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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doxorubicin is one of the most active drugs in oncology, with cardiotoxicity as a serious side effect of its application. The aim of this study was to investigate dexrazoxane and amifostine impact on the evolution of myocardial changes induced by doxorubicin. BalbC female mice were treated with doxorubicin only (10 mg/kg, single intravenous push), or with dexrazoxane (200 mg/kg, intraperitoneal [ip]) or amifostine (200 mg/kg, ip) 60 mins or 30 mins prior to treatment with doxorubicin, respectively. Blood sampling for determination of conventional serum-marker activity was performed 48 hrs later. The grade of histopathology changes was evaluated by light microscopy 1.5 and 3 months after treatments using the Billingham scoring method. Control groups consisted of nontreated mice. After doxorubicin-only treatment, the grade of heart tissue damage was found to increase in the period between 1.5 and 3 months. A similar but less intense progression was also detected in amifostine-pretreated animals, with significant difference among median Billingham scores between the two time points. The pretreatment with dexrazoxane suspended expansion of tissue lesions in time. Changes in serum enzyme activity revealed two correlations: the greater reduction in alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) leakage is associated with a lower percentage of damaged tissue, and the creatine kinase to alpha-HBDH percent of difference ratio being greater than one is correlated with limited spreading of pathological lesions. Our results indicate that the development of doxorubicin-induced heart failure is based on a slow and persistent expansion of pathological process even long after the completion of the treatment. Dexrazoxane has proved to be successful and superior over amifostine against such an evolution of doxorubicin cardiomyopathy.
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PMID:Effects of dexrazoxane and amifostine on evolution of Doxorubicin cardiomyopathy in vivo. 1804 65

Doxorubicin is a widely used antineoplastic agent that may cause irreversible dilated cardiomyopathy. Doxorubicin-induced cardiomyopathy (DIC) can occur several years after exposure and carries a poor prognosis. Although cardiac resynchronization therapy (CRT) is a useful intervention in end-stage heart failure unresponsive to optimal medical therapies, its efficacy in DIC remains unknown. Four consecutive patients receiving CRT for DIC were evaluated before and after CRT. CRT resulted in improvements in the mean left ventricular ejection fraction at 1 month from 21+/-4.7% to 34+/-5% (p=0.03) and at 6 months (to 46+/-7.5%, p=0.01). CRT-induced reverse remodeling was observed, with a mean reduction in left ventricular internal diameter at end-diastole from 54.75+/-3.7 to 52.5+/-1.9 mm at 1 month (p=0.06) and further to 47+/-2.3 mm at 6 months (p=0.03). All patients experienced reductions in heart failure symptoms and improvements in New York Heart Association functional class (p<0.05). The impact of CRT was sustained over a follow-up of 18.5+/-3.5 months. In conclusion, this study suggests that patients with DIC, refractory to optimal pharmacologic therapy and meeting criteria for resynchronization device implantation, may achieve sustained benefit from CRT.
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PMID:Usefulness of cardiac resynchronization therapy in the management of Doxorubicin-induced cardiomyopathy. 1843 75

Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.
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PMID:A mouse model for juvenile doxorubicin-induced cardiac dysfunction. 1861 63

Effectiveness and informativity of various experimental pharmacological models of the chronic heart failure (CCF) in rats have been evaluated by means of ultrasonic cardiography. It has been established that isoproterenol (INN isoprenaline) (80 mg/kg, s.c., twice with an interval of 24 h) produces compensated CCF. Monocrotaline (single dose 60 mg/kg, i.p.) caused the development of pulmonary hypertension, right ventricle hypertrophy, and pronounced right ventricle failure in a fraction of experimental rats. Doxorubicin administration (cumulative doze 15 mg/kg, i.p., divided into 6 injections within 14 days) resulted in decreased left ventricle contractility, eccentric heart remodeling, and CCF development in most cases. Thus, the doxorubicin-induced disorder in rats can be considered the most effective pharmacological model of CCF, leading to the development of pronounced and progressive CCF in the majority of experimental animals.
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PMID:[Comparative characteristics of some pharmacological models of chronic heart failure]. 1914 May 9

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. DOX-induced heart failure is thought to be caused by reduction/oxidation cycling of DOX to generate oxidative stress and cardiomyocyte cell death. Resveratrol (RV), a stilbene found in red wine, has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to test the ability of RV to protect against DOX-induced cardiomyocyte death. We hypothesized that RV protects cardiomyocytes from DOX-induced oxidative stress and subsequent cell death through changes in mitochondrial function. DOX induced a rapid increase in reactive oxygen species (ROS) production in cardiac cell mitochondria, which was inhibited by pretreatment with RV, most likely owing to an increase in MnSOD activity. This effect of RV caused additional polarization of the mitochondria in the absence and presence of DOX to increase mitochondrial function. RV pretreatment also prevented DOX-induced cardiomyocyte death. The protective ability of RV against DOX was abolished when Sirt1 was inhibited by nicotinamide. Our data suggest that RV protects against DOX-induced oxidative stress through changes in mitochondrial function, specifically the Sirt1 pathway leading to cardiac cell survival.
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PMID:Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. 1930 34

Doxorubicin (DOX) is a highly effective antineoplastic drug. However, DOX-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy and heart failure, which limits DOX clinical application. Leonurine is a special alkaloid for Herba leonuri, a traditional herb with cardioprotective effects. In current study, we investigated possible protective effects of Leonurine against DOX-induced cardiomyopathy in H9c2 cells. DOX-injured H9c2 cell model was made by application of 2 microM DOX. Leonurine was added to cells 2 h before DOX treatment. Pre-treated with Leonurine could attenuate DOX-induced apoptotic death of H9c2 cell, reduce MDA formation and intracellular Ca2+ overload. Leonurine also attenuated DOX-induced high expression of Bax, increased Bcl-2 expression in both protein and mRNA level. Myocardial mitochondrion is the target organelle of DOX-induced toxicity in cardiomyocytes. Leonurine moderated the dissipation of mitochondrial membrane potential (DeltaPsim) caused by DOX treatment. Our results indicated that Leonurine attenuated DOX-induced apoptosis in H9c2 cell by increasing anti-oxidant, anti-apoptotic ability and protecting mitochondrial function.
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PMID:Herba leonurine attenuates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells. 1935 31

Doxorubicin (DOX) is a potent anti-tumor drug known to cause heart failure. The transcription factor GATA4 antagonizes DOX-induced cardiotoxicity. However, the protective mechanism remains obscure. Autophagy is the primary cellular pathway for lysosomal degradation of long-lived proteins and organelles, and its activation could be either protective or detrimental depending on specific pathophysiological conditions. Here we investigated the ability of GATA4 to inhibit autophagy as a potential mechanism underlying its protection against DOX toxicity in cultured neonatal rat cardiomyocytes. DOX markedly increased autophagic flux in cardiomyocytes as indicated by the difference in protein levels of LC3-II (microtubule-associated protein light chain 3 form 2) or numbers of autophagic vacuoles in the absence and presence of the lysosomal inhibitor bafilomycin A1. DOX-induced cardiomyocyte death determined by multiple assays was aggravated by a drug or genetic approach that activates autophagy, but it was attenuated by manipulations that inhibit autophagy, suggesting that autophagy contributes to DOX cardiotoxicity. DOX treatment depleted GATA4 protein levels, which predisposed cardiomyocytes to DOX toxicity. Indeed, GATA4 gene silencing triggered autophagy that rendered DOX more toxic, whereas GATA4 overexpression inhibited DOX-induced autophagy, reducing cardiomyocyte death. Mechanistically, GATA4 up-regulated gene expression of the survival factor Bcl2 and suppressed DOX-induced activation of autophagy-related genes, which may likely be responsible for the anti-apoptotic and anti-autophagic effects of GATA4. Together, these findings suggest that activation of autophagy mediates DOX cardiotoxicity, and preservation of GATA4 attenuates DOX cardiotoxicity by inhibiting autophagy through modulation of the expression of Bcl2 and autophagy-related genes.
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PMID:Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. 1990 Oct 28

Doxorubicin-induced heart failure is a rare, but serious illness and is well-known to be difficult to treat. Prevention strategies have not demonstrated the expected success and unfortunately, this specific type of heart failure does not respond to the usual medical therapies as do other kinds of heart failure. Therefore, surgical procedures may be necessary in some patients. Cardiac transplantation is performed in most cases but this requires cure of the neoplastic disease. This usually requires a recurrence-free interval of several years which is associated with a high attrition rate in these patients due to their cardiac disease. Therefore, ventricular assist devices may be implanted in selected patients as a bridge to transplantation or destination therapy. This review focuses on the surgical options for doxorubicin-induced heart failure and discusses their efficacy as well as their clinical applicability.
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PMID:Surgical treatment of doxorubicin-induced heart failure. 2007 69

Doxorubicin (Adriamycin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is restricted by a cumulative and progressive cardiomyopathy that develops with repeated dosing. Fundamental to the cardiac failure is an interference with mitochondrial respiration and inhibition of oxidative phosphorylation. Global gene expression arrays in cardiac tissue indicate that inhibition of mitochondrial oxidative phosphorylation by doxorubicin (DOX) is accompanied by a decreased expression of genes related to aerobic fatty acid oxidation and a corresponding increase in expression of genes involved in anaerobic glycolysis, possibly as an alternate source for ATP production. The aim of this investigation was to determine whether this is also manifest at the metabonomic level as a switch in metabolic flux in cardiac tissue, and whether this can be averted by co-administering the cardioprotective drug, dexrazoxane (DZR). (13)C-isotopomer analysis of isolated perfused hearts from male Sprague-Dawley rats receiving 6 weekly s.c. injections of 2mg/kg DOX demonstrated a shift from the preferential oxidation of fatty acids to enhanced oxidation of glucose and lactate plus pyruvate, indicative of a compensatory shift towards increased pyruvate dehydrogenase activity. Substrate-selective isotopomer analysis combined with western blots indicate an inhibition of long-chain fatty acid oxidation and not MCAD activity or fatty acyl-carnitine transport. Co-administering DZR averted many treatment-related changes in cardiac substrate metabolism, consistent with DZR being an effective cardioprotective agent against DOX-induced cardiomyopathy. This switch in substrate metabolism resembles that described for other models of cardiac failure; accordingly, this change in metabolic flux may represent a general compensatory response of cardiac tissue to imbalances in bioenergetic demand and supply, and not a characteristic unique to DOX-induced cardiac failure itself.
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PMID:Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. 2013 57

This study was designed to assess the effects of dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) from fish oil on the response of doxorubicin-induced chronic heart failure in rats. Male Sprague-Dawley rats were treated daily for 8 weeks with normal saline or n-3 PUFA intragastrically after induction of myocardial injury by intraperitoneal injection of doxorubicin 2 mg/kg once weekly for 8 weeks. Cardiac function was assessed by echocardiography. The cytoprotective role of n-3 PUFA against doxorubicin-induced myocardial injury was demonstrated by light microscopy, and serum cytokines (tumour necrosis factor-alpha and interleukin-10) were analysed by enzyme-linked immunosorbent assay. Doxorubicin induced death, alterations in echocardiography parameters and histological damage, all of which are features that characterize heart failure. There were significant differences between the doxorubicin-induced heart failure group and the n-3 PUFA-treated group in terms of echocardiography parameters and cytokine changes. Thus, dietary supplementation with n-3 PUFA attenuated doxorubicin-induced cardiac dysfunction, an effect that might be associated with recovery from an imbalance of the cytokine network.
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PMID:The beneficial effect of n-3 polyunsaturated fatty acids on doxorubicin-induced chronic heart failure in rats. 2081 30


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