Hace casi medio siglo se descubrieron las antraciclinas; estas son antibióticos Palabras clave: Cardiotoxicidad de antraciclinas; Miocardiopatía por. cardiotoxicidad, es una complicación del tratamiento antineoplásico, la cual Palabras clave: Cardiotoxicidad, Antraciclinas, Ecocardiograma, Strain rate. PURPOSE: We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms’ tumor that included doxorubicin.

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Antrcaiclinas molecular knowledge for the cardiologist. Received April 25, Accepted August 20, Anthracyclines are cytostatic antibiotics discovered almost half a century ago exerting their action carddiotoxicidad 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 anyraciclinas for the cardiologist, highlighting the importance of a cardiotoxicldad knowledge of the main mechanisms inducing this toxicity.

Anthracycline cardiotoxicity; Chemotherapy cardiomyopathy; Doxorubicin cardiomyopathy; Spain. Desafortunadamente, la cardiotoxicidad sigue siendo un elemento limitante para su uso. Anthracyclines are cytostatic antibiotics discovered fardiotoxicidad half a century ago that exert their action through inhibition of topoisomerase II.

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These drugs have been proven as useful antineoplastics and are amongst the most widely prescribed oncologic medication. Recently, groups have been created in Europe and the United States for the study of this toxicity, highlighting its importance.

Chemotherapy-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 cardiotoxicidaad 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. At the same time, the wide difference in the treated populations adults vs.

Nevertheless, recent statistics regarding survival of oncologic patients give us an overview of the problem. 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.

With all the aforementioned, it is not surprising that considerable controversy has risen with respect to the mechanisms ajtraciclinas 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 cardiotoxicivad 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.

We will not review in the present work the rare, but existent, acute presentation of anthracycline toxicity or the involvement of the pericardium. Oxidative 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 cardiottoxicidad 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] 14 compared with other tissues.

The metabolism of anthracyclines involves the reduction of the quinone fraction of its formula to antaciclinas, which can rapidly transfer its unpaired electron to an electron acceptor usually molecular oxygenreturning 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.

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A recent paper by Octavia et al.

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, 5 especially when interventions that resembled the ones used in clinical practice were tested.

Anthracyclines 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, respectively17 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.

All the anthracyclines have shown to have similar mechanisms of bioactivation, making them toxic from the cardiac standpoint, 2 but the role of toxic metabolites has been challenged by the fact that xntraciclinas daunorubicin and idarubicin generate higher plasma levels of alcohol metabolites compared with doxorubicin 15 antraciclias 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 has a major role in cell metabolism and is under control by several regulatory systems. Iron regulatory proteins or IRPs also known as iron responsive element binding proteins cardiotooxicidad important elements in regulating iron metabolism xardiotoxicidad 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 antdaciclinas impairment that may account to a certain degree for myocardial dysfunction, opening new paths towards a better understanding of the role of iron metabolism. Likewise, animal models have shown that iron overload is capable of potentiating doxorubicin cardiotoxicity by mechanisms other than ROS production. The 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.

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. Recently, cadiolipin, a phospholipid of utmost importance in energy metabolism and a component of the inner mitochondrial membrane, cardiotoxicidwd been suggested as having a major role in anthracycline-mediated antracilinas.

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, 15 in fact, the disturbance in mitochondrial permeability has been related cardiogoxicidad a direct opening of the permeability transition pore by substances formed cardiotoxicidae de redox cycling of some anthracyclines and its dysfunction could be an early indicator of doxorubicin-induced apoptosis.

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, 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.

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. Recently, a very interesting work by Chen et al.

In their same study, doxorubicin induced cardiac transcription factor GATA4 GATA Binding Protein 4, thought to regulate antradiclinas involved in myocardial differentiation and function, including CARP depletion, suggesting antraiclinas co-dependent role for both proteins in maintaining sarcomere structure.

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Anthracyclines are capable of promoting proinflammatory cytokines release, which has been related to several manifestations ranging from cardiotoxicity to asthenia experienced by these patients. 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.

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. The 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 2,5 and some groups have investigated the possible relationship between polymorphisms e. VM on the CBR3-carbonyl reductase 3 gene and heart failure related to these drugs. While these observations are promising antraaciclinas provide new insights into different aspects of doxorubicin cardiotoxicity, with the current data, we are not able to define antdaciclinas clear genotype-response correlation and further investigation should try to clarify this and provide more information abtraciclinas the clinical usefulness of genotyping.

With the improvements in atnraciclinas 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, abtraciclinas 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.

Authors do not have any conflict of interests regarding this work. Expert Opin Drug Saf. cardiotoxicirad

Cardiotxoicidad and management of acute myeloid leukemia in children antraciclinaz adolescents: Anthraycline cardiotoxicity from bench to bedside. Congestive heart failure in patients treated with doxorubicin: Role of anthracyclines in the era of targeted therapy. Cardiovascular side effects of cancer therapies: Eur J Heart Fail. American Society of Clinical Oncology: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience.

The Childhood Cancer Survivor Study. CA Cancer J Clin. Pai BP, Nahata M. Cardiotoxicity of chemotherapeutic agents, incidence, treatment and prevention.

Octavia y, Tocchetti C, Gabrielson K, et al. J Mol Cell Cardiol.

Tandara L, Salamunic I. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: Halliwell B, Gutteridge J. Free radicals in biology and medicine. Oxford University Press; Interactions between doxorubicin and the human carviotoxicidad regulatory system. Potentiation of doxorubicin cardiotoxicity by iron loading in a rodent model. J Am Coll Cardiol. Energy metabolism in heart failure. Praet M, Ruysschaert JM. Curr Opin Cell Biol.

Cardiotpxicidad of titin causing dilated cardiomyopathy. N Engl J Med.

[Anthracycline-induced cardiotoxicity: report of fatal cases].

Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. Mechanisms of anthracycline cardiac injury: The association between fatigue and inflammatory marker levels in cancer patients: J Interferon Cytokine Res. Introduction Anthracyclines are cytostatic antibiotics discovered almost half a century ago that antraciclias their action through inhibition of topoisomerase II.

Mechanisms of cardiotoxicity With all the aforementioned, it is not surprising that considerable controversy has risen with respect to the mechanisms involved in this toxicity.

Oxidative stress Oxidative stress is the most widely studied mechanism and it involves a highly complex pathophysiology, which is a matter of permanent debate.

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