Thomas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Physiol Heart Circ Physiol"
                        "fecha" => "2006"
                        "volumen" => "291"
                        "paginaInicial" => "H370"
                        "paginaFinal" => "H378"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Doxorubicin-induced cardiomyopathy&#58; from molecular mechanisms to therapeutic strategies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "y Octavia"
                            1 => "C&#46; Tocchetti"
                            2 => "K&#46; Gabrielson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yjmcc.2012.03.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Mol Cell Cardiol"
                        "fecha" => "2012"
                        "volumen" => "52"
                        "paginaInicial" => "1213"
                        "paginaFinal" => "1225"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22465037"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A new insight intro adriamycin-induced cardiotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46;X&#46; Fu"
                            1 => "F&#46; Waagstein"
                            2 => "A&#46; Hjalmarson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "1990"
                        "volumen" => "29"
                        "paginaInicial" => "15"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2262210"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthracycline cardiotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "P&#46; Menna"
                            1 => "E&#46; Salvatorelli"
                            2 => "L&#46; Gianni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/128_2007_11"
                      "Revista" => array:6 [
                        "tituloSerie" => "Top Curr Chem"
                        "fecha" => "2008"
                        "volumen" => "283"
                        "paginaInicial" => "21"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23605627"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron metabolism&#58; current facts and future directions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Tandara"
                            1 => "I&#46; Salamunic"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Biochem Med"
                        "fecha" => "2012"
                        "volumen" => "22"
                        "paginaInicial" => "311"
                        "paginaFinal" => "328"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes&#58; evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "G&#46; Minotti"
                            1 => "R&#46; Ronchi"
                            2 => "E&#46; Salvatorelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "2001"
                        "volumen" => "61"
                        "paginaInicial" => "8422"
                        "paginaFinal" => "8428"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11731422"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthracycline-induced cardiotoxicity&#58; overview of oxidative stress and free cellular iron"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46; Simunek"
                            1 => "M&#46; Sterba"
                            2 => "O&#46; Popelov&#225;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Pharm Rep"
                        "fecha" => "2009"
                        "volumen" => "61"
                        "paginaInicial" => "154"
                        "paginaFinal" => "171"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Free radicals in biology and medicine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46; Halliwell"
                            1 => "J&#46; Gutteridge"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "2007"
                        "editorial" => "Oxford University Press"
                        "editorialLocalizacion" => "Oxford&#44; NY"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interactions between doxorubicin and the human iron regulatory system"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "X&#46; Brazzolotto"
                            1 => "M&#46; Andriollo"
                            2 => "P&#46; Guiraud"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "2003"
                        "volumen" => "17"
                        "paginaInicial" => "209"
                        "paginaFinal" => "218"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Potentiation of doxorubicin cardiotoxicity by iron loading in a rodent model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "G&#46;S&#46; Pantjrath"
                            1 => "V&#46; Patel"
                            2 => "N&#46; Valdiviezo Cl Narula"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2007.02.060"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2007"
                        "volumen" => "49"
                        "paginaInicial" => "2457"
                        "paginaFinal" => "2464"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17599610"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "A&#46; Cascales"
                            1 => "B&#46; S&#225;nchez-Vega"
                            2 => "N&#46; Navarro"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2010.09.046"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2012"
                        "volumen" => "154"
                        "paginaInicial" => "282"
                        "paginaFinal" => "286"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20974500"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Energy metabolism in heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Ventura-Clapier"
                            1 => "A&#46; Garnier"
                            2 => "V&#46; Veksler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1113/jphysiol.2003.055095"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Physiol"
                        "fecha" => "2004"
                        "volumen" => "555"
                        "paginaInicial" => "1"
                        "paginaFinal" => "13"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14660709"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "In-vivo and in-vitro mitochondrial membrane damages induced in mice by adriamycin and derivatives"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Praet"
                            1 => "J&#46;M&#46; Ruysschaert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "1993"
                        "volumen" => "1149"
                        "paginaInicial" => "79"
                        "paginaFinal" => "85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8391322"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Doxorubicin-induced cardiac mitochondrionopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46;B&#46; Wallace"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacol Toxicol"
                        "fecha" => "2003"
                        "volumen" => "93"
                        "paginaInicial" => "105"
                        "paginaFinal" => "115"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12969434"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New insights into doxorubicin-induced cardiotoxicity&#58; the critical role of cellular energetics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46; Tokarska-Schlattner"
                            1 => "M&#46; Zaugg"
                            2 => "C&#46; Zuppinger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yjmcc.2006.06.009"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Mol Cell Cardiol"
                        "fecha" => "2006"
                        "volumen" => "41"
                        "paginaInicial" => "389"
                        "paginaFinal" => "405"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16879835"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The sarcomeric cytoskeleton&#58; who picks up the strain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46; Gautel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ceb.2010.12.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Cell Biol"
                        "fecha" => "2011"
                        "volumen" => "23"
                        "paginaInicial" => "39"
                        "paginaFinal" => "46"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21190822"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Truncations of titin causing dilated cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "D&#46;S&#46; Herman"
                            1 => "L&#46; Lam"
                            2 => "M&#46;R&#46; Taylor"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1110186"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2012"
                        "volumen" => "366"
                        "paginaInicial" => "619"
                        "paginaFinal" => "628"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22335739"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetics&#58; broken giant linked to heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;M&#46; McNally"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2012"
                        "volumen" => "14"
                        "paginaInicial" => "281"
                        "paginaFinal" => "282"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "C&#46;C&#46; Lim"
                            1 => "C&#46; Zuppinger"
                            2 => "X&#46; Guo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2004"
                        "volumen" => "27"
                        "paginaInicial" => "8290"
                        "paginaFinal" => "8299"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms of anthracycline cardiac injury&#58; can we identify strategies for cardio-protection"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "D&#46; Sawyer"
                            1 => "X&#46; Peng"
                            2 => "B&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pcad.2010.06.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Prog Cardiovasc Dis"
                        "fecha" => "2010"
                        "volumen" => "53"
                        "paginaInicial" => "105"
                        "paginaFinal" => "113"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20728697"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Disruption of GATA4&#47;Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray&#58; implications for anthracycline cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "B&#46; Chen"
                            1 => "L&#46; Zhong"
                            2 => "S&#46; Roush"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS ONE"
                        "fecha" => "2012"
                        "volumen" => "7"
                        "paginaInicial" => "1"
                        "paginaFinal" => "13"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The association between fatigue and inflammatory marker levels in cancer patients&#58; a quantitative review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "C&#46; Schubert"
                            1 => "S&#46; Hong"
                            2 => "L&#46; Natarajan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbi.2006.11.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Brain Behav Immun"
                        "fecha" => "2007"
                        "volumen" => "21"
                        "paginaInicial" => "413"
                        "paginaFinal" => "427"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17178209"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46; Wong"
                            1 => "L&#46;B&#46; Smith"
                            2 => "E&#46;A&#46; Magun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4161/cbt.22628"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Biol Ther"
                        "fecha" => "2013"
                        "volumen" => "14"
                        "paginaInicial" => "56"
                        "paginaFinal" => "63"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23114643"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Change in TNF-alpha receptor expression is a relevant event in doxorubicin-induced H9c2 cardiomyocyte cell death"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "E&#46; Chiosi"
                            1 => "A&#46; Spina"
                            2 => "A&#46; Sorrentino"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/jir.2006.0161"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Interferon Cytokine Res"
                        "fecha" => "2007"
                        "volumen" => "27"
                        "paginaInicial" => "589"
                        "paginaFinal" => "597"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17651020"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD&#40;P&#41;H&#58;quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;G&#46; Blanco"
                            1 => "W&#46;M&#46; Leisenring"
                            2 => "V&#46;M&#46; Gonz&#225;lez-Covarrubias"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.23534"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "2008"
                        "volumen" => "112"
                        "paginaInicial" => "2789"
                        "paginaFinal" => "2795"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18457324"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NAD&#40;P&#41;H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "L&#46; Wojnowski"
                            1 => "B&#46; Kulle"
                            2 => "M&#46; Schirmer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.105.576850"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2005"
                        "volumen" => "112"
                        "paginaInicial" => "3754"
                        "paginaFinal" => "3762"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16330681"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/14059940/0000008400000003/v1_201408290019/S1405994014000688/v1_201408290019/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "11606"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Art&#237;culos de revisi&#243;n"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/14059940/0000008400000003/v1_201408290019/S1405994014000688/v1_201408290019/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994014000688?idApp=UINPBA00004N"
]

Article information

ISSN: 14059940
Original language: English

DOI:10.1016/j.acmx.2013.08.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	3	0	3
2024 October	65	6	71
2024 September	62	19	81
2024 August	54	11	65
2024 July	44	7	51
2024 June	57	1	58
2024 May	53	11	64
2024 April	55	12	67
2024 March	71	8	79
2024 February	91	10	101
2024 January	90	1	91
2023 December	84	7	91
2023 November	60	11	71
2023 October	53	4	57
2023 September	32	4	36
2023 August	57	4	61
2023 July	34	8	42
2023 June	69	6	75
2023 May	94	19	113
2023 April	109	12	121
2023 March	109	9	118
2023 February	69	9	78
2023 January	61	11	72
2022 December	54	5	59
2022 November	76	16	92
2022 October	52	7	59
2022 September	80	12	92
2022 August	34	8	42
2022 July	45	11	56
2022 June	43	7	50
2022 May	58	9	67
2022 April	37	9	46
2022 March	63	12	75
2022 February	60	5	65
2022 January	87	11	98
2021 December	37	12	49
2021 November	36	12	48
2021 October	52	15	67
2021 September	60	11	71
2021 August	28	10	38
2021 July	22	11	33
2021 June	47	8	55
2021 May	50	13	63
2021 April	95	25	120
2021 March	69	18	87
2021 February	43	9	52
2021 January	39	14	53
2020 December	39	8	47
2020 November	43	9	52
2020 October	35	12	47
2020 September	52	10	62
2020 August	40	11	51
2020 July	41	13	54
2020 June	41	5	46
2020 May	54	6	60
2020 April	24	5	29
2020 March	28	4	32
2020 February	42	10	52
2020 January	34	7	41
2019 December	35	20	55
2019 November	30	23	53
2019 October	31	8	39
2019 September	36	12	48
2019 August	37	5	42
2019 July	33	7	40
2019 June	103	24	127
2019 May	254	56	310
2019 April	101	4	105
2019 March	25	5	30
2019 February	29	12	41
2019 January	19	16	35
2018 December	17	6	23
2018 November	26	7	33
2018 October	67	19	86
2018 September	42	5	47
2018 August	29	3	32
2018 July	17	7	24
2018 June	25	4	29
2018 May	23	6	29
2018 April	34	2	36
2018 March	21	5	26
2018 February	18	0	18
2018 January	22	2	24
2017 December	18	5	23
2017 November	17	2	19
2017 October	20	7	27
2017 September	31	8	39
2017 August	36	7	43
2017 July	24	5	29
2017 June	41	14	55
2017 May	45	7	52
2017 April	43	7	50
2017 March	35	122	157
2017 February	31	8	39
2017 January	55	7	62
2016 December	41	16	57
2016 November	64	9	73
2016 October	95	25	120
2016 September	71	15	86
2016 August	57	11	68
2016 July	34	6	40
2016 June	36	17	53
2016 May	59	20	79
2016 April	48	20	68
2016 March	42	21	63
2016 February	55	36	91
2016 January	36	25	61
2015 December	36	30	66
2015 November	55	34	89
2015 October	33	28	61
2015 September	36	30	66
2015 August	77	16	93
2015 July	70	20	90
2015 June	42	17	59
2015 May	64	32	96
2015 April	28	20	48
2015 March	35	24	59
2015 February	23	17	40
2015 January	40	22	62
2014 December	72	37	109
2014 November	66	32	98
2014 October	45	53	98

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter