Anthracycline Cardiotoxicity Research Articles

Speckle tracking echocardiography in the early detection and prediction of anthracycline cardiotoxicity in diffuse large B-cell lymphoma treated with (R)-CHOP regimen.

Despite speckle tracking echocardiography (STE) has emerged as a sensitive technique for identifying myocardial dysfunction, there are little data available on the appropriate timing to perform STE in the serial assessment after anthracycline administration. Moreover, further uncertainty is increased in the context of STE application in diffuse large B-cell lymphoma (DLBCL) research, as most recommendations are inferred by studies conducted primarily in breast cancer. This study aimed to determine whether early measurement of strain parameters derived by STE could predict the development of cardiotoxicity. Sixty-five patients were included in the final analysis. The patients were evaluated at baseline, after the third cycle and sixth-eighth cycle, and during follow-up. Global longitudinal strain (GLS) was analyzed using STE, and left ventricular ejection fraction (LVEF) was calculated by real time 3D echocardiography (RT3DE). There was a significant decrease in GLS after the third cycle of chemotherapy and remained decreased during subsequent follow-up, whereas LVEF decreased only at follow-up. A percentage reduction in GLS of 13.8% between baseline and the third cycle of chemotherapy was the best predictor of further LVEF reduction. Earlier monitoring timing and more accurate assessment methods might be helpful in the prevention of irreversible heart failure.

Evaluation of the cost-effectiveness of dexrazoxane for the prevention of anthracycline-related cardiotoxicity in children with sarcoma and haematologic malignancies: a European perspective

BackgroundAnthracycline-treated childhood cancer survivors are at higher risk of cardiotoxicity, especially with cumulative doses received above 250 mg/m2. Dexrazoxane is the only option recommended for cardiotoxicity prevention in high-risk patients supported by randomised trials but its cost-effectiveness in paediatric cancer patients has not been established.MethodsA cost-effectiveness model applicable to different national healthcare system perspectives, which simulates 10,000 patients with either sarcoma or haematologic malignancies, based upon baseline characteristics including gender, age at diagnosis, cumulative anthracycline dose and exposure to chest irradiation. Risk equations for developing congestive heart failure and death from recurrence of the original cancer, secondary malignant neoplasms, cardiac death, pulmonary death, and death from other causes were derived from published literature. These are applied to the individual simulated patients and time until development of these events was determined. The treatment effect of dexrazoxane on the risk of CHF or death was based upon a meta-analysis of randomised and non-randomised dexrazoxane studies in each tumour type. The model includes country specific data for drug and administration costs, all aspects of heart failure diagnosis and management, and death due to different causes for each of the five countries considered; France, Germany, the UK, Italy, and Spain.ResultsDexrazoxane treatment resulted in a mean QALY benefit across the five countries ranging from 0.530 to 0.683 per dexrazoxane-treated patient. Dexrazoxane was cost-effective for paediatric patients receiving anthracycline treatment for sarcoma and for haematologic malignancies, irrespective of the cumulative anthracycline dose received. The Incremental Cost Effectiveness Ratio (ICER) was favourable in all countries irrespective of anthracycline dose for both sarcoma and haematological malignancies (range: dominant to €2196). Individual ICER varied considerably according to country with dominance demonstrated for dexrazoxane in Spain and Italy and ratios approximately double the European average in the UK and Germany.ConclusionsDexrazoxane is a highly cost-effective therapy for the prevention of anthracycline cardiotoxicity in paediatric patients with sarcoma or haematological malignancies in Europe, irrespective of the healthcare system in which they receive treatment. These benefits persist when patients who receive doses of anthracycline > 250 mg/m2 are included in the model.

Bioinformatic analysis of peripheral blood miRNA of breast cancer patients in relation with anthracycline cardiotoxicity

BackgroundThe current diagnostic methods and treatments still fail to lower the incidence of anthracycline-induced cardiotoxicity effectively. In this study, we aimed to (1) analyze the cardiotoxicity-related genes after breast cancer chemotherapy in gene expression database and (2) carry out bioinformatic analysis to identify cardiotoxicity-related abnormal expressions, the biomarkers of such abnormal expressions, and the key regulatory pathways after breast cancer chemotherapy.MethodsCardiotoxicity-related gene expression data (GSE40447) after breast cancer chemotherapy was acquired from the Gene Expression Omnibus (GEO) database. The biomarker expression data of women with chemotherapy-induced cardiotoxicity (group A), chemotherapy history but no cardiotoxicity (group B), and confirmatory diagnosis of breast cancer but normal ejection fraction before chemotherapy (group C) were analyzed to obtain the mRNA with differential expressions and predict the micro RNAs (miRNAs) regulating the differential expressions. The miRanda formula and functional enrichment analysis were used to screen abnormal miRNAs. Then, the Gene Ontology (GO) analysis was adapted to further screen the miRNAs related to cardiotoxicity after breast cancer chemotherapy.ResultThe data of differential analysis of biomarker expression of groups A, B, and C using the GSE40447-related gene expression profile database showed that there were 30 intersection genes. The differentially expressed mRNAs were predicted using the miRanda and Target Scan software, and a total of 2978 miRNAs were obtained by taking the intersections. Further, the GO analysis and targeted regulatory relationship between miRNA and target genes were used to establish miRNA-gene interaction network to screen and obtain seven cardiotoxicity-related miRNAs with relatively high centrality, including hsa-miR-4638-3p, hsa-miR-5096, hsa-miR-4763-5p, hsa-miR-1273 g-3p, hsa-miR6192, hsa-miR-4726-5p and hsa-miR-1273a. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p had the highest centrality. The PCR verification results were consistent with those of the chip data. There are differentially expressed miRNAs in the peripheral blood of breast cancer patients with anthracycline cardiotoxicity. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p are closely associated with the onset of anthracycline cardiotoxicity in patients with breast cancer. The signaling pathway is mainly concentrated in TGF-β signaling pathway and adhesion signaling pathway.ConclusionsChanges in expression of hsa-miR-4638-3p and hsa-miR-1273 g-3p may contribute to the detection of anthracyclines induced cardiac toxicity, and their potential function may be related to TGF-β signaling pathway and adhesion signaling pathway.

Rutin protects against pirarubicin-induced cardiotoxicity by adjusting microRNA-125b-1-3p-mediated JunD signaling pathway.

Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.

Dexrazoxane cost effective in preventing anthracycline cardiotoxicity

Dexrazoxane cost effective in preventing anthracycline cardiotoxicity

Dexrazoxane cost effective in preventing anthracycline cardiotoxicity

Dexrazoxane cost effective in preventing anthracycline cardiotoxicity

A case of reversible severe left ventricular dysfunction which induced by Anthracycline cardiotoxicity

A case of reversible severe left ventricular dysfunction which induced by Anthracycline cardiotoxicity

Reversibility of trastuzumab induced cardiotoxicity in breast cancer patients: A prospective observational study

Trastuzumab has led to a significant improvement in the treatment of both advanced and early breast cancer that over-expresses HER2 receptors. However, it is associated with an important cardiotoxicity that requires a systematic monitoring of left ventricular ejection fraction (LVEF) before and during the treatment. We present our experience with patients who developed trastuzumab-related cardiotoxicity. To evaluate the incidence and the reversibility of trastuzumab induced cardiotoxicity (TIC) in our cardio-oncology unit. We conducted a prospective observational study from January 2017 to november 2018 in the cardio-oncology unit of Casablanca, Morocco. In total, 973 patients were included. The average LVEF before initiation of trastuzumab was 59.9 ± 11.2% and 51.9 ± 6.6% at the end of treatment. A decreased LVEF was detected in 38 patients (3.9%), symptomatic in 20 cases, asymptomatic in 18 patients. TIC occured for a mean cumulative dose > 40 mg/m 2 . During the follow-up, 32 patients (84.2%) had a retrieval of their LVEF after a mean period of 6.4 months after trastuzumab termination. 6 cases of TIC were irreversible despite an optimal cardioprotective therapy. Patients who develop TIC generally improve their LVEF on removal of the agent and after initiation of cardioprotective therapy. The clinical outcome is more favorable than anthracycline cardiotoxicity. This reversibility is usually observed in early identified patients, showing the importance of a systematic monitoring of LV function before, during and after the treatment.

Meta-Analysis of the Effect of Prophylactic Beta Blocker and RAA Inhibitor on Anthracycline Cardiotoxicity

Meta-Analysis of the Effect of Prophylactic Beta Blocker and RAA Inhibitor on Anthracycline Cardiotoxicity

Cardiovascular Magnetic Resonance Relaxometry in Early Detection of Anthracycline Cardiotoxicity

To provide an overview of the published data on the value of cardiovascular magnetic resonance (CMR) based T1 and T2 and extracellular volume (ECV) fraction quantification to identify myocardial abnormalities related to anthracycline treatment in patients with cancer. In animal models of anthracycline cardiotoxicity, elevations in myocardial T1 and T2 values appear to occur early during treatment followed by ventricular remodeling, persistent elevation in T1, and increase in ECV. These findings suggest early myocardial inflammation/edema followed by myocardial fibrosis and ventricular dysfunction. Similarly in patients receiving cancer therapy, T1 and ECV values increase early after anthracycline therapy. The value of T2 mapping in this setting has not been established. Likewise, adult cancer survivors with or without LV dysfunction have increased ECV values which may be associated with worse diastolic parameters. The value of ECV to identify subclinical cardiomyopathy in pediatric cancer survivors remains controversial. Quantitative CMR tissue characterization techniques may have a unique role in identifying the pathophysiology of anthracycline-induced cardiomyopathy and for early detection of myocardial injury. In cancer survivors, these techniques have a potential role in identifying early and subclinical myocardial injury. However, the overall literature on quantitative CMR tissue characterization techniques to detect anthracycline cardiotoxicity is limited.

Diagnostic echocardiographic parameters of early cardiotoxicity of anthracyclines in pediatric population

Hematological malignancies are the most common tumors in pediatrics. Anthracyclines represent the molecule of choice in their treatments, and are responsible for improving survival. Their cardiovascular complications, increased the morbidity. Evaluate diagnostic echocardiographic parameters of early cardiotoxicity of anthracyclines in children. Prospective observational study (18 months) including 43 patients followed in onco-hematology for hematological malignancy, on anthracycline, who had a cardiovascular assessment and follow-up. The average age is 7.4 years (range 6 months to 16 years), with male predominance (sex ratio = 2.07). All patients were followed for hematologic malignancy: 14 cases of LH, 12 cases of NHL, 12 cases of ALL, and 5 cases of AML. 21 patients were in treatment, 12 patients in remission, and 10 patients scheduled for bone marrow transplantation. All patients were on anthracyclines, with an average cumulative dose of 223 mg/m 2 . A complete cardiovascular assessment was performed in all patients with a control before each treatment in patients in treatment and every 3 months in patients in remission. Echocardiographic parameters that varied significantly in post chemotherapy were: Ea, Sa, and SGL. Tissue Doppler parameters decreased in 14% of cases after an average cumulative dose of 160 mg/m 2 . SGL decreased significantly in 7% of cases after an average cumulative anthracycline dose of 290 mg/m 2 . The tissue doppler and the global longitudinal strain have an interest in both the child and the adult in the early detection of anthracycline cardiotoxicity, allowing better management.

P375 To evaluate the effectiveness of primary prevention of anthracycline cardiotoxicity using modern STE technologies

Abstract Funding Acknowledgements without financial supports Introduction Despite the high efficiency, the use of chemotherapeutic drugs involves to the development of cardiomyopathy and heart failure. Correction of myocardial damage is most effective before the appearance of clinical manifestations of cardiomyopathy. Aim of study. To evaluate the effectiveness of primary prevention of anthracycline cardiotoxicity using modern STE technologies. Material and methods.The study included 65 patients with breast cancer. All patients had a collection of anamnesis, echocardiography with STE , were performed before the study. All patients were prescribed chemotherapy with anthracycline, after which the patients included in the study were randomly randomized into two groups. Patients of the first group, in which 27 patients were included, were additionally assigned ivabradine in a daily dose of 10 mg, followed by titration of the dose to achieve a heart rate of less than 70 beats per minute. The comparison group consisted of 38 patients who received only chemotherapy. Results A six-month treatment with ivabradine was accompanied by a significant decrease in heart rate by the first month (from 83.6 ± 9.5 to 67.1 ± 7.5 bpm, p <0.001) and persisted until the sixth month (from 83.6 ± 9.5 Up to 74.2 ± 14.9 beats per minute, p <0.001). The analysis of echocardiographic indices did not reveal significant differences between the groups.The reliable dynamics of the LV ejection fraction was not detected in both groups.To assess the effect of ivabradine on the development of subclinical systolic dysfunction of the left ventricle during chemotherapy, a global longitudinal systolic deformation was also evaluated. The groups did not differ in terms of global longitudinal strain (-20.4 ± 1.8% in the ivabradine group and -19.9 ± 2.0% in the control group). In the control group, there was a tendency to decrease global deformation (from -19.9 ± 2.0% to -19.0 ± 1.8% by 3 months to -18.9 ± 1.7% by the 6th month of observation), and in Group of ivabradine, the deformation parameters were at a stable level (from -20.4 ± 1.8% to-20.6 ± 2.4% by 3 months and -20.4 ± 1.9% by the 6th month of observation), which led to significant differences between groups at the first and third and sixth month of observation (-21.1 ± 1.8% to 1 month and -20.6 ± 2.4% to 3 months and -20.4 ± 1.9% to 6 months in the ivabradine group compared to -19.6 ± 2.1% to 1 Month and -19.0 ± 1.8% by 3 months and -18.9 ± 1.7 by the 6th month of observation p <0.05 in the control group). Conclusions.Therapy with ivabradine in patients with breast cancer with heart rate> 70 beats per minute is safe. The appointment of ivabradine is accompanied by a significant decrease in the number of patients with complaints of heart beat, contributes to the preservation of normal global longitudinal deformation of the left ventricle against chemotherapy, while in the control group has a negative dynamics with a maximum at the 6th month of follow-up

Molecular mechanisms of the cardiotoxic action of anthracycline antibiotics and statin-induced cytoprotective reactions of cardiomyocytes

The manifestation of the side cardiotoxic effect of anthracycline antibiotics limits their use in the treatment of malignant processes in some patients. The review analyzes the main causes of the susceptibility of cardiomyocytes to the damaging effect of anthracyclines, primarily associated with an increase in the processes of free radical oxidation. Currently, research is widely carried out to find ways to reduce anthracycline cardiotoxicity, in particular, the use of cardioprotective agents in the complex treatment of tumors. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve the function and metabolism of the cardiovascular system under various pathological impacts, therefore, it is proposed to use them to reduce cardiotoxic complications of chemotherapy. Statins exhibit direct (hypolipidemic) and pleiotropic effects due to the blockade of mevalonic acid synthesis and downward biochemical cascades that determine their cardioprotective properties. The main point of intersection of the pharmacological activity of anthracyclines and statins is the ability of both to regulate the functioning of small GTPase from the Rho family, and their effect in this regard is the opposite. The influence of statins on the modification and membrane dislocation of Rho proteins mediates the indirect antioxidant, anti-inflammatory, endothelioprotective, antiapoptotic effect. The mechanism of statin inhibition of doxorubicin blockade of the DNA-topoisomerase complex, which may be important in preventing cardiotoxic damage during chemotherapy, is discussed. At the same time, it should be noted that the use of statins can be accompanied by adverse side effects: a provocation of increased insulin resistance and glucose tolerance, which often causes them to be canceled in patients with impaired carbohydrate metabolism, so further studies are needed here. The review also analyzes data on the antitumor effect of statins, their ability to sensitize the tumor to treatment with cytostatic drug. It has been shown that the relationship between anthracycline antibiotics and statins is characterized not only by antagonism, but also in some cases by synergism. Despite some adverse effects, statins are one of the most promising cardio- and vasoprotectors for use in anthracycline cardiomyopathy.

1029 Anthracycline and trastuzumab-induced subclinical cardiac damage and its prevention in the SAFE trial. Myocardial strain imaging and 3D echo interim analysis data

Abstract Background Benefit of anthracyclines and trastuzumab therapies on disease-free survival in breast cancer is well known. Cardiotoxicity is a feared potential complication of both drugs. It usually progresses from cardiomyocyte injury to silent left ventricular dysfunction (LVD) which often becomes symptomatic and irreversible. Therefore, its prevention and early detection are of paramount importance in these cancer patients. Purpose SAFE trial (CT registry ID: NCT2236806) is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effects of Bisoprolol (B) (5 mg, twice daily), Ramipril (R) (5 mg, twice daily) or the combination of the two (R + B), compared to placebo (P), on subclinical heart heart damage. Interim data of left ventricular function monitored with 3D Echo and Myocardial Strain Imaging are presented. Methods Out of 225 patients asked to participate, 191 were enrolled (mean age 48.9 ± 9.0 years). Follow-up monitoring (at 3, 6, 12 months[m]) comprised 3D ejection fraction (3D-LVEF) and Global Longitudinal Strain (GLS). One patient had sub-acute anthracyclines cardiotoxicity. Data at one year of 123 patients were available (34 P, 28 R, 31 B, 30 R + B). Results At time 0, no significant differences in age, body mass index, hemodynamic parameters were observed among arms. Data of 3D-LVEF and GLS at time 0 and during follow-up are reported in the figure (p level versus time 0 – GLS repeated measures). There was a significant reduction in 3D LVEF and increase in GLS in P arm (3D LVEF: 3m: -3.3%, 6m: - 5.2%, 12m: -3.7%; GLS: 3m: +5,7%, 6m: +7.8%, 12m: + 7,1%). A similar, though less significant, worsening of 3D LVEF (-2.4%,-1.9%,-2.2% at 3, 6, 12m, respectively) and GLS (+2.7%, +3.2% at 3 and 6m, respectively) was found in R arm. In B and B +R arms there was a worsening at 6m (3D LVEF -2.5%, GLS +2.7%), whereas at 12m only GLS increased (+3.2%) in B, not in B + R. Arm differences were significant (repeated measures two ways) both for 3D LVEF (two-way repeated measures ANOVA, p level = 0.038, observed power 0.855) and GLS (p level = 0.002, observed power 0.973). Conclusions This interim analysis of the SAFE trial shows that demonstration of subclinical cardiotoxicity is feasible with 3D echo and myocardial strain imaging. Significant subclinical damage potentially leading to LVD is present at one year. Both B alone on in combination with R may be a successful cardioprotective strategy in patients treated with anthracyclines and trastuzumab. Abstract 1029 Figure. Time course of GLS and 3D LVEF

Amelioration of doxorubicin-induced cardiotoxicity by oral lyophilized Dunaliella salina supplement in a female wistar rat model with active estrous cycle and surgical menopause

Background: Whole-cell Dunaliella salina is effective in preventing doxorubicin (DOX)-induced cardiotoxicity in female Wistar rats with surgical menopause. Materials and Methods: In our experiment, we surgically induced menopause in a group of Wistar rats and given doses of DOX and/or D. salina lyophilized powder and compared its effects with the group of rats having a normal estrous cycle. A cumulative dose of 25 mg/kg BW of DOX was given to induce cardiotoxicity and was countered by 1000 mg/kg BW of D. salina oral supplement or 10 mg/kg BW of tamoxifen. Totally two groups of rats were supplemented with D. salina , in one of the groups it was given either a week before DOX initiation, and in the other group, it was given alongside DOX doses. Results: The concomitant D. salina supplement has been found to reduce the cardiac damage due to DOX better than the groups that received the supplement beforehand DOX initiation or tamoxifen. Besides, the supplement was also found to maintain nitroso-redox balance, thus preventing cardiomyocyte death as compared with the rats that received DOX alone. It was evident from the histopathological examination and serum levels of cardiac troponin-T. Conclusion: Thus, oral carotenoid supplementation can be a promising functional food over tamoxifen, which would help in recovering from menopause and prevent anthracycline cardiotoxicity.

Screening for in-vivo regional contractile defaults to predict the delayed Doxorubicin Cardiotoxicity in Juvenile Rat.

Anthracyclines are key chemotherapeutic agents used in various adult and pediatric cancers, however, their clinical use is limited due to possible congestive heart failure (HF) caused by acute and irreversible cardiotoxicity. Currently, there is no method to predict the future development of the HF in these patients. In order to identify early biomarkers to predict anthracycline cardiotoxicity in long-term survivors of childhood cancer, this longitudinal study aimed to analyze early and late in-vivo regional myocardial anthracycline-induced cardiotoxicity, related to in-vitro cardiac myocytes dysfunction, in a juvenile rat model.Methods: Young male Wistar rats (4 weeks-old) were treated with different cumulative doses of doxorubicin (7.5, 10 or 12.5 mg/kg) or NaCl (0.9%) once a week for 6 weeks by intravenous injection. Cardiac function was evaluated in-vivo by conventional (left ventricular ejection fraction, LVEF) and regional two-dimensional (2D) speckle tracking echocardiography over the 4 months after the last injection. The animals were assigned to preserved (pEF) or reduced EF (rEF) groups at the end of the protocol and were compared to controls.Results: We observed a preferential contractile dysfunction of the base of the heart, further altered in the posterior segment, even in pEF group. The first regional alterations appeared 1 month after chemotherapy. Functional investigation of cardiomyocytes isolated from the LV base 1 month after doxorubicin treatment showed that early in-vivo contractile alterations were associated with both decreased myofilament Ca2+ sensitivity and length-dependent activation. Changes in post-translational modifications (phosphorylation; S-glutathionylation) and protein degradation of the cardiac myosin binding protein-C may contribute to these alterations.Conclusion: Our data suggest that screening of the contractile defaults of the base of the heart by regional 2D strain echocardiography is useful to detect subclinical myocardial dysfunction prior to the development of delayed anthracycline-induced cardiomyopathy in pediatric onco-cardiology.

P1781 Cardio-protective role of dexrazoxane co-administered with anthracyclines: long-term echocardiographic follow-up in adult survivors of pediatric cancer

Abstract Background Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer treated with anthracyclines. A decrease in left ventricular (LV) ejection fraction (LVEF) and fractional shortening may be observed during follow-up. Previous studies reported non-negligible prevalence of subclinical systolic dysfunction assessed with deformation imaging at short-, mid- and long-term follow up. Co-administration of Dexrazoxane has been shown to significantly reduce short-term and mid-term cardiotoxicity. The usefulness of dexrazoxane in preventing late (>10 years) anthracycline cardiotoxicity remains under discussion. Purpose Aim of this study was to assess cardiac function in long-term (>10 years) survivors of childhood tumors treated with dexrazoxane/anthracycline association. Methods Twenty cancer survivors previously treated with co-administration of anthracyclines and dexrazoxane for childhood renal tumors or sarcoma and a control group of 20 healthy non-athletic subjects matched for age, sex and body surface area were enrolled in the study. Echocardiographic measurements included 3D LVEF and LV and right ventricular (RV) global longitudinal strain (GLS). Cancer survivors were evaluated at median follow-up time of 21.5 years (range 10-26). Results No evidence of cardiac toxicity, as defined by current guidelines, was reported in all survivors. None of survivors presented LVEF < 50% or abnormal longitudinal strain, defined as a value >2 SDs below the mean using sex-specific and age-specific strain values. No significant differences in standard and deformation imaging parameters were observed between survivors and controls (3D LVEF 58 ± 3 % vs 60 ± 5 % p = NS; LV GLS -21 ± 1 % vs - 21 ± 2 % p= NS; RV GLS - 23 ± 2 % vs - 23 ± 5 % p= NS). Moreover, considering subjects who received a cumulative dose of anthracyclines above the median (doxorubicin-equivalent dose ≥208 mg/m2) no significant differences were found as compared to the group receiving a lower dose. Conclusions No evidence of cardiac toxicity was detected in all survivors. Our findings support the cardio-protective role of dexrazoxane in children undergoing anthracycline-based treatment. Parameters Cancer survivors (n= 20) Controls (n= 20) P 3D LVEF (%) 58 ± 3 60 ± 5 NS LV GLS (%) -21 ± 1 -21 ± 2 NS RV GLS (%) -23 ± 2 -23 ± 5 NS 3 D LVEF: Three-Dimensional Left Ventricular Ejection Fraction, LV GLS: Left Ventricular Global Longitudinal Strain; LV; RV GLS: Right Ventricular Global Longitudinal Strain. Abstract P1781 Figure. LV strain analysis in a survivor

The correlation of doxorubicin related cardiotoxicity with B-type natriuretic peptide levels in South Indian population

Background: Anthracyclines represent the greatest risk for development of cardiotoxicity. Cardiotoxicity of anthracyclines may develop during the treatment (acute cardiotoxicity) and during the follow-up (chronic and late cardiotoxicity). Natriuretic peptides - Atrial Natriuretic Peptide (ANP), B-type Natriuretic Peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) are released by myocardium in response to wall strain and pressure overload. The applicability of natriuretic peptides (ANP, BNP, NT-pro-BNP) as markers for Anthracycline-induced cardiotoxicity has been investigated only in a few studies and there is scarcity of data from India. Aims and Objectives: To observe correlation of NT-pro-BNP levels with cardiotoxicity in patients receiving doxorubicin. Methods and Materials: Eighty patients who were planned for treatment with Doxorubicin > 200 mg/m2 were included in this study. Each patient was assessed clinically (History, Pulse rate, Blood pressure) along with ECG, ECHO and NT-pro-BNP levels prior to initiation of chemotherapy, after completion of 200 mg/m2 of Doxorubicin, 3 months and 6 months after chemotherapy. Result: There were total of 80 patients in the study and they received a total of 384 cycles of Doxorubicin containing regimens according to respective protocols. The median number of cycles was four (range four to six cycles). The mean cumulative dose of doxorubicin was 267.75 mg/m2. As none of the patients developed any cardiac symptoms during or after the planned chemotherapy nor was there a drop in Ejection Fraction on serial ECHO, correlation with BNP levels was not possible. There were 4 patients who had very high values of NT-pro-BNP (>300 pg/ml) and 4 patients with moderate elevation of NT-pro-BNP (200-300 pg/ml) prior to the initiation of chemotherapy. 14 patients had serially increasing values of NT-pro-BNP in the 6 months follow-up. Conclusion: Based on the findings in this study it can be concluded that high upfront BNP values or increasing values of BNP does not correlate with the incidence of acute and early onset chronic cardiotoxicity. Whether or not the BNP values correlate with the incidence of late onset cardiotoxicity can be concluded only with a longer follow-up of these patients.

Left ventricle segmental function in childhood cancer survivors using speckle-tracking echocardiography.

Anthracycline-associated cardiotoxicity in childhood cancer survivors may relate to global or segmental left ventricular abnormalities from associated thromboembolic events and myocardial microinfarcts. We characterized left ventricular segmental changes by two-dimensional speckle-tracking echocardiography in anthracycline-treated asymptomatic childhood cancer survivors. Childhood cancer survivors' echocardiograms with normal left ventricular fractional shortening >1 year after anthracycline chemotherapy were studied. Cancer-free control children had normal echocardiograms. Apical two-, three-, and four-chamber peak systolic left ventricular longitudinal and global longitudinal strain, and peak systolic left ventricular radial and circumferential strain at papillary muscle levels were analyzed. The mean (standard deviation) age was 12.7 (3.8) years in 41 childhood cancer survivors. The median (interquartile range) follow-up after anthracycline chemotherapy was 4.73 (2.15-8) years. The median (range) cumulative anthracycline dose was 160.2 (60-396.9) mg/m2. In childhood cancer survivors, the mean (standard deviation) left ventricular longitudinal strain was lower in two- (-18.6 [3.2] versus -21.3 [2.5], p < 0.001), three- (-16.3 [6.0] versus -21.7 [3.0], p < 0.001), and four- (-17.6 [2.7] versus -20.8 [2.0], p < 0.001) chamber views compared to controls. The left ventricular global longitudinal strain (-17.6 [2.7] versus -21.3 [2.0]) and circumferential strain (-20.8 [4.3] versus -23.5 [2.6], p < 0.001) were lower in childhood cancer survivors. Among childhood cancer survivors, 12 out of 16 left ventricular segments had significantly lower longitudinal strain than controls. Asymptomatic anthracycline-treated childhood cancer survivors with normal left ventricular fractional shortening had lower global longitudinal and circumferential strain. The left ventricular longitudinal strain was lower in majority of the segments, suggesting that anthracycline cardiotoxicity is more global than regional.

Doxorubicin persistently rewires cardiac circadian homeostasis in mice.

Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles.