Doxorubicin-induced Heart Failure Research Articles

Intramyocardial injection of SERCA2a-expressing lentivirus improves myocardial function in doxorubicin-induced heart failure.

Doxorubicin is an effective anticancer drug. The major limitation to its use is the induction of dose-dependent cardiomyopathy. No specific treatment exists for doxorubicin-induced cardiomyopathy and treatments used for other forms of heart failure have only limited beneficial effects. The contraction-relaxation cycle of the heart is controlled by cytosolic calcium concentrations, which, in turn, are critically regulated by the activity of the sarcoplasmic reticulum Ca(2) (+) ATPase (SERCA2a) pump. We hypothesized that SERCA2a gene transfer would ameliorate doxorubicin-induced cardiomyopathy. Lentiviral vectors LV-SERCA2a-GFP and LV-GFP were constructed and in vitro gene transfer of LV-SERCA2a-GFP confirmed SERCA2a expression by western blot analysis. Heart failure was induced by giving a single intraperitoneal injection of doxorubicin. LV-SERCA2a-GFP, LV-GFP vectors and phosphate-buffered saline (PBS) were injected under echocardiographic control to the anterior wall of the left ventricle. Echocardiography analyses were performed on the injection day and 28 days postinjection. On the injection day, there were no significant differences in the average ejection fractions (EFs) among SERCA2a (40.0%), GFP (41.1%) and PBS (39.4%) injected animals. On day 28, EF in the SERCA2a group had increased by 16.6 ± 6.7% to 46.4 ± 2.1%. By contrast, EFs in the GFP (40.2 ± 1.3%) and PBS (40.6 ± 1.4%) groups remained at pre-injection levels. In addition, end systolic and end diastolic left ventricle volumes were significantly smaller in the SERCA2a group compared to controls. SERCA2a gene transfer significantly improves left ventricle function and dimensions in doxorubicin-induced cardiomyopathy, thus making LV-SERCA2a gene transfer an attractive treatment modality for doxorubicin-induced heart failure. Copyright © 2016 John Wiley & Sons, Ltd.

Doxorubicin may damage cardiomyocytes more than cardiac progenitor cells

Long term survival of childhood cancers is now more than 70%. Unfortunately, adult survivors of childhood cancer are at risk for treatment‐related adverse health outcomes. Survivors with a median time from diagnosis of 25 years found 56% had cardiac dysfunction. Analysis of heart transplantation patients found doxorubicin as the underlying cause in 2–3% of all cases. Doxorubicin is a topoisomerase poison that accumulates in the nucleus and the mitochondria. Doxorubicin impacts heavily on the mitochondria as significant mtDNA depletion and mtDNA rearrangements have been reported. Unfortunately nearly all preclinical studies have only determined short effects. Very few studies have examined the long term effects of doxorubicin or used doses that were comparable to clinical treatment protocols. We have developed a murine model for late onset doxorubicin induced heart failure in which the onset was delayed and mimicked that seen clinically (~18 human years). Doxorubicin was injected (1–45 mg/kg, i.p.) at 3 weeks of age. We observed no change in cardiovascular function 2–4 months post‐injection, but a significant decrease in ejection shortening was observed after 6–8 months post‐injection. Low doses of doxorubicin (1–15 mg/kg) did not significantly alter cardiovascular function even out to 16 months post injection. Using flow cytometry we examined cell populations from the left ventricle, circulating non‐RBC cells, and bone marrow. Despite degradation of cardiovascular function we observed significant increases (p<.05) in c‐kit+, SSEA1+, and Nkx2.5+ cells within the heart. In contrast, significant decreases of the c‐kit+, SSEA1+ cells were found in the circulating cells, while no changes were observed in the cell populations from the bone marrow compartment. We assessed mtDNA damage and observed significant increases in mtDNA damage in the ventricular cells and but not ventricular c‐kit+ cells. In cultured neonatal cardiomyocytes, doxorubicin increased mtDNA damage and promoted cell death below the threshold that significantly increase intramitochondrial superoxide levels. Measuring mitochondrial topoisomerase function we observed that H2O2 significantly increased DNA relaxation of supercoiled DNA suggesting that low levels of ROS alter mitochondrial topoisomerase function to promote DNA strand breakage. These findings suggest the heart attempted to regenerate by increased replacement of healthy cardiac progenitor cells but that degradation cardiomyocytes may have been the underlying cause of cardiovascular dysfunction. This suggests that the ability of the heart to direct self repair may be limited and that although the stem cell compartment attempted to compensate for cardiomyocyte loss, the degradation of cardiac function indicated that it was not successful.Support or Funding InformationSupported in part by NIH RO3HD065551

Abstract 166: Qiliqiangxin Attenuates Doxorubicin-induced Cardiomyopathy via Regulating Autophagy

Aims: Doxorubicin-induced cardiomyopathy, as a common complication of cancer chemotherapy, greatly limits the clinical implication of doxorubicin in the treatment of cancer. Our previous clinical trial and animal studies have shown that Qiliqiangxin, a traditional Chinese medication, was protective for adverse cardiac remodeling. This study aimed at determine the therapeutic effect of Qiliqiangxin in mouse doxorubicin-induced cardiomyopathy. Methods and results: Three groups of mice (control, n=6; doxorubicin+saline, n=7; doxorubicin+Qiliqiangxin, n=7) were followed up for 4 weeks. Echocardiography was taken at the end of 4 weeks to evaluate cardiac function. Mice from the doxorubicin+saline group showed reduced ejection fraction (EF) and fractional shortening (FS) as compared with the mice from the control group. Qiliqiangxin could partly restore the reduction of EF and FS in doxorubicin-induced cardiomyopathy mice. Genes related with autophagosome formation (becline1, ATG4, ATG7, LC3) and autophagosome-lysosome fusion (Cathepsin B, Cathepsin D, Cathepsin L) were determined by quantitative reverse transcription polymerase chain reactions (RT-PCRs) in heart samples from mice of the three groups (control, doxorubicin+saline, doxorubicin+Qiliqiangxin) at the end of 4 weeks. All these 7 genes were found to be increased in doxorubicin-induced cardiomyopathy mice, implying doxorubicin may disturb the autophagy flux of mice hearts through promoting autophagosome formation and inhibiting autophagosome-lysosome fusion. Interestingly, the expression of these 7 genes were decreased in the doxorubicin+Qiliqiangxin group, implying that Qiliqiangxin may protect the cardiac function in doxorubicin-treated mice through regulating the autophagy flux of mice hearts. Moreover, autophagy-related proteins LC3 and P62 were determined by western blotting. Qiliqiangxin reversed the increase of LC3II level and the decrease of P62 level in the doxorubicin-treated mice hearts. Conclusion: Qiliqiangxin may protect the cardiac function of doxorubicin-induced heart failure mice through regulating autophagy in the heart. Qiliqiangxin might be a novel drug for doxorubicin-induced cardiomyopathy.

Notch-1 mediated cardiac protection following embryonic and induced pluripotent stem cell transplantation in doxorubicin-induced heart failure.

Doxorubicin (DOX), an effective chemotherapeutic drug used in the treatment of various cancers, is limited in its clinical applications due to cardiotoxicity. Recent studies suggest that transplanted adult stem cells inhibit DOX-induced cardiotoxicity. However, the effects of transplanted embryonic stem (ES) and induced pluripotent stem (iPS) cells are completely unknown in DOX-induced left ventricular dysfunction following myocardial infarction (MI). In brief, C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were injected with cumulative dose of 12 mg/kg of DOX and 2 weeks later, MI was induced by coronary artery ligation. Following ligation, 5×104 ES or iPS cells were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice were sacrificed, and hearts were harvested for further analyses. Our data reveal apoptosis was significantly inhibited in ES and iPS cell transplanted hearts compared with respective controls (DOX-MI+ES: 0.48±0.06% and DOX-MI+iPS: 0.33±0.05% vs. DOX-MI: 1.04±0.07% and DOX-MI+CC: 0.96±0.21%; p<0.05). Furthermore, a significant increase in levels of Notch-1 (p<0.05), Hes1 (p<0.05), and pAkt (p<0.05) were observed whereas a decrease in the levels of PTEN (p<0.05), a negative regulator of Akt, was evident following stem cell transplantation. Moreover, hearts transplanted with stem cells demonstrated decreased vascular and interstitial fibrosis (p<0.05) as well as MMP-9 expression (p<0.01) compared with controls. Additionally, heart function was significantly improved (p<0.05) in both cell-transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the Notch pathway.

Zebrafish heart failure models for the evaluation of chemical probes and drugs.

Heart failure is a complex disease that involves genetic, environmental, and physiological factors. As a result, current medication and treatment for heart failure produces limited efficacy, and better medication is in demand. Although mammalian models exist, simple and low-cost models will be more beneficial for drug discovery and mechanistic studies of heart failure. We previously reported that aristolochic acid (AA) caused cardiac defects in zebrafish embryos that resemble heart failure. Here, we showed that cardiac troponin T and atrial natriuretic peptide were expressed at significantly higher levels in AA-treated embryos, presumably due to cardiac hypertrophy. In addition, several human heart failure drugs could moderately attenuate the AA-induced heart failure by 10%-40%, further verifying the model for drug discovery. We then developed a drug screening assay using the AA-treated zebrafish embryos and identified three compounds. Mitogen-activated protein kinase kinase inhibitor (MEK-I), an inhibitor for the MEK-1/2 known to be involved in cardiac hypertrophy and heart failure, showed nearly 60% heart failure attenuation. C25, a chalcone derivative, and A11, a phenolic compound, showed around 80% and 90% attenuation, respectively. Time course experiments revealed that, to obtain 50% efficacy, these compounds were required within different hours of AA treatment. Furthermore, quantitative polymerase chain reaction showed that C25, not MEK-I or A11, strongly suppressed inflammation. Finally, C25 and MEK-I, but not A11, could also rescue the doxorubicin-induced heart failure in zebrafish embryos. In summary, we have established two tractable heart failure models for drug discovery and three potential drugs have been identified that seem to attenuate heart failure by different mechanisms.

Cardiac overexpression of Translationally Controlled Tumor Protein (TCTP) prevents the development of doxorubicin-induced heart failure

Cardiac overexpression of Translationally Controlled Tumor Protein (TCTP) prevents the development of doxorubicin-induced heart failure

Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology

IntroductionNanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery.Aims and objectivesThe aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells.Material and methodsWe performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180–200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested.ResultsWe designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both).ConclusionsGold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.

Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection

Despite of its known cardiotoxicity, doxorubicin is still a highly effective anti-neoplastic agent in the treatment of several cancers. In the present study, the cardioprotective effect of nicorandil was investigated on hemodynamic alterations and mitochondrial dysfunction induced by cumulative administration of doxorubicin in rats. Doxorubicin was injected i.p. over 2 weeks to obtain a cumulative dose of 18mg/kg. Nicorandil (3mg/kg/day) was given orally with or without doxorubicin treatment. Heart rate and aortic blood flow were recorded 24h after receiving the last dose of doxorubicin. Rats were then sacrificed and hearts were rapidly excised for estimation of caspase-3 activity, phosphocreatine and adenine nucleotides contents in addition to cytochrome c, Bcl2, Bax and caspase 3 expression. Moreover, mitochondrial oxidative phosphorylation capacity, creatine kinase activity and oxidative stress markers were measured together with the examination of DNA fragmentation and ultrastructural changes. Nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotides contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection via inhibition of apoptotic signaling pathway, DNA fragmentation and mitochondrial ultrastructural changes. Interestingly, nicorandil did not interfere with cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. In conclusion, nicorandil was effective against the development of doxorubicin-induced heart failure in rats as indicated by improvement of hemodynamic perturbations, mitochondrial dysfunction and ultrastructural changes without affecting its antitumor activity.

Higenamine Combined with [6]-Gingerol Suppresses Doxorubicin-Triggered Oxidative Stress and Apoptosis in Cardiomyocytes via Upregulation of PI3K/Akt Pathway

Sini decoction is a well-known formula of traditional Chinese medicine, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that Sini decoction prevented doxorubicin-induced heart failure in vivo. However, its active components are still unclear. Thus, we investigated the active components of Sini decoction and their cardioprotective mechanisms in the in vitro neonatal rat cardiomyocytes and H9c2 cell line models of doxorubicin-induced cytotoxicity. Our results demonstrated that treatment with higenamine or [6]-gingerol increased viability of doxorubicine-injured cardiomyocytes. Moreover, combined use of higenamine and [6]-gingerol exerted more profound protective effects than either drug as a single agent, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. In addition, we found that treatment with doxorubicin reduced SOD activity, increased ROS generation, enhanced MDA formation, induced release of LDH, and triggered the intrinsic mitochondria-dependent apoptotic pathway in cardiomyocytes, which was inhibited by cotreatment of higenamine and [6]-gingerol. Most importantly, the cytoprotection of higenamine plus [6]-gingerol could be abrogated by LY294002, a PI3K inhibitor. In conclusion, combination of higenamine and [6]-gingerol exerts cardioprotective effect against doxorubicin-induced cardiotoxicity through activating the PI3K/Akt signaling pathway. Higenamine and [6]-gingerol may be the active components of Sini decoction.

Arginase is Critically Involved in Human Heart Failure and Its Blockade Retards the Development of Doxorubicin-induced Heart Failure in Mice

Arginase is Critically Involved in Human Heart Failure and Its Blockade Retards the Development of Doxorubicin-induced Heart Failure in Mice

HSF-1 Deletion Induces Multidrug Resistance (MDR1) Gene Expression in the Heart and Reduces Doxorubicin-induced Heart Failure

HSF-1 Deletion Induces Multidrug Resistance (MDR1) Gene Expression in the Heart and Reduces Doxorubicin-induced Heart Failure

Erythropoietin protects against doxorubicin-induced heart failure

The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 ± 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 μM for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented AD-induced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis.

Regulation of Kinase Cascade Activation and Heat Shock Protein Expression by Poly(ADP-ribose) Polymerase Inhibition in Doxorubicin-induced Heart Failure

Cardiomyopathy is one of the most severe side effects of the chemotherapeutic agent doxorubicin (DOX). The formation of reactive oxygen species plays a critical role in the development of cardiomyopathies, and the pathophysiological cascade activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), and kinase pathways. We characterized the effects of the PARP-inhibitor and kinase-modulator compound L-2286 in DOX-induced cardiac injury models. We studied the effect of the established superoxide dismutase-mimic Tempol and compared the effects of this agent with those of the PARP inhibitor. In the rat H9C2 cardiomyocytes, in which DOX-induced poly(ADP-ribosyl)ation, L-2286 protected them from the DOX-induced injury in a concentration-dependent manner. In the in vivo studies, mice were pretreated (for 1 week) with L-2286 or Tempol before the DOX treatment. Both the agents improved the activation of cytoprotective kinases, Akt, phospho-specific protein kinase C &epsiv;, ζ/λ and suppressed the activity of cell death promoting kinases glycogen synthase kinase-3β, JNK, and p38 mitogen-activated protein kinase, but the effect of PARP inhibitor was more pronounced and improved the survival as well. L-2286 activated the phosphorylation of proapoptotic transcription factor FKHR1 and promoted the expression of Hsp72 and Hsp90. These data suggest that the mode of the cytoprotective action of the PARP inhibitor may include the modulation of kinase pathways and heat shock protein expression.

Testosterone modulation of cardiac β-adrenergic signals in a rat model of heart failure

In this study, we examined the effects of castration and testosterone replacement on β-adrenoceptor and G protein expression in rats subjected to doxorubicin-induced heart failure. Five groups were included in this report: control, sham-castration with heart failure, castration with heart failure, castration+testosterone replacement with heart failure and castration+testosterone replacement and flutamide with heart failure. At 4 weeks post-treatment, echocardiography, hemodynamics and histopathology were assessed. Castration led to a further deterioration in myocardial performance, apoptosis and fibrosis, while testosterone replacement ameliorated these effects. Data obtained from Western blots revealed that testosterone upregulated the expression of β2-adrenoceptor, Gs, Gi2 and bcl2 levels, downregulated the expression of β3-adrenoceptor, Gi3 and GRK2 levels, and did not modify the expression of β1-adrenoceptor levels in the hearts of castrated rats subjected to doxorubicin-induced heart failure. Analyses of serum 17β-estradiol concentrations test confirmed that these effects of testosterone were exerted through the androgen pathway. Thus our findings suggest that testosterone may have beneficial effects for male heart failure patients with androgen deficiency and this protection involves modulation of the cardiac β-adrenergic system.

Fighting doxorubicin-induced cardiotoxicity with adiponectin

This editorial refers to ‘Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation’ by M. Konishi et al. , pp. 309–319, this issue. Doxorubicin, an anthracycline drug widely used for the treatment of various solid-organ tumours and haematological malignancies, has significant cardiac toxicity that limits its utilization. Doxorubicin can cause both an acute and a chronic form of cardiotoxicity and heart failure. Chronic cardiotoxicity, which ranges from an incidence of ∼1% at a cumulative dose of 550 mg/m2 to >30% at cumulative doses above 560–1160 mg/m2, can occur at any time after initiation of treatment and even years after cessation of therapy.1 The clinical presentation is that of classic progressive idiopathic heart failure, with histological evidence of cardiac damage defined by swelling of the sarcoplasmic reticulum and myofibrillar loss. However, the occurrence of doxorubicin-induced cardiotoxicity can vary widely regardless of cumulative drug dosage, and the assessment of parameters that modify risk is of great interest. Doxorubicin-induced cardiotoxicity and heart failure can also be induced in mice, presenting a model system to identify the mechanisms by which doxorubicin-induced heart failure occurs and to test therapeutic approaches by which this toxicity may be prevented. Despite the availability of model systems, the anti-neoplastic and cardiotoxic mechanisms of doxorubicin are not entirely clear. Doxorubicin is reduced by NADPH oxidase2 to a semi-quinone free radical that can, in the presence of iron, interact with oxygen to …

Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation

Doxorubicin-based chemotherapy is limited by the development of dose-dependent left ventricular dysfunction and congestive heart failure caused by reactive oxygen species (ROS). Uncoupling proteins (UCP) can inhibit mitochondrial ROS production as well as decrease myocyte damage from exogenous ROS. Prior studies have shown that cardiac UCP2 and UCP3 mRNA expression is decreased with acute doxorubicin treatment. However, the expression of UCP protein in hearts with doxorubicin cardiotoxicity and the resultant changes in mitochondrial function and oxidant stress have not been determined. Heart failure was induced in Sprague-Dawley rats with intraperitoneal injections of doxorubicin (2 mg/kg t.i.w., total dose: 18 mg/kg). Mitochondria were isolated from mice receiving doxorubicin or saline injections for determination of UCP2 and UCP3 expression. In addition, mitochondrial respiration, ATP synthesis and ROS production were determined. Doxorubicin-induced heart failure was associated with significant decreases in UCP2 and UCP3 protein expression compared with nonfailing hearts (P < 0.05). While the rates of state 3 and state 4 respiration and ATP synthesis were lower in mitochondria isolated from failing hearts, the respiratory control ratio was 15% higher (P < 0.05), and the ratio of ATP production to oxygen consumption was 25% higher (P < 0.05) in mitochondria from failing hearts, indicating greater coupling between citric acid cycle flux and mitochondrial ATP synthesis. However, the decrease in UCP expression was associated with 50% greater mitochondrial ROS generation (P < 0.05). Downregulation of myocardial UCP2 and UCP3 in the setting of doxorubicin-induced heart failure is associated with improved efficiency of ATP synthesis, which might compensate for abnormal energy metabolism. However, this beneficial effect is counterbalanced by greater oxidant stress.

The Beneficial Effect of n-3 Polyunsaturated Fatty Acids on Doxorubicin-induced Chronic Heart Failure in Rats

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.

Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice

Treating cancer patients with chemotherapeutics, such as doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure because of oxidative stress. On the other hand, heat shock factor-1 (HSF-1), a transcription factor for heat shock proteins (Hsps), is also known to be activated in response to oxidative stress. However, the possible role of HSF-1 activation and the resultant Hsp25 in chemotherapeutic-induced heart failure has not been investigated. Using HSF-1 wild-type (HSF-1(+/+)) and knock-out (HSF-1(-/-)) mice, we tested the hypothesis that activation of HSF-1 plays a role in the development of Dox-induced heart failure. Higher levels of Hsp25 and its phosphorylated forms were found in the failing hearts of Dox-treated HSF-1(+/+) mice. More than twofold increase in Hsp25 mRNA level was found in Dox-treated hearts. Proteomic analysis showed that there is accumulation and aggregation of Hsp25 in Dox-treated failing hearts. Additionally, Hsp25 was found to coimmunoprecipitate with p53 and vice versa. Further studies indicated that the Dox-induced higher levels of Hsp25 transactivated p53 leading to higher levels of the pro-apoptotic protein Bax, but other p53-related proteins remained unaltered. Moreover, HSF-1(-/-) mice showed significantly reduced Dox-induced heart failure and higher survival rate, and there was no change in Bax upon treating with Dox in HSF-1(-/-) mice. From these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 because of oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.

Surgical Treatment of Doxorubicin-Induced Heart Failure

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.

Exercise training in doxorubicin-induced heart failure: effects on the L-arginine–NO pathway and vascular reactivity

Heart failure (HF) is the end-stage of cardiovascular disease and is associated with a high incidence of thrombotic events. Nitric oxide (NO) mediates vasodilation and prevents platelet activation, providing an important antithrombotic effect. The aim of this study was to investigate the effects of aerobic training on survival, platelet L-arginine–NO pathway, and vasodilator properties in doxorubicin (DOX)-induced HF. Sprague Dawley rats were randomly assigned to saline/sedentary (SAL/SED), saline/exercise (SAL/EX), DOX/sedentary (DOX/SED), and DOX/exercise (DOX/EX) groups. Four weeks after intraperitoneal DOX injection (1 mg/kg -1/d -1; 10 days), shortening fraction in DOX/SED and DOX/EX was significantly reduced. Treadmill exercise was performed during 6 weeks, 5 days/week -1, 30 minutes/day -1, 50% to 60% of maximum velocity. Survival was higher in DOX/EX (67%) than DOX/SED (33%). No differences were observed in intraplatelet L-arginine transport assessed by incubation with L- [ 3H]-arginine, nor in NOS activity measured by the conversion of L- [ 3H]-arginine into L- [ 3H]-citrulline among the groups. Vasodilation response to acetylcholine was impaired in DOX/SED and DOX/EX; in nitroglycerine, it was limited to DOX/SED. Aerobic training reduced mortality in DOX-induced HF animals and restored vascular smooth muscle relaxation properties. However, it did not ameliorate intraplatelet NO bioavailability and endothelial function during the period studied.