Late Cardiotoxicity Research Articles

Chemotherapy-induced cardiomyopathy in breast cancer patients.

Dear Editor The globally increasing incidence of cancer and its associated mortality has become a main challenge for humankind. This problem is more serious in developing countries, like Iran. Among different malignancies affecting people, breast cancer continues to be a main and worldwide cause of morbidity and mortality (1). Parallel to the increasing cancer burden in the modern world, there have been notable progresses in the management and therapy (either medical or nonmedical) of malignancies including breast cancer, leading to a significant increase in the number of survived patients. This necessitates a close follow-up of such patients after their initial management (2). Patients with cancer face daily problems, some of which are difficult to overcome. Among these are possible complications associated with their chemotherapeutic regimens, particularly cardiovascular issues (3). Cardiotoxic nature of drugs used for the management of patients with cancer puts them at risk of numerous life-threatening cardiovascular events, like pericarditis, cardiomyopathy, cardiac arrhythmias, myocardial ischemia, and some others. Factors including cumulative drug doses, mediastinal radiation, rate of drug administration, younger age, advanced age, female gender, hypertension, and preexisting heart diseases are the recognized risk factors for developing early (within one year, but not acute) and late chemotherapy-induced cardiotoxicity (Table 1) (4). Table 1. Cardiac Review and Evaluation Committee Diagnostic Criteria for Drug-Associated Cardiotoxicity (3) a A wide variety of chemotherapeutic drugs can cause cardiotoxicity, among which anthracyclines, a main drug class used for patients with breast cancer, are one of the most common etiologies (5). Doxorubicin, a main member of this group, can lead to dose-dependent, irreversible and recurrent cardiotoxicity. It can cause myocardial damage through disorganization of myofibrillar morphology, necrosis and interstitial fibrosis (6). The other instance is Trastuzumab, a monoclonal antibody which inhibits growth of tumor cells that overexpress human epidermal growth factor 2 protein. This medication can cause reversible cardiac side effects regardless of the administration dosage, and with low possibility of recurrence (7). Some points were suggested to be beneficial in reducing the risk of cardiotoxicity following chemotherapy. Among these are decreasing the cumulative doses of anthracyclines, administration of anthracyclines as infusion (rather than bolus), and the liposomal encapsulation of doxorubicin. Using β receptor blockers (like carvedilol or metoprolol), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and using nutritional supplements (antioxidants like vitamin E) are the other recommendations (4, 8). Access to cancer medicine is of great importance for patients, also their follow-up for early detection of chemotherapy-induced cardiotoxicity is important. At present, different methods including measurement of left ventricular ejection fraction as the most common screening technique, measurement of serum biochemical cardiac markers, targeted cardiac imaging and some others have been used to reach this purpose. However, each of these methods has its own advantages and disadvantages. In fact, lack of a comprehensive guideline for approaching chemotherapy-induced cardiotoxicity necessitate the need for further investigations in this area of research (9). The incidence of breast cancer in Iran has increased over the recent years (10). As a point of criticism, a review of the current medical literature reveals no available strong survey for the assessment of forthcoming problems, in particular cardiovascular diseases, facing Iranian patients with breast cancer after their initial treatment. Undeniably, after the diagnosis of such patients, every effort is made to provide them an appropriate care and therapy; however, there is a strong need for a close collaboration between oncologists and cardiologists for a systematic and planned follow-up of patients with breast cancer following receiving their medical therapies. This would be a valuable help in decreasing morbidity in this group of patients from cardiovascular problems and improving their quality of life after the initiation of therapy.

Uncovering Cardioprotective Strategies For Anthracycline Therapy By Analysis Of Redox and Apoptotic Effects

Anthracyclines are among the most powerful drugs used for the treatment of leukemia, however their use has been associated with cardiotoxicity. Reactive oxygen species (ROS) are generated in both cancer and normal cells after anthracycline exposure and have been implicated in both early and late onset cardiotoxicity. Counteracting this ROS generation are intracellular antioxidants such as the ubiquitous antioxidant glutathione (GSH), levels of which are depleted upon anthracycline exposure. Basal expression of GSH pathway components and other antioxidants vary greatly between different cell types. Due to this differential expression of cellular antioxidants in cardiomyocytes versus leukemia cells, we posit that anthracyclines exert distinct effects on oxidative stress and consequent apoptosis induction in leukemia cells and nontransformed hematopoietic cells (PBMC) relative to cardiomyocytes. As a result, we expect potentially varied mechanisms of cell death induction in these cell lines after anthracycline treatment. To test this hypothesis, the acute leukemia cell lines Jurkat and ML-1 and the cardiomyocyte line H9C2 were used. Dose responses with the anthracyclines, doxorubicin and daunorubicin, were carried out and trypan blue exclusion and propidium iodide staining followed by flow cytometry were used to assess viability and DNA fragmentation respectively. Cardiomyocytes had a 25-150 fold higher IC50 value than the acute leukemia cell lines, indicating selectivity. To assess whether apoptosis was induced by anthracyclines, caspase 3 activity was measured and found to be increased at 24 hours in Jurkat cells which preceded decreases in viability, supporting an apoptotic mechanism of cell death. GSH levels also decreased markedly after 24 hours of treatment with anthracyclines in this cell line, however, a pan-caspase inhibitor did not block GSH depletion, indicating that these events occur independent of each other. To evaluate whether antioxidants conferred protection against loss of viability in all cell types, cells were pretreated for at least 30 minutes with antioxidants and then treated with doxorubicin and daunorubicin for 24 hours. Antioxidants used were N-acetylcysteine (NAC, a GSH precursor and amino acid source), GSH ethyl ester (cell permeable form of GSH), tiron (free radical scavenger) and trolox (a water soluble form of vitamin E). GSH ethylester did not prevent cytotoxicity of anthracyclines in acute leukemia lines or cardiomyocytes. Therefore boosting GSH levels in leukemia cells does not reverse cytotoxicity. Trolox, however, did block anthracycline induced cell death in ML-1 cells, suggesting that vitamin E supplementation would counteract leukemia cell specific effects of anthracyclines on AML cells. Tiron protected PBMC from doxorubicin cytotoxicity but did not protect leukemia cells or cardiomyocytes, hinting at a protective strategy for normal non-leukemia blood cells. Interestingly, NAC did not interfere with the cytotoxic effects of anthracyclines on acute leukemia cells or PBMC, but protected H9C2 cells from daunorubicin cytotoxicity. Taken together, these data reveal differential protective effects of antioxidants in cardiomyocytes and PBMCs relative to ALL and AML cells. Our work indicates that NAC can protect cardiomyocytes without interfering with anthracycline cytotoxicity in acute leukemia cells. In humans, one randomized control trial tested the addition of NAC to doxorubicin therapy, detecting no evidence of cardioprotective activity by chronic administration of NAC. However, the schedule used for administration of NAC in that study may not have been optimal, and biomarkers for oxidative stress reduction by NAC were not incorporated into the trial. Previously, other antioxidants have been used with very limited clinical success and possible contributing factors include inadequate sample size, choice of agent, dose used, duration of intervention and the lack of biomarker endpoints. Designing a cardioprotective and antioxidant strategy with attention to these factors may prove to be efficacious in protecting cardiac cells without interfering with the antitumoral effect of anthracyclines. To this end, our data suggests that trolox and vitamin E analogues should not be used in acute leukemia as they may interfere with the cytotoxic action of anthracyclines but NAC or cysteine may be used as cardioprotectants. Disclosures:No relevant conflicts of interest to declare.

Mitochondrial Cumulative Damage Induced by Mitoxantrone: Late Onset Cardiac Energetic Impairment

Mitoxantrone (MTX) is a chemotherapeutic agent, which presents late irreversible cardiotoxicity. This work aims to highlight the mechanisms involved in the MTX-induced cardiotoxicity, namely the effects toward mitochondria using in vivo and in vitro studies. Male Wistar rats were treated with 3 cycles of 2.5mg/kg MTX at day 0, 10, and 20. One treated group was euthanized on day 22 (MTX22) to evaluate the early MTX cardiac toxic effects, while the other was euthanized on day 48 (MTX48), to allow the evaluation of MTX late cardiac effects. Cardiac mitochondria isolated from 4 adult untreated rats were also used to evaluate in vitro the MTX (10nM, 100nM, and 1μM) direct effects upon mitochondria functionality. Two rats of MTX48 died on day 35, and MTX treatment caused a reduction in relative body weight gain in both treated groups with no significant changes in water and food intake. Decreased levels of plasma total creatine kinase and CK-MB were detected in the MTX22 group, and increased plasma levels of lactate were seen in MTX48. Increased cardiac relative mass and microscopic changes were evident in both treated groups. Considering mitochondrial effects, for the first time, it was evidenced that MTX induced an increase in the complex IV and complex V activities in MTX22 group, while a decrease in the complex V activity was accompanied by the reduction in ATP content in the MTX48 rats. No alterations in mitochondria transmembrane potential were found in isolated mitochondria from MTX48 rats or in isolated mitochondria directly incubated with MTX. This study highlights the relevance of the cumulative MTX-induced in vivo mitochondriopathy to the MTX cardiotoxicity.

Therapeutic Concentrations of Mitoxantrone Elicit Energetic Imbalance in H9c2 Cells as an Earlier Event

Mitoxantrone (MTX) is a chemotherapeutic agent that emerged as an alternative to anthracycline therapy. However, MTX also causes late cardiotoxicity, being oxidative stress and mitochondrial-impaired function proposed as possible mechanisms. This work aimed to investigate the relevance of these mechanisms to the MTX toxicity in H9c2 cells, using therapeutic concentrations. The observed cytotoxicity of MTX was time and concentration dependent in both lactate dehydrogenase leakage assay and MTT reduction assay. Two therapeutic concentrations (100 nM and 1μM) and three time points were selected (24, 48, and 96h) for further studies. Both MTX concentrations caused a significant increase in caspase-3 activity, which was not prevented by inhibiting MTX CYP450-metabolism. Significant decreases were observed in the total and reduced glutathione levels only in MTX 100nM at 96h; however, neither alterations in oxidized glutathione nor increases in the malondialdehyde levels were observed at any time or concentrations tested. On the other hand, changes in the intracellular ATP levels, mitochondrial membrane potential, and intracellular calcium levels were observed in both concentrations and all time tested. Noteworthy, decreased levels of ATP-synthase expression and activity and increases in the reactive species generation were observed at 96h in both working concentrations. However, the radical scavenger N-acetylcysteine or the mitochondrial function enhancer L-carnitine did not prevent MTX cytotoxicity. Thus, this work evidenced the early MTX-induced energetic crisis as a possible key factor in the cell injury.

Activity of Dexrazoxane and Amifostine Against Late Cardiotoxicity Induced by the Combination of Doxorubicin and Cyclophosphamide In Vivo

Cardiotoxicity is one of the main limiting side effects of doxorubicin and cyclophosphamide (DC) treatment, and this study was organized to identify cardioprotective activity of amifostine and dexrazoxane against DC combination. BalbC/NIH mice underwent DC treatment (DC group), were pre-treated with amifostine (ADC group) or dexrazoxane (IDC group) and were killed at 1.5 and 3months after treatments when the grade of myocardial damage was analysed by light microscopy using the Billingham scoring method. DC treatment induced severe myocardial damage with one lethal event before evaluation at 3months. Main characteristics of DC cardiotoxicity were polymorphic myocyte degeneration and alterations in blood vessels followed by ecchymoses, haemorrhage and thromboses. Polymorphism was also found in the IDC and ADC groups, but its morphological patterns were different. In animals subject to IDC treatment, the blood vessels were better preserved than in the ADC group, whereas thrombosis was not seen in either of these two groups. Quantitatively, grade of myocardial injury in the ADC and IDC groups was significantly higher compared with the non-treated group at both times of estimation and significantly lower compared with the DC group at 1.5months. At 3months, significance against DC treatment was lost in the ADC group, while preserved in the IDC-treated animals. Also, there was significant progression in the ADC group comparing scores between 1.5 and 3months. These results revealed that the cardiotoxicity of DC combination displays specific morphological hallmark and evolution in time, different to those described after doxorubicin single treatment. Neither amifostine nor dexrazoxane prevented development of cardiomyopathy induced by DC treatment.

Cardiotoxicity After Anthracycline Treatment in Survivors of Adult Cancers: Monitoring by USCOM, Echocardiography and Serum Biomarkers.

BackgroundAnthracyclines are agents with a well known documented anti-tumoral activity. Cardiac side effects are the principal toxicity. Here we evaluate and monitor the onset of late anthracycline-induced cardiotoxicity with real-time CW-Doppler ultrasound cardiac output monitoring (USCOM®) and echocardiography in combination with serum biomarkers.MethodsFifty-two patients without cardiac disease who had received an anthracycline-based regimen for various cancer types were included in this study. Patients’ hemodynamic parameters as stroke volume (SV USCOM (mL)) and ejection fraction (EF ECHOCARDIOGRAPHY (%)) were measured with USCOM and echocardiography and correlated to serum biomarkers (NT-pro-BNP and cTnT).ResultsEighteen patients (34.6%) developed cardiac disease (NYHA I-III). An increasing cumulative anthracycline dose was associated with a decrease of the EF determined by echocardiography as well the SV by USCOM and with a higher NYHA class. Those patients who experienced cardiac disease showed a reduction of the EF and SV and increased serum biomarkers.ConclusionsReal-time CW-Doppler USCOM, is a fast and reliable method to monitor late hemodynamic changes as a symptom of anthracycline-induced cardiotoxicity comparable to the findings by echocardiography and serum biomarkers.

Defining late onset occult asymptomatic cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy: a cardiac magnetic resonance imaging study

Background There are over 270,000 childhood cancer survivors in the US. Of these survivors, more than 50% have been treated with anthracyclines and are at risk of developing progressive cardiotoxicity. Novel cardiac magnetic resonance imaging (CMRI) techniques are now able to reliably detect diffuse myocardial fibrosis and changes in regional myocardial function. We hypothesized that these novel CMRI techniques will identify occult asymptomatic cardiotoxicity in a cohort of childhood cancer survivors with normal global systolic function. Methods Twenty seven long-term childhood cancer survivors between 11.8-28.8 years with a cumulative dose >240mg/ m2 (mean 363±89) and normal systolic function (SF>29%) were studied 2.4-24 years after exposure to anthracycline therapy. Patients underwent CMRI techniques to characterize changes in T1 relaxation time, left ventricular myocardial peak circumferential and longitudinal strain parameters and were analyzed using the 17-segment model. Extracellular volume (ECV) was measured in 13 subjects all of whom were late gadolinium enhancement (LGE) negative. We performed standard CMRI assessment and quantification of myocardial mass, end-systolic and end-diastolic volumes, ejection fraction, and end systolic fiber stress. Results Twenty seven of 60 planned subjects have been imaged. End systolic fiber stress was significantly increased with higher cumulative anthracycline dose (R2=0.18, p<0.03) and younger age at diagnosis (R2=0.20, p<0.02). Lower average circumferential strain magnitude (ecc) and regional changes in peak circumferential strain were seen in multiple segments despite n ormal values of global systolic function by echocardiography and CMRI (Figure1). T1 maps are depicted in Figure 1. The mean T1 values of the myocardium were not significantly different between patients and controls at 4 min (375±67ms vs.389±36, p<0.07) and 10 min (433±52 ms vs.435±36, p<0.39), but were significantly lower at 20 minutes (455±50ms vs. 487 ±44, p<0.003) (Figure 2). Low myocardial T1 at 20 minutes was significantly associated with increases in end systolic fiber stress (R2=0.7, p<0.002). Higher mean ECV was observed in patients with cumulative dose ≥400mg/m2 (0.27 vs. 0.21, p<0.05). Conclusions

Pediatrics Digest

Pediatrics Digest| December 01 2012 Pediatrics Digest Pediatrics (2012) 130 (6): D1–D6. https://doi.org/10.1542/peds.digest1306 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Pediatrics Digest. Pediatrics December 2012; 130 (6): D1–D6. 10.1542/peds.digest1306 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP Grand RoundsAAP NewsAll AAP Sites Search Advanced Search Topics: asthma, body mass index procedure, fever, infant, premature, obesity, tuberculosis, attitude, overweight, preschool child, prenatal care Previous studies have demonstrated that booster seat legislation decreased fatalities in children. However, these studies have not accounted for confounding factors such as other legislation and temporal trends in safety. This study demonstrates that state booster seat laws are associated with decreased rates of fatalities and injuries in children 4 to 7 years of age in the United States, with the strongest effects in the older children. Doxorubicin therapy, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. This multicenter randomized trial assessed whether continuous-infusion of doxorubicin in pediatric patients provides long-term cardioprotection or improvement in event-free survival over bolus-infusion in acute lymphoblastic leukemia. Continuous-infusion of doxorubicin provided no cardioprotection or improvement in event-free survival. The impact of relative age at school entry on academic progress and the risk of being... You do not currently have access to this content.

Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes

Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

Excess Reduction of Anthracyclines Results in Inferior Event-Free Survival in Core Binding Factor Acute Myeloid Leukemia in Children; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract ▪409▪This icon denotes a clinically relevant abstract Background:Intensive combination chemotherapy of Ara-C and anthracyclines, together with optimal risk stratification, led to 70% probability of survival (pOS) in childhood acute myeloid leukemia (AML) nowadays. Therefore, one of the main subjects for AML chemotherapy in children is to reduce anthracyclines to avoid late cardiotoxicity which could occur in lower cumulative dose compared to adults. High-dose (HD) Ara-C has contributed to improved survival especially in core binding factor (CBF)-AML, and we hypothesized that the intensive use of HD Ara-C could compensate for reduction of anthracycline dose in children with CBF-AML. Patients & Methods:JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients including 2 children with t(8;21) who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Patients with CBF-AML, t(8;21) or inv(16), and good bone marrow response to the first induction course were stratified to the low risk (LR) group, and further received 3 courses of chemotherapy; 4/5 courses consisted of HD Ara-C, and the total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was reduced from 300 to 225 mg/m2 compared to the LR chemotherapy in the previous AML99 study (Tsukimoto I. J Clin Oncol 2009;27:4007–13). Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results:Three-year probability of event-free survival (pEFS) and 3y-pOS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years).One hundred fifty-five CBF-AML patients [34.9%; t(8;21), N=123 (27.7%); inv(16), N=32 (7.2%)] in the AML-05 and 89 patients [37.0%; t(8;21), N=77 (32.0%); inv(16), N=12 (5.0%)] in AML99 were compared. There were no differences in basic characteristics such as sex and age/WBC at diagnosis. CR rate was identical between the 2 cohorts (95.5% vs. 97.8%, p = 0.36). There was a tendency of lower 3y-pEFS in the AML-05 cohort [69.3% (95%CI, 60.8 – 76.3%) vs. 80.9% (71.1 – 87.7%), p = 0.078], however, 3y pOS did not differ [92.2% (85.8 – 95.8%) vs. 92.1% (84.2 – 96.2%), p= 0.94].One hundred thirty-six CBF-AML patients were stratified to the LR group in AML-05; 8 patients were stratified to the HR group and allocated to allogeneic hematopoietic transplantation in 1CR because of poor treatment response (N=5) or FLT3-ITD positivity (N=3), and 11 patients were off protocol therapy before risk stratification because of various reasons. These 136 LR patients were compared with 83 CBF-AML patients in AML99 who fulfilled AML-05 LR criteria; 7/83 t(8;21) cases with WBC ≥ 50,000/μL in AML99 received intermediate risk (IR) chemotherapy with 375 mg/m2 of anthracyclines according to the protocol. The 3y-pEFS was significantly lower in the AML-05 cohort [69.6% (60.6 – 77.0%) vs. 83.1% (73.2 – 89.6%), p = 0.041], although the 3y-pOS was not different [92.6% (85.6 – 96.3%) vs. 94.0% (86.1 – 97.5%), p= 0.74]. Conclusions:The pEFS of children with CBF-AML treated with very low cumulative dose of anthracyclines were inferior to the historical control even treated with intensive use of HD Ara-C, therefore, caution is needed to reduce cumulative anthracycline doses to below 300mg/m2. However, the fact that nearly 70% of the CBF-AML patients are cured with lower dose of anthracyclines suggest the presence of underlying biological factors to be identified for future stratification of CBF-AML in children. Disclosures:No relevant conflicts of interest to declare.

Role of NT-proBNP in detection of myocardial damage in childhood leukemia survivors treated with and without anthracyclines

BackgroundExposure to anthracyclines (ANT) during childhood represents a high risk for development of late cardiotoxicity. Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction have already occurred. Early detection of cardiotoxicity may lead to better therapeutic outcome. N-terminal pro-brain natriuretic peptide (NTproBNP) has been hypothesized to reflect increased left ventricular wall stress before development of echocardiographic abnormalities. The aim of this study was to detect cardiac abnormalities using plasma NTproBNP and echocardiography in asymptomatic childhood leukemia survivors treated with or without cardiotoxic anthracycline therapy.MethodsSerum levels of NTproBNP were determined in 69 asymptomatic survivors of childhood leukemia treated with or without anthracyclines and in 44 apparently healthy controls. The survivors were divided into two treatment groups: 36 patients after chemotherapy containing anthracyclines (ANT) and 33 patients after chemotherapy without anthracyclines (nonANT). Levels of NTproBNP were measured by using the Elecsys 2010 immunoassay analyzer (Roche Diagnostics). Echocardiography using M-mode, two-dimensional and Doppler measurements were performed on the same day as blood samples were obtained for NTproBNP analysis in survivors.ResultsSerum levels of NTproBNP were significantly higher in the ANT group than in controls (median 51.52 vs 17.37 pg/ml; p=0.0026). Survivors exposed to ANT had significantly increased levels of NTproBNP compared with patients treated without ANT (median 51.52 vs 12.24 pg/ml; p=0.0002). Female exposed and unexposed survivors had significantly higher NTproBNP levels than males. Four of the 36 survivors (11%) treated with ANT and two of the 33 patients (6%) not exposed to ANT had abnormal NTproBNP levels. Although no patient had echocardiographic abnormalities, significant differences were found in values of left ventricular ejection fraction (LVEF) and deceleration time (DT) between survivors treated with or without anthracyclines.ConclusionsHigher levels of NTproBNP detected in childhood leukemia survivors after low anthracycline cumulative doses might reflect an initial stage of ANT cardiotoxicity before the development of echocardiographic abnormalities. Although the current studies support NTproBNP as one of the best available biochemical markers of late anthracycline cardiotoxicity, a possible strategy toward further improvement and combination with other cardiac biomarkers and novel echocardiographic methods should be explored in additional studies.

Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes

The clinical use of anthracyclines in cancer therapy is limited by dose-dependent cardiotoxicity that involves cardiomyocyte injury and death. We have tested the hypothesis that anthracyclines affect protein degradation pathways in adult cardiomyocytes. To this aim, we assessed the effects of doxorubicin (Doxo) on apoptosis, autophagy and the proteasome/ubiquitin system in long-term cultured adult rat cardiomyocytes. Accumulation of poly-ubiquitinated proteins, increase of cathepsin-D-positive lysosomes and myofibrillar degradation were observed in Doxo-treated cardiomyocytes. Chymotrypsin-like activity of the proteasome was initially increased and then inhibited by Doxo over a time-course of 48 h. Proteasome 20S proteins were down-regulated by higher doses of Doxo. The expression of MURF-1, an ubiquitin-ligase specifically targeting myofibrillar proteins, was suppressed by Doxo at all concentrations measured. Microtubule-associated protein1 light chain 3B (LC3)-positive punctae and both LC3-I and -II proteins were induced by Doxo in a dose-dependent manner, as confirmed by using lentiviral expression of green fluorescence protein bound to LC3 and live imaging. The lysosomotropic drug chloroquine led to autophagosome accumulation, which increased with concomitant Doxo treatment indicating enhanced autophagic flux. We conclude that Doxo causes a downregulation of the protein degradation machinery of cardiomyocytes with a resulting accumulation of poly-ubiquitinated proteins and autophagosomes. Although autophagy is initially stimulated as a compensatory response to cytotoxic stress, it is followed by apoptosis and necrosis at higher doses and longer exposure times. This mechanism might contribute to the late cardiotoxicity of anthracyclines by accelerated aging of the postmitotic adult cardiomyocytes and to the susceptibility of the aging heart to anthracycline cancer therapy.

TH‐C‐213AB‐06: Risk of Radiation‐Induced Cardiotoxicity and Secondary Cancers in Hodgkin's Lymphoma Patients

Purpose: To evaluate the potential reduction of risk of late radiation‐ induced effects for young patients with Hodgkin's lymphoma treated with intensity modulated proton therapy (IMPT) as compared to 3D conformal involved‐field photon radiotherapy. The late effects considered were cardiac mortality and secondary cancer in the lungs and breasts (for female patients). Methods: Patient data was acquired for eleven patients who were under thirty years of age and were treated with radiotherapy for Hodgkin's lymphoma in Quebec in 2010. The original CT simulation images were used to re‐plan the patients with IMPT using commercially‐available treatment planning software. The contours of the critical organs of interest were reviewed for each patient by a physician and modified when necessary for consistency. The dose‐volume matrices of the original photon plans and the new proton plans were analyzed using radiobiological models to assess the risk of late effects. The relative seriality model was utilized to predict excess risk of fatal cardiotoxicity. The organ equivalent dose concept was utilized in conjunction with a modified linear quadratic model to predict the excess absolute risk for induction of lung cancer and breast cancer. Parameters for each model were derived from retrospective studies in the literature. Results: Mean excess risk of fatal cardiotoxicity was 0.9% for photon plans and 0.6% for proton plans. Mean excess absolute risk of developing lung cancer thirty years post‐treatment was 11.9/10,000 patients per year (PY) for photons and 6.9/10,000 PY for protons. Mean excess absolute risk of developing breast cancer thirty years post‐treatment was 6.0/10,000 PY for photons and 2.1/10,000 PY for protons. Conclusions: IMPT has the potential to reduce the risk of fatal, radiation‐induced late cardiotoxicity as well as the risk of radiation‐induced secondary cancers in the lungs and breasts of young patients receiving radiotherapy for Hodgkin's lymphoma. This work has been funded in part by a grant from the Fonds de recherche Santé Quebec (FRSQ).

Effectiveness of using cardiac biomarkers to detect late anthracycline cardiotoxicity in childhood leukemia survivors.

9592 Background: Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction has already occurred. Cardiac biomarkers (troponin T and N-terminal fragment brain natriuretic peptide precursor) have been hypothesized to reflect subclinical anthracycline cardiotoxicity earlier than echocardiography. This study aims to assess the effectiveness of using cTNT and NTproBNP in asymptomatic long-term survivors of childhood leukemia treated with and without antracyclines (ANT). Methods: Sixty-nine childhood leukemia survivors 5 - 25 years after completion of therapy were evaluated with immunochemical analysis of cTnT and NT-proBNP and echocardiography. Patients from group I (n = 36) received combined therapy with anthracyclines (ANT) with total cumulative dose 95-600 (median 221) mg/m2, patients from group II (n = 33) received therapy without anthracyclines (nonANT). Control group consisted from 44 age- and gender-matched apparently healthy subjects. Results: Levels of NTproBNP were significantly higher in ANT group than in controls (median 51,52 vs 17,37 pg/ml; p=0.0026). Patients treated with ANT had significantly increased median values of NTproBNP compared with patients in non ANT group (51,52 vs 12,24 pg/ml; p=0.0002). CTnT levels remained below the diagnostic cut-off levels in all groups. No patient had echocardiographic abnormalities, but significant differences were found in mean values of left ventricular ejection fraction and deceleration time between patients treated with and without ANT. Conclusions: Assessment of plasma NTproBNP concentrations may be an effective tool for detection of late subclinical cardiac damage in survivors of childhood leukemia previously treated with low ANT doses. Higher NTproBNP levels in patients after ANT therapy might reflect an initial stage of cardiotoxicity before the development of echocardiographic abnormalities. This study was supported by a grant from Ministry of Health 2007/42-UK-18, Slovakia.

Biomarkers and early detection of late onset anthracycline-induced cardiotoxicity in children

BackgroundThe main strategy for minimizing anthracycline cardiotoxicity is early detection of high-risk patients.Aim of the studyTo investigate the role of cardiac biomarkers; cardiac troponin T (cTnT) and N-terminal probrain natriuretic peptide (NT-pro-BNP), and tissue Doppler imaging (TDI), as early predictors of chronic cardiotoxicity in survivors of acute leukemia.Patients and methodsWe carried a retrospective study on 50 asymptomatic survivors of acute leukemia who received anthracycline in their treatment protocols. All patients underwent blood sampling to determine the levels of NT-pro-BNP and cTnT along with conventional echocardiography and TDI.ResultsNone had abnormal cTnT levels. About 20% had abnormal NT-pro-BNP levels. Diastolic dysfunction of the left ventricle was the most significant in conventional echocardiography. TDI was superior as it detected myocardial affection in 10% more than echo. TDI demonstrated global myocardial damage with significant aberrations in peak myocardial velocities and ratios.ConclusionsNT-pro-BNP can be used as a sensitive cardiac biomarker in monitoring of anthracycline-induced cardiotoxicity. Follow up is essential to validate the role of NT-pro-BNP as an early marker for late onset anthracycline-induced cardiotoxicity. Tissue Doppler is marvelous as it could detect early cardiac dysfunction even in those with normal study by conventional echocardiography.

018 The breast cancer, early disease: toxicity from therapy with epirubicin regimens ¨ c cardiac assessment and risk evaluation (better-care), cardiovascular magnetic resonance (CMR) sub-study: cycle 1 changes predict late anthracycline cardiotoxicity

IntroductionA growing number of patients are at risk from chronic anthracycline cardiotoxicity (cAC) as a result of improving prognosis of cancer. This is true even at low, adjuvant doses. In...

Subclinical Anthracycline Cardiotoxicity in Patients With Acute Promyelocytic Leukemia in Long‐Term Remission After the AIDA Protocol

Anthracycline chemotherapy remains a critical component of cancer treatment despite its established risk of cardiotoxicity. To investigate whether the AIDA protocol, which combines idarubicin, mitoxantrone, and all-trans retinoic acid (ATRA) for treatment of acute promyelocytic leukemia (APL) results in late cardiotoxicity, 34 APL patients in long-term remission were evaluated. The cumulative dose of idarubicin and mitoxantrone were 80 mg/m(2) and 50 mg/m(2), respectively. Median follow-up was 7 years. Segmental wall motion abnormalities (SWMAs) were detected in 11 AIDA patients who still presented with an ejection fraction (EF) within normal limits (EF 56% in the AIDA group vs 59% in the control group, P=.01). However, parameters of diastolic dysfunction were significantly impaired in the AIDA group (E/A ratio: 1.04 in the AIDA group vs 1.28 in the control group, P=.001; E/E' lateral ratio: 10.04 in the AIDA group vs 5.79 in the control group, P≤.001) as well as left atrial volume (52 mL in the AIDA group vs 35 mL in the control group, P<.001). Cardiac toxicity due to anthracycline therapy is often frequent. Changes in diastolic function are helpful in the detection of subclinical anthracycline cardiotoxicity in long-term cardiac follow-up despite a preserved systolic ventricular function.

Abstract 9402: Diffuse Myocardial Fibrosis Negatively Correlates with Exercise Capacity in Children with Subclinical Anthracycline Cardiotoxicity

Background The effectiveness of anthracycline chemotherapy in improving survival is limited by late cardiotoxicity. The aim of this study was to examine novel cardiac MRI and echocardiography measures to detect subclinical cardiotoxicity in childhood cancer survivors, and to determine its relationship to exercise capacity. Methods Thirty patients (15±3years, 50% male), 8±5 years after anthracycline therapy (cumulative dose 197±84 mg/m 2 ), underwent cardiac MRI, echocardiography and cardiopulmonary (cycle ergometer) exercise testing (VO 2peak ). Cardiac MRI assessed volumetric function, mass, and myocardial extra-cellular volume (ECV), a measure of diffuse fibrosis based on changes in blood and myocardial T1 values pre and post gadolinium. Tissue Doppler annular velocities (E’, A’) and peak circumferential and longitudinal strain, strain rate (SR) and torsion, from speckle tracking, were compared to 35 healthy controls (13±4 years). Data (mean ± SD) was analysed using Pearson's product-moment coefficient and unpaired t-tests (p&lt;0.05). Results Patients were asymptomatic with normal LVEF (59±7%) but VO 2peak was 15% lower than age and gender determined healthy predicted values. Myocardial ECV was inversely correlated with mass/volume ratio (r = -0.5, p&lt;0.01), and VO 2peak (r = -0.5, p&lt;0.01), and lower VO 2peak correlated with increased cumulative dose (r = 0.4, p&lt;0.05). Echocardiographic measures of systolic function were significantly reduced compared to controls (decreased circumferential and longitudinal strain, longitudinal SR and torsion, p&lt;0.01). Diastolic dysfunction was evident with decreased circumferential and longitudinal diastolic SR and decreased annular velocities (p&lt;0.01) relative to controls. There was no correlation between echocardiographic parameters and ECV or VO 2peak . Conclusion Diffuse myocardial fibrosis (increased ECV) is correlated with reduced mass/volume ratios and VO 2peak in children post anthracyline. While there were abnormalities of systolic and diastolic function, these metrics did not correlate with ECV or VO 2peak . Myocardial ECV provides a non-invasive early marker of ventricular remodelling that is related to exercise capacity which may be of prognostic value in childhood cancer survivors.

Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients

Background:The aim of this study was to assess the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting late cardiotoxicity in patients treated with not-high-dose chemotherapy (NHDC), and to compare the predictive value of NT-proBNP and cardiac troponin I (cTnI).Methods:In 71 patients undergoing NHDC with anthracyclines, NT-proBNP and cTnI levels were measured before and 24 h after each NHDC cycle. Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up.Results:During NHDC, only NT-proBNP showed abnormal values. According to NT-proBNP behaviour, patients were divided into two groups: group A (n=50) with normal (n=23) or transiently elevated NT-proBNP levels (n=27), and group B (n=21) with persistently elevated NT-proBNP levels. At follow-up, LV impairment was significantly worse in group B than in group A. %Δ (baseline–peak) NT-proBNP was predictive of LV impairment at 3-, 6- and 12-month follow-up, with a cutoff of 36%.Conclusion:Serial measurements of NT-proBNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity.

Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood

IntroductionLate cardiotoxicity is a known complication of anthracycline therapy but the long-term effects of low cumulative doses are not well documented. We studied late cardiotoxicity in survivors of childhood acute lymphoblastic leukemia (ALL) treated with low anthracycline doses 10 to 20 years earlier.MethodsSeventy-seven ALL survivors who received a cumulative anthracycline dose <250 mg/m² and were at least 10 years after treatment were evaluated for signs of clinical heart failure. Cardiac function was assessed by echocardiography including tissue Doppler measurements of the septal mitral annulus in 37 ALL survivors 10.6–18.3 years (median 13.3 years) after anthracycline treatment with cumulative doses of 180 (n = 19) or 240 mg/m² (n = 18). The control group consisted of 30 healthy volunteers matched for age, sex, BSA, and BMI.ResultsNo clinical relevant cardiotoxicity was found. Left ventricular shortening fraction (SF) was significantly reduced in male ALL survivors. Three of the 19 male ALL survivors had an SF below 30%. Male ALL survivors showed a significantly lower early filling velocity to atrial contraction velocity ratio but myocardial velocity during early filling was comparable between patients and controls. ALL survivors had a significantly longer isovolumetric relaxation time (IVRT). Thirty percent of the ALL survivors have an abnormal IVRT compared to the normal range of the controls.Conclusion and implications for cancer survivorsAt a median of 13.3 years after exposure to cumulative doses of anthracyclines of 180 or 240 mg/m², no clinical relevant cardiotoxicity was found but subclinical cardiac abnormalities were present in 30% of the patients.