Gene/Protein Disease Symptom Drug Enzyme Compound
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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 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

Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.
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PMID:Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. 1765 6

Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel two-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240 to 260 g) received doxorubicin 2.5 mg/k i.v. per wk for 10 (n=4) or 12 wk (n=10); 17 controls received saline (10 wk, n=7 and 12 wk, n=10). Serial 2DSE from 0 to 12 wk was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the two-dimensional (2D) image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 wk: 26.7+/-3 versus 38.3+/-2.6%, p=0.006), with significant difference by 8 wk whereas fractional shortening was lower with doxorubicin only after 12 wk (30.2+/-1.7 versus 37.6+/-1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85+/-0.09 versus 1.14+/-0.04 g, p=0.001), higher caspase-3 activity (1.95+/-0.2 fold increase over control, p<0.0001) and fibrosis (3.9 +/- 0.7 versus 0.7+/-0.1%, p=0.005). Radial strain was related directly to cardiac mass (r=0.61, p=0.0007) and inversely to caspase-3 activity (r= -0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.
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PMID:Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. 1793 67

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.
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PMID:The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. 1797 86


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