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

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
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PMID:Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. 1621 Apr 42

Doxorubicin is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15 mg/kg of doxorubicin once; and 2) in a chronic model, they receive 3 mg/kg weekly for 12 wk. Using echocardiography, we have monitored left ventricular function during treatment in the chronic model and seen the expected development of dilated cardiomyopathy. Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a muscle-specific cDNA microarray. We have identified genes that respond to doxorubicin exposure in both models and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity. These include STARS, a hypertrophy-responsive gene; SNF1-kinase, a potential modulator of ATP levels; and AXUD1, a downstream target of the proapoptotic regulator AXIN1.
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PMID:Transcriptional analysis of doxorubicin-induced cardiotoxicity. 1624 10

The purpose of this study was to investigate the protective effects of Panax ginseng on adriamycin-induced heart failure. Wistar rats were divided into four groups: control, adriamycin, ginseng and adriamycin with ginseng. Adriamycin (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks. Ginseng was administered via an oral feeding tube once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5 week post-treatment period, the hearts of the rats were used to study the synthesis rates of DNA, RNA and protein, myocardial antioxidants and lipid peroxidation. At the end of 3 weeks treatment, heart failure was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid as well as protein synthesis was inhibited, lipid peroxidation was increased and myocardial glutathione peroxidase activity was decreased indicating adriamycin-induced heart failure. In contrast, the administration of ginseng, before and concurrent with adriamycin, significantly attenuated the myocardial effects, lowered the mortality as well as the amount of ascites, increased in myocardial glutathione peroxidase, macromolecular biosynthesis and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. These findings indicated that ginseng may be partially protective against adriamycin-induced heart failure.
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PMID:Panax ginseng reduces adriamycin-induced heart failure in rats. 1637 66

Doxorubicin is a chemotherapeutic agent successfully used in the treatment of a wide range of cancers. However, with cumulative doses, doxorubicin also is known to have cardiotoxic effects, including cardiomyopathy and heart failure. Identification and quantification of myocardial cell damage has been a point of Controversy. We sought to identify these changes by measuring the levels of troponin I both 24 and 48 hr after the administration of doxorubicin as part of an antineoplastic treatment regimen. Thirty-eight patients scheduled to undergo treatment with doxorubicin were screened and approached for enrollment in the study. Thirty-one of them fulfilled all the inclusion criteria and also signed informed consent. All the patients enrolled in the study had blood drawn before the administration of doxorubicin and also 24 and 48 hr later. Electrocardiograms were performed prior to and 48 hr following the administration of chemotherapy. The dose of doxorubicin administered was calculated by the oncologist and ranged from 450 mg/m2-650 mg/m2 (mean 520 mg/m2). Only one patient was found to have en elevation of troponin levels both 24 and 48 hr (2.3 ng/mL and 2.1 ng/mL, respectively) after the administration of the drug. During that time, the patient denied any chest pain, shortness of breath or palpitations. Repeat ECG did not show any changes from the baseline. The remaining participants continued to maintain a troponin level of less than 0.3 ng/mL during the follow-up. In these patients, no electrocardiographic changes were noted in the follow-up ECG compared to the baseline; however, a slight drop in the ejection fraction without any impact on the clinical presentation was recorded. We concluded that the cTnl level does not change after the administration of doxorubicin, and thus cannot be used as a predictor of doxorubicin-induced cardiotoxicity.
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PMID:Troponin I as a marker of doxorubicin induced cardiotoxicity. 1641 82

Doxorubicin-induced heart failure is a rare but serious illness due to the well-known treatment difficulties. Prevention strategies have not demonstrated the expected success and unfortunately, this specific type of heart failure does not respond to the usual medical therapy as other kinds of heart failure. Therefore, surgical procedures may be necessary in some patients. Cardiac transplantation is performed in most cases but it requires the 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, other conservative and surgical treatment concepts were developed during the last years. This review presents the most common procedures and discusses their efficacy as well as their clinical applicability.
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PMID:Doxorubicin in experimental and clinical heart failure. 1690 9

Doxorubicin is one of the most prescribed anticancer drugs, due to its important activity in hematological malignancies as in solid tumors. However, its important cardiac toxicity still limits its long-term use and prevents from reaching optimal benefits. Numerous ways have been proposed to avoid cardiac toxicity, such as protracted infusions or special formulations, development of less cardiotoxic analogues and of cardioprotectors. There is a need for preclinical models able to screen rapidly these various approaches and to provide rational bases for clinical trials. The first model is the long-term rabbit model. Weanling rabbits given weekly injections of doxorubicin for 4 months developed a cardiomyopathy which was obvious from a clinical (cardiac failure) and from a pathological point of view. This model has been widely used afterwards for the discovery of cardioprotective molecules. Models in other animals such as rats or mice were similarly implemented, also with long-term exposures to the drug, resulting in cardiac failure and severe pathological alterations which could be graded for comparison. Starting from the evidence that the damage caused by anthracyclines on cardiomyocytes was immediate after each injection and that the functional efficiency of the myocardium should be affected by the anthracyclines long before the morphological alterations become detectable, we developed a short-term model studying the cardiac performances of isolated perfused hearts of rats that had been treated within 12 days by repetitive administrations of the molecule(s) to be tested. This model appeared easy to implement and provided the data expected from clinical experience: epirubicin appeared less cardiotoxic than doxorubicin; liposomal formulations appeared less cardiotoxic than free drug formulations; dexrazoxane strongly protected against doxorubicin cardiotoxicity. We were then to show that paclitaxel could potentiate doxorubicin cardiotoxicity, but that docetaxel did not so; or that a high dose of dexrazoxane brought significantly higher protection than a conventional dose. Based upon these various contributions, we can encourage the use of the short-term model of isolated perfused rat heart to screen the preclinical cardiotoxicity of anthracycline molecules, formulations and combinations.
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PMID:Preclinical assessment of anthracycline cardiotoxicity in laboratory animals: predictiveness and pitfalls. 1704 47

Doxorubicin (DOX) is a potent antitumor agent for different types of cancer, but the cumulative, dose-related cardiotoxicity limits its clinical use. The incidence of abnormal cardiac function after treatment with DOX appears to increase with time. Therefore, late cardiotoxicity is-especially in young surviving patients-a major concern. The aim of this study was to evaluate in mice whether the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) also protected against DOX-induced cardiotoxicity after a long period of follow-up. Four groups of 6 Balb/c mice were treated weekly during 6 weeks with saline, DOX alone (4 mg/kg i.v.), DOX preceded by monoHER (500 mg/kg i.p.), or DOX preceded by monoHER followed by long-term weekly monoHER injections during the observation period of 6 months. Half of the mice treated with DOX only developed DOX-induced heart failure and died within 6 months of observation. Two mice co-treated with monoHER showed weight loss and shortness of breath, whereas one mouse was found dead in its cage known with weight loss. The group receiving DOX plus long-term repeated doses of monoHER started to lose weight. Five out of six mice in this group developed shortness of breath and died before the end of the study with symptoms of cardiac failure induced by DOX. Statistical comparison of the histological heart damage between the different experimental groups was not possible, because the animals died at different time-points in the observation period and DOX-induced cardiotoxicity progressed with time. Nevertheless, it was clear that the initial cardioprotective effect of monoHER was not prolonged during the half-year observation period. It was even suggested that addition of repeated doses of monoHER tended to aggravate DOX-induced cardiotoxicity. It cannot be excluded that the dose and frequency of monoHER administration is crucial in obtaining an optimal antioxidant activity without a pro-oxidant activity of monoHER.
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PMID:Long-term effects of 7-monohydroxyethylrutoside (monoHER) on DOX-induced cardiotoxicity in mice. 1717 67

We studied structural reorganization of the liver after toxic injury caused by a single injection of doxorubicin in a sublethal dose (10 mg/kg). The morphogenesis of doxorubicin injury to the liver is determined by two main pathogenetic factors: cytotoxic effect of doxorubicin and its metabolites on liver cell populations (primarily hepatocytes) and pronounced hemodynamic disorders in the greater circulation resulting from the development of chronic cardiac insufficiency. Changes in hepatocyte caused by doxorubicin manifest by fatty degeneration in the periportal zones and by pronounced lytic changes in the pericentral zones, most pronounced by day 30 of the experiment. Doxorubicin in the studied dose exhibited no cytostatic effect on the hepatocyte population. Hepatocyte proliferation, observed during the entire experiment, leads to an appreciable increase in their count and liver weight.
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PMID:Structural reorganization of the rat liver under cytotoxic effect of doxorubicin. 1718 Oct 73

We compared three methods: arteriovenous anastomosis, doxorubicin administration, and combination of anastomosis and doxorubicin, with the intention of designing a simple, stable model of chronic heart failure. Twelve dogs were divided into three groups of four. One group received carotid-jugular anastomosis (Ana series), another group received anastomosis and doxorubicin injection (A/D series), and the last group received only doxorubicin (Dox series). Animals were followed for eight weeks. Fifteen different haemodynamic parameters were tracked and compared to baseline values. After eight weeks, diastolic pressure in the right atrium increased from 3.8+/-2.0 mmHg at baseline to 5.3+/-5.9 mmHg in the Ana series, to 6.3+/-3.3 mmHg in the Dox series and to 8.0+/-2.0 mmHg in the A/D series (P<0.05 A/D vs. baseline). Systolic pulmonary wedge pressure increased from 11.6+/-2.0 mmHg at baseline to 15.5+/-3.4 mmHg in the Ana series, 14.0+/-3.7 mmHg in the Dox series and 17.3+/-4.2 mmHg in the A/D series (P = NS vs. baseline). Left ventricular ejection fraction decreased from 53.9+/-10% at baseline to 36.1+/-5.6% in the Ana series (P<0.05 vs. baseline), 31.5+/-5.4% in the Dox series (P<0.05 vs. baseline) and 25.8+/-5.8% in the A/D series (P<0.001 vs. baseline, P<0.05 vs. Ana series and Dox series). In conclusion, eight weeks are not enough to produce stable heart failure using arteriovenous anastomosis alone. Doxorubicin administration alone produces a left ventricular failure. However, a combination of both of these interventions provides a more stable model of right-and left-sided heart failure.
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PMID:Induction of heart failure: haemodynamic comparison of three different canine models. 1723 51

Doxorubicin is a highly effective antineoplastic drug associated with a dose-dependent cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. Gene variants of the superoxide-generating enzyme NAD(P)H oxidase have recently been associated with this phenotype. We investigated the mechanism of this association using lucigenin-enhanced chemiluminescence, spectrophotometry, electrochemical sensor, and electron paramagnetic resonance spectroscopy. Superoxide production was measured in female wild-type and NAD(P)H oxidase-deficient (gp91phox knockout) mice. The magnitude of the increase in superoxide production on the addition of doxorubicin was much higher in hearts of wild-type mice than in enzyme-deficient mice. An increase in superoxide production was observed also on the addition of the NADPH cytochrome P450 reductase. However, doxorubicin reacted with NADPH producing superoxide even in the absence of any enzymatic activity. Taken together, gp91phox-containing NAD(P)H oxidase and NADPH cytochrome P450 reductase can enhance superoxide production caused by the chemical interaction of doxorubicin and NADPH. These findings are in agreement with the recently reported reduced cardiotoxicity following doxorubicin treatment in gp91phox knockout mice and with associations between NAD(P)H oxidase gene variants and sensitivity to doxorubicin.
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PMID:Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH. 1727 78


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