Anthracycline Cardiotoxicity Research Articles

The prognostic value of the NT-proBNP biomarkers and Fas ligand in assessing the risk of cardiotoxicity of anthracycline chemotherapy

Aim. To study the mechanisms, features of clinical manifestations and predicting of cardiotoxicity resulting from anthracycline chemotherapy.Material and methods. We examined 176 women with breast cancer who received anthracycline antibiotics as part of polychemotherapeutic (PCT) treatment. Patients were divided into 2 groups: with the development of cardiotoxic remodeling — group 1 (n=52) and with preserved heart function — group 2 (n=124). We conducted echocardiographic (EchoCG) tests before the start, during and after anthracycline chemotherapy. In the serum after the termination of PCT treatment, the concentrations of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and soluble Fas ligand (sFas-L) were determined.Results. Analysis of EchoCG parameters in patients after 12 months of PCT finish, showed a significant difference in the final systolic and end diastolic sizes, as well as a significant decrease in the left ventricular ejection fraction in group 1 compared with those before the start of treatment. A direct correlation was found between the end-systolic and end-diastolic volumes and inverse correlation between left ventricular ejection fraction and the resulting summary dose of doxorubicin. EchoCG changes in women of group 1 after the first course of PCT treatment were recorded in 49% of cases and 11% of cases — in group 2. The concentrations of sFas-L and NT-proBNP after PCT therapy finish in group 1 were significantly higher compared with group 2. Patients with significantly elevated NT-proBNP levels were had a high risk of heart disease developing during 12 months follow-up. A high concentration of NT-proBNP is a predictor of cardiovascular complications, which is more sensitive than EchoCG.Conclusion. Fas-associated apoptosis plays an important role in the pathogenesis of anthracycline cardiotoxicity. NT-proBNP may be an important biomarker for cardiotoxicity development, which already effective when EchoCG or clinical signs is absent.

EARLY DETECTION OF ANTHRACYCLINE CARDIOTOXICITY IN POPULATIONS WITH PREVALENT UNRELATED CARDIAC DISORDERS

Detection of anthracycline cardiotoxicity remains controversial. If large left ventricular ejection fraction(LVEF) and/or strain(S) and S rate(SR) reductions are required, diagnosis is late and reversibility limited. Further, older populations have many unrelated cardiac disorders. We examined the

Cardioprotection in cancer therapy: novel insights with anthracyclines.

Anthracyclines are a class of antineoplastic agents that remain critical to modern-day cancer treatment. However, their propensity to cause cardiotoxic effects limits their use and can cause increased morbidity and mortality among patients with cancer. Currently available methods to minimize the impact of anthracycline cardiotoxicity have not been widely successful. While it is largely accepted that the generation of oxygen radicals contributes to the development of anthracycline cardiotoxicity, the exact mechanisms of cardiomyocyte injury remain unclear. In this review, we discuss the current state of basic and translational research on the cardiotoxic mechanisms of anthracyclines that have led to the discovery of new therapeutic targets. Pending validation in patient populations, these recent advances have the potential to be translated into clinical approaches that will minimize anthracycline cardiotoxicity and improve outcomes in cancer survivors.

Role of biomarkers and electrocardiography assessment as individual predictors of anthracycline cardiotoxicity in lymphoma patients

The significant progress in the treatment of non-Hodgkin lymphomas, translating into prolongation of overall survival results in the manifestation of long-term adverse events, like anthracycline-related cardiotoxicity. Despite the dose-dependent cardiac dysfunction and the presence of risk factors, the increasing probability of cardiotoxicity arises from individual predisposition. Identification of high- -risk patients gives the opportunity to implement the prevention strategies to reduce the incidence of cardiac complications. The study evaluated the utility of biomarkers: N-terminal B-type natriuretic peptide, troponin I and electrocardiography with spatial QRS-T angle assessment, as indicators of individual sensitivity of cardiomyocytes to doxorubicin resulting in myocardial damage. Thirty-five treatment-naïve patients at increased risk of cardiotoxicity, were subjected prospectively during (R)-CHOP treatment to echocardiographic assessment and analysis of biomarkers: TnI and NT-proBNP plasma level and spatial QRS-T assessment before and 24 hours after each cycle of chemotherapy. The analysis of QRS-T angle was consistent with the results of NT-proBNP assessment and allowed to identify, after the first cycle of chemotherapy, patients at increased risk of developing cardiovascular complications, who require thorough echocardiographic analysis and primary cardioprotection implementation. Our data did not reveal the role of TnI in the identification of cardiac events. Our findings, though promising, should be confirmed in a larger group of patients in real-life or clinical trials.

Recognition and Management of Preclinical Cardiomyopathies in Children: Special Focus on Duchenne Muscular Dystrophy and Anthracycline Cardiotoxicity

Recognition and Management of Preclinical Cardiomyopathies in Children: Special Focus on Duchenne Muscular Dystrophy and Anthracycline Cardiotoxicity

How to improve quality of life in patients with acute leukemia and comorbid ischemic heart disease treated with anthracycline-based induction chemotherapy.

To evaluate the quality of life (QoL) parameters in patients with acute leukemia (AL) during standard induction chemotherapy, depending on the presence of concomitant ischemic heart disease and to improve them by the prevention of anthracycline cardiotoxicity with L-arginine. A total of 147adult AL patients (72males and 75females with the mean age 54.7 ± 9.3years) were enrolled in the study. QoL assessment was performed at baseline and after induction chemotherapy using SF-36questionnaire. Both physical and mental parameters were evaluated. The QoL analysis of patients with AL at the time of initial diagnosis showed extremely low QoL level in all subgroups compared with healthy individuals. It should be noted that the level of patients' QoL after achieving remission remained significantly lower than those of practically healthy, which is primarily due to the need for further long-term treatment and, probably, the fear of the disease relapse development. It was found that the administration of L-arginine during induction chemotherapy in order to reduce the risk of anthracycline cardiotoxicity development has allowed improving the QoL in patients with concomitant ischemic heart disease. L-arginine decreases the risk of anthracycline-induced myocardial injury and improves QoL in AL patients.

Study of some clinical parameters and cardiac biomarkers for early diagnosis of anthracycline-induced cardiotoxicity in child

Cardiomyopathy induced by the anthracycline cardiotoxicity aggravates the prognosis of the underlying disease and requires an early diagnosis even before the clinical manifestations of myocardial infarction. Establishing the utility of QT and QTc interval dispersion research and cardiac biomarker values, natriuretic peptide B (BNP), for the early detection of anthracycline-induced cardiotoxicity in children with haematological malignancies. Patients - 46 children (aged 2 months to 18 years) treated with anthracyclines for haematological malignancies (leukemias, malignant lymphomas). Control group: 20 apparently healthy children without a history of cardiovascular disease. Patients and the control group were evaluated by clinical examination, 12-channel ECG (3 consecutive QT/QTc interval dispersion), echocardiography (Echo), BNP plasma concentrations. Changes in the parameters investigated: (1) Increased QT/QTc intervals 73% of cases, particularly in patients with a combined anthracycline dose > 250 mg/m 2 and in patients with Echo modifications induced by anthracycline cardiotoxicity, even just a diastolic dysfunction of VS. QT interval average: 80 milliseconds in patients/40 milliseconds in controls; QTc median dispersion: 87,103 milliseconds in patients vs. 55.47 milliseconds in controls; (2) Elevated BNP in 45.7% of patients: mean baseline 89 ng/mL to 240 ng/mL Biological changes were correlated with the presence of clinical signs, echo-induced cardiotoxicity changes and increased QT/QTc interval dispersion. Elevated BNP and QT/QTc intervals in children treated with anthracyclines correlate positively with the occurrence of severe cardiotoxicity manifestations, represent a useful indicator for cardiotoxicity. Changes in these parameters occurred early in cardiotoxicity-induced echo changes and systematic monitoring of these parameters during and after cytostatic treatment is required.

Keeping the Heart Fitm2 during Chemotherapy.

Keeping the Heart Fitm2 during Chemotherapy.

Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity.

Doxorubicin (DOX) is a widely used and effective anti-cancer therapeutic. DOX treatment is associated with both acute and late onset cardiotoxicity, limiting its overall efficacy. Here, the impact of cardiomyocyte cell cycle activation was examined in a juvenile model featuring aspects of acute and late onset DOX cardiotoxicity. Two-week old MHC-cycD2 transgenic mice (which express cyclin D2 in postnatal cardiomyocytes and exhibit sustained cardiomyocyte cell cycle activity; D2 mice) and their wild type (WT) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), cardiac function was suppressed in both groups. Acute DOX cardiotoxicity in D2 and WT mice was associated with similar increases in the levels of cardiomyocyte apoptosis and Ku70/Ku80 expression (markers of DNA damage and oxidative stress), as well as similar reductions in hypertrophic cardiomyocyte growth. Cardiac dysfunction persisted in WT mice for 13 weeks following the last DOX treatment (late stage) and was accompanied by increased levels of cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. In contrast, D2 mice exhibited a progressive recovery in cardiac function, which was indistinguishable from saline-treated animals by 9 weeks following the last DOX treatment. Improved cardiac function was accompanied by reductions in the levels of late stage cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. These data suggest that cardiomyocyte cell cycle activity can promote recovery of cardiac function and preserve cardiac structure following DOX treatment.

Updates in Anthracycline-Mediated Cardiotoxicity.

Cardiotoxicity is one of the main adverse effects of chemotheraphy, affecting the completion of cancer therapies and the short- and long-term quality of life. Anthracyclines are currently used to treat many cancers, including the various forms of leukemia, lymphoma, melanoma, uterine, breast, and gastric cancers. World Health Organization registered anthracyclines in the list of essential medicines. However, anthracyclines display a major cardiotoxicity that can ultimately culminate in congestive heart failure. Taking into account the growing rate of cancer survivorship, the clinical significance of anthracycline cardiotoxicity is an emerging medical issue. In this review, we focus on the key progenitor cells and cardiac cells (cardiomyocytes, fibroblasts, and vascular cells), focusing on the signaling pathways involved in cellular damage, and the clinical biomarkers in anthracycline-mediated cardiotoxicity.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen

Background: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or β-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. Methods: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. Results: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. Conclusions: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

PO315 “Premature Coronary Artery Disease (PCAD) in Women: Demographic, Clinical and Angiographic Profile – Reflections From the PCAD Registry”

Anthracycline drugs such as doxorubicin, epirubicin, idarubicin play a highly significant role in chemotherapy. These agents have been in use for about six decades now and have proven to be greatly effective. However, progressive cardiotoxicity has been outlined to be the greatest concern of these drugs during the treatment, especially with first time users. Although it is usually noticed in recent users, research has shown that it can occur after a longer duration due to the cumulation of the dose which is less studied as compared to the early onset studies. Despite the vast effort in terms of research that has been conducted to ensure safety, a specific treatment regimen is yet to be drafted due to divergent ideologies within the field.The development of cardio-oncology, a branch of cardiology that specializes in the prevention or treatment of cardiac issues due to cancer treatment, has brought more understanding about molecular mechanisms behind anthracycline-induced cardiotoxicity (AIC). There have been divergent proposed mechanisms such as generation of ROS, calcium homeostasis dysregulation, autophagy and mitochondrial dynamism impairment. Interestingly, all these mechanisms converge on deregulation of mitochondrial function which needs wider research for verification that is yet to be conducted. Clinical symptoms evaluation, acquisition scans, systolic function detection by echocardiography and magnetic resonance imaging are the main ways of evaluating AIC.Our methodology involved a preliminary search on the PubMed, OVID Medline, Embase, ScienceDirect, Web of Science, and Google Scholar databases where keywords such as “DOX induced cardiotoxicity, anthracycline induced cardiotoxicity and cardiotoxicity prevention and management” were used.This review outlines the recent steps in the prevention and management of anthracycline cardiotoxicity and identifies research gaps that necessitate the need for further research. Our results suggest that great advancement has been achieved over the years but still there is need for more prospective researches that have involve more patients for consensus to be achieved. Also, there is need for translation of the knowledge into practice which is yet to be duly fulfilled.

1714P - Predicting the occurrence and prevention of early anthracycline cardiotoxicity of chemotherapy in patients with breast cancer

1714P - Predicting the occurrence and prevention of early anthracycline cardiotoxicity of chemotherapy in patients with breast cancer

THE ROLE OF POLYMORPHIC VARIANTS OF NO-SYNTHASE, RECEPTOR ENDOTHELIN-1 AND NADPH-OXIDASE IN THE DEVELOPMENT OF HEART FAILURE RESULTED FROM CHEMOTHERAPY-INDUCED CARDIOTOXICITY

Aim. To study the clinical and genetic aspects of the influence of polymorphic variants of the genes of endothelial NO-synthase (NOS3), the receptor of endothelin-1 type A (EDNRA) and NADPH-oxidase on the development of cardiotoxic remodeling of the left ventricle and heart failure during anthracycline-based regimens for patients with breast cancer.Methods. 176 women with breast cancer receiving anthracycline antibiotics as part of multiple drug chemotherapy regimens were examined. According to the results of the examination, 12 months after the end of multiple drug chemotherapy, all the patients with the main disease in remission were divided into 2 groups: patients with cardiac remodeling caused by cardiotoxicity (Group 1 = 52) and those with preserved heart function (Group 2 = 124). All patients underwent echocardiographic assessment before chemotherapy, during the treatment regimen with anthracyclines and after the therapy. Genetic material (buccal cells) was collected from all patients for the subsequent typing of alleles of genes NOS3 (rs1799983), EDNRA (rs5335) and NADPH-oxidase (rs4673).Results. Analysis of echocardiographic parameters in patients 12 months after the completion of multiple drug chemotherapy in comparison with those before treatment showed a statistically significant difference between end-systolic and end-diastolic dimensions, as well as a significant reduction in the left ventricular ejection fraction in the group of women who developed cardiotoxicity with anthracycline cardiotoxicity. An association between the development of cardiotoxic lesions with the presence of mutant allele of NOS3 rs1799983 and NADPH-oxidase rs4673 genes has been determined. The presence of the T/T genotype of the NOS3 rs1799983 gene was associated with myocardial damage during multiple drug chemotherapy, along with the T/T genotype of the NADPHoxidase gene rs4673. Importantly, the genotype G/G of the gene NOS3 rs1799983 was more frequently determined in Group 2, suggesting its protective effect against cardiotoxic myocardial damage.Conclusion. The development of the strategy aimed at preventing or reducing the risk of cardiovascular complications in the treatment of cancer is a crucial problem. Genetic typing is an effective measure to predict the increased risk of cardiotoxic effects of anthracyclines.

Mitochondrial Peroxynitrite Mediation of Anthracycline-Induced Cardiotoxicity as Visualized by a Two-Photon Near-Infrared Fluorescent Probe.

Anthracyclines rank among the most efficacious anticancer medications. However, their clinical utility and oncologic efficacy are severely compromised by the cardiotoxicity risk facing the early-diagnosis difficulty and their unclear molecular mechanism. Herein, a two-photon-excitable and near-infrared-emissive fluorescent probe, TPNIR-FP, was fabricated and endowed with extraordinary specificity and sensitivity and a rapid response toward peroxynitrite (ONOO-), as well as mitochondria-targeting ability. With the aid of TPNIR-FP, we demonstrate that mitochondrial ONOO- is upregulated in the early stage and contributes to the onset and progression of anthracycline cardiotoxicity in cardiomyocyte and mouse models; therefore, it represents an early biomarker to predict subclinical cardiotoxicity induced by drug challenge. Furthermore, TPNIR-FP is proved to be a robust imaging tool to provide critical insights into drug-induced cardiotoxicity and other ONOO--related pathophysiological processes.

Tissue Doppler Imaging for anthracycline cardiotoxicity monitoring in pediatric patients with cancer

BackgroundCardiotoxic effects of anthracycline therapy are a major cause of morbidity for childhood cancer survivors. The aim of this retrospective evaluation is to assess the efficacy of Tissue Doppler Imaging in the early detection of myocardial alterations in these patients.MethodsA population of 50 childhood cancer survivors (32 males and 18 females) who have been treated with anthracyclines was evaluated by standard and TDI echocardiographic examination of the basal and median region of the interventricular septum (IVSb, IVSm), of the left ventricular posterior wall (LVPWb, LVPWm), and of the mitral annulus; the results were compared with those obtained from a population of 50 healthy age-matched and sex-matched controls by using the Student test. The clinical and echocardiographic data of the two groups were compared also with the independent samples t-test. All data were expressed as mean ± standard deviation. A two-tailed P-value < 0.05 was considered statistically significant. Statistical analysis was performed using STATA 7.0.ResultsThe case-control analysis showed statistically significant differences (p < 0,05) between the patients and the controls values. The systolic performance of the patients was normal (LVEF (p = 0,0029) and LVFS (p = 0,0002)). Statistically significant differences between patients and controls were found for diastolic function measurements obtained with PW Doppler such as IVRT (p = 0,0000), DT (p = 0,0041), E (p = 0,0000), A (p = 0,0458), even if E/A ratio was not altered. TDI analysis also show significant differences between patients and controls in both LVPW and IVS (basal and middle segments); E/E’ ratio and E’/A’ ratio did not vary significantly. Linear Regression and multivariate analysis showed that Hematopoietic Stem Cell Transplantation had the highest impact on our measurements.ConclusionsThe results showed a myocardial diastolic impairment with preserved ejection fraction. Since the median follow-up time of our cohort was 2 years, further evaluation is needed to better define the diastolic alterations. TDI analysis showed high sensitivity for the detection of mild myocardial dysfunction; the implementation of this novel method as standard practice in the follow-up of selected childhood cancer survivors might help to achieve a better management of long-term complications of cardiotoxic chemotherapy.

Abstract 223: Activation of CDK2 Mediates Doxorubicin-induced Cardiotoxicity

With the rapid increase of cancer survivors due to improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent concern for modern society. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, is known to cause cardiomyopathy through induction of cardiomyocyte apoptosis. We previously showed that the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOX-induced apoptosis. In this study, we demonstrated that CDK2 activity and expression were significantly increased following DOX exposure in mouse heart and cultured neonatal rat cardiomyocytes (NRCMs). DOX-induced apoptosis, as measured by cleavage of caspase 3 and PARP, TUNEL staining, and MTT assay, was significantly suppressed by inhibition of CDK2 activity using small-molecule inhibitors, or CDK2-specific siRNA. Conversely, overexpression of CDK2 augmented DOX-induced apoptosis. DOX injection-induced CDK2 activation in mouse heart was correlated with upregulation of the BH3-only protein Bim. Mechanistically, CDK2 mediated DOX-induced expression of Bim, which was essential in triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Pharmacological inhibition of CDK2 robustly repressed DOX-induced mitochondrial depolarization. These findings identify CDK2 as a key determinant of DOX-induced apoptosis in cardiomyocytes. Activation of CDK2 is necessary for DOX-induced Bim expression and mitochondrial damage. Also, pharmacological inhibition of CDK2 might be an effective cardioprotective strategy against anthracycline cardiotoxicity.

P2785Early microcirculation impairment in a pig model of anthracycline cardiotoxicity: evaluation by cardiac magnetic resonance and coronary physiology assessment

P2785Early microcirculation impairment in a pig model of anthracycline cardiotoxicity: evaluation by cardiac magnetic resonance and coronary physiology assessment

Role of ACE inhibitors in anthracycline-induced cardiotoxicity: A randomized, double-blind, placebo-controlled trial.

Several measures including drugs have been tried to reduce anthracycline cardiotoxicity. The lack of randomized trials prompted this study to assess the role of an angiotensin converting enzyme (ACE) inhibitor (enalapril) in anthracycline-induced cardiotoxicity in children with hematological malignancies. A randomized, double-blind, placebo-controlled trial was conducted on 84 patients with leukemia (41) and lymphoma (43) who received anthracyclines (doxorubicin and/or daunorubicin) at cumulative dose ≥200mg/m2 . The patients were randomized to receive either enalapril [group A (n=44)] or placebo [group B (n=40)] for 6months. Left ventricular ejection fraction (LVEF) and cardiac biomarkers (cardiac troponin I [cTnI], probrain natriuretic peptide [proBNP], and creatine kinase MB [CK-MB]) were assessed at baseline and 6months. The primary outcome was a measured decrease in LVEF (≥20%). Secondary outcome measures were changes in cardiac biomarkers and the development of heart failure or arrhythmias. LVEF decreased in both groups at 6months, more so in group B (62.25±5.49vs 56.15±4.79, P<0.001). A ≥20% decrease was seen in 3 patients in group B but none in group A (P=0.21). Cardiac biomarkers increased more in group B at 6months, and the increase was significant for proBNP (49.60±35.97vs 98.60±54.24, P<0.001) and cTnI (0.01±0.00vs 0.011±0.003, P=0.035) but not significant for CK-MB (1.08±0.18vs 1.21±0.44, P=0.079). In group A, 9.1% of the patients showed an increase in proBNP level ≥100 compared with 37.5% in group B (P<0.001). No patient developed heart failure or arrhythmia. Enalapril has a role in reducing cardiac toxicity after anthracycline administration.

Non-invasive imaging of mitochondrial dysfunction and anthracycline cardiotoxicity by repurposing 99mTc Sestamibi SPECT imaging

Non-invasive imaging of mitochondrial dysfunction and anthracycline cardiotoxicity by repurposing 99mTc Sestamibi SPECT imaging