Anthracycline-induced Cardiomyopathy Research Articles

Anthracycline-Induced Cardiomyopathy in Cancer Survivors: Management and Long-Term Implications.

Recent advancements in personalized treatments, such as anthracycline chemotherapy, coupled with timely diagnoses, have contributed to a decrease in cancer-specific mortality rates and an improvement in cancer prognosis. Anthracyclines, a potent class of antibiotics, are extensively used as anticancer medications to treat a broad spectrum of tumors. Despite these advancements, a considerable number of cancer survivors face increased risks of treatment complications, particularly the cardiotoxic effects of chemotherapeutic drugs like anthracyclines. These effects can range from subclinical manifestations to severe consequences such as irreversible heart failure and death, highlighting the need for effective management of chemotherapy side effects for improved cancer care outcomes. Given the lack of specific treatments, early detection of subclinical cardiac events post-anthracycline therapy and the implementation of preventive strategies are vital. An interdisciplinary approach involving cardiovascular teams is crucial for the prevention and efficient management of anthracycline-induced cardiotoxicity. Various factors, such as age, gender, duration of treatment, and comorbidities, should be considered significant risk factors for developing chemotherapy-related cardiotoxicity. Tools such as electrocardiography, echocardiography, nuclear imaging, magnetic resonance imaging, histopathologic evaluations, and serum biomarkers should be appropriately used for the early detection of anthracycline-related cardiotoxicity. Furthermore, understanding the underlying biological mechanisms is key to developing preventive measures and personalized treatment strategies to mitigate anthracycline-induced cardiotoxicity. Exploring specific cardiotoxic mechanisms and identifying genetic variations can offer fresh perspectives on innovative, personalized treatments. This chapter aims to discuss cardiomyopathy following anthracycline therapy, with a focus on molecular mechanisms, preventive strategies, and emerging treatments.

Cardioprotective Diet to Prevent Anthracycline-Induced Cardiotoxicity in Patients with Breast Cancer: A Randomized Open-Label Controlled Trial.

Objectives: Several studies have indicated that dietary interventions may offer protection against the development of cardiac damage in the case of anthracycline-induced cardiomyopathy (AIC). The goal of this study was to assess whether an evidence-based cardioprotective diet can be effective in preventing AIC in patients with breast cancer. Design: Randomized, open-label, controlled trial. The study period was set for 18 weeks, and the data were analyzed by generalized estimating equation modeling and one-way repeated measures analysis of variance. Setting/Location: Shahid Rajaie Hospital affiliated (Tehran, Iran). Subjects: Fifty anthracycline-treated patients with breast cancer. Interventions: Patients were randomized to receive either a 2-hour training in evidence-based cardio-protective diet or Carvedilol 6.25 mg bid. Outcome Measures: The primary outcome was the number of patients with abnormal left ventricular ejection fraction (LVEF) after 18 weeks. Results: At week 18, 12 (48%) out of 25 participants in the cardioprotective diet group had abnormal LVEF in comparison with 21 (84%) out of 25 in the carvedilol group (p = 0.007). Also, 2 (8%) out of 25 in the cardioprotective diet group compared with 7 (28%) out of 25 participants in the carvedilol group had abnormal global longitudinal strain (p = 0.066). The diet group showed significant improvements in the quality-of-life dimensions named "health change" and "general health" compared with the carvedilol group using the Short Form-36 Health Survey questionnaire. Conclusions: This study suggests that an evidence-based cardioprotective diet can contribute to the prevention of AIC. Although current treatments for AIC can be effective, further research is mandatory for more options.

Protective Effects of Hesperetin on Cardiomyocyte Integrity and Cytoskeletal Stability in a Murine Model of Epirubicin-Induced Cardiotoxicity: A Histopathological Study

Anthracyclines, including epirubicin (Epi), are effective chemotherapeutics but are known for their cardiotoxic side effects, primarily inducing cardiomyocyte apoptosis. This study investigates the protective role of hesperetin (HSP) against cardiomyopathy triggered by Epi in a murine model. Male CD1 mice were divided into four groups, with the Epi group receiving a cumulative dose of 12 mg/kg intraperitoneally, reflecting a clinically relevant dosage. The co-treatment group received 100 mg/kg of HSP daily for 13 days. After the treatment period, mice were euthanized, and heart tissues were collected for histopathological, immunofluorescence/immunohistochemistry, and transmission electron microscopy (TEM) analyses. Histologically, Epi treatment led to cytoplasmic vacuolization, myofibril loss, and fiber disarray, while co-treatment with HSP preserved cardiac structure. Immunofluorescent analysis of Bcl-2 family proteins revealed Epi-induced upregulation of the pro-apoptotic protein Bax and a decrease in anti-apoptotic Bcl-2, which HSP treatment reversed. TEM observations confirmed the preservation of mitochondrial ultrastructure with HSP treatment. Moreover, in situ detection of DNA fragmentation highlighted a decrease in apoptotic nuclei with HSP treatment. In conclusion, HSP demonstrates a protective effect against Epi-induced cardiac injury and apoptosis, suggesting its potential as an adjunctive therapy in anthracycline-induced cardiomyopathy. Further studies, including chronic cardiotoxicity models and clinical trials, are warranted to optimize its therapeutic application in Epi-related cardiac dysfunction.

Heart transplantation in patients with anthracycline-induced cardiomyopathy

Heart transplantation in patients with anthracycline-induced cardiomyopathy

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model.

Background: Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage. Method: Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3mg/kg/week; for five and 10weeks), while the control group received saline solution. Myocardial miRNA expression was first screened using TaqMan Advanced miRNA microfluidic card assays, after which 32 miRNAs were selected for targeted analysis using qRT-PCR. Results: The first subclinical signs of cardiotoxicity (significant increase in plasma cardiac troponin T) were observed after 5weeks of daunorubicin treatment. At this time point, 10 miRNAs (including members of the miRNA-34 and 21 families) showed significant upregulation relative to the control group, with the most intense change observed for miRNA-1298-5p (29-fold change, p < 0.01). After 10weeks of daunorubicin treatment, when a further rise in cTnT was accompanied by significant left ventricle systolic dysfunction, only miR-504-5p was significantly (p < 0.01) downregulated, whereas 10 miRNAs were significantly upregulated relative to the control group; at this time-point, the most intense change was observed for miR-34a-5p (76-fold change). Strong correlations were found between the expression of multiple miRNAs (including miR-34 and mir-21 family and miR-1298-5p) and quantitative indices of toxic damage in both the early and late phases of cardiotoxicity development. Furthermore, plasma levels of miR-34a-5p were strongly correlated with the myocardial expression of this miRNA. Conclusion: To the best of our knowledge, this is the first study that describes alterations in miRNA expression in the myocardium during the transition from subclinical, ANT-induced cardiotoxicity to an overt cardiotoxic phenotype; we also revealed how these changes in miRNA expression are strongly correlated with quantitative markers of cardiotoxicity.

Anthracycline-Induced Cardiomyopathy: Clinical Relevance and Response to Pharmacologic Therapy

Anthracycline-Induced Cardiomyopathy: Clinical Relevance and Response to Pharmacologic Therapy

Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy - A COG-ALTE03N1 Report.

Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo−/− mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy

Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at ‘CpG’ sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case–control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe ‘cg15939386’ in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study's objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Cardio-oncology for Pediatric and Adolescent/Young Adult Patients.

As chemotherapy continues to improve the lives of patients with cancer, understanding the effects of these drugs on other organ systems, and the cardiovascular system in particular, has become increasingly important. The effects of chemotherapy on the cardiovascular system are a major determinant of morbidity and mortality in these survivors. Although echocardiography continues to be the most widely used modality for assessing cardiotoxicity, newer imaging modalities and biomarker concentrations may detect subclinical cardiotoxicity earlier. Dexrazoxane continues to be the most effective therapy for preventing anthracycline-induced cardiomyopathy. Neurohormonal modulating drugs have not prevented cardiotoxicity, so their widespread, long-term use for all patients is currently not recommended. Advanced cardiac therapies, including heart transplant, have been successful in cancer survivors with end-stage HF and should be considered for these patients. Research on new targets, especially genetic associations, may produce treatments that help reduce cardiovascular morbidity and mortality.

Left Ventricle Size Correlates with Peak Exercise Capacity in Pediatric Cancer Survivors Exposed to Anthracycline Chemotherapy.

Cancer survivors exposed to anthracycline chemotherapy are at risk for developing cardiomyopathy, which may have delayed clinical manifestation. In a retrospective cross-sectional study, we evaluated the utility of cardiopulmonary exercise testing (CPET) for detecting early cardiac disease in 35 pediatric cancer survivors by examining the associations between peak exercise capacity (measured via percent predicted peak VO2) and resting left ventricular (LV) function on echocardiography and cardiac magnetic resonance imaging (cMRI). We additionally assessed the relationships between LV size on resting echocardiography or cMRI and percent predicted peak VO2 since LV growth arrest can occur in anthracycline-exposed patients prior to changes in LV systolic function. We found reduced exercise capacity in this cohort, with low percent predicted peak VO2 (62%, IQR: 53-75%). While most patients in our pediatric cohort had normal LV systolic function, we observed associations between percent predicted peak VO2 and echocardiographic and cMRI measures of LV size. These findings indicate that CPET may be more sensitive in manifesting early anthracycline-induced cardiomyopathy than echocardiography in pediatric cancer survivors. Our study also highlights the importance of assessing LV size in addition to function in pediatric cancer survivors exposed to anthracyclines.

Renin-angiotensin System Antagonists and Beta-blockers in Prevention of Anthracycline Cardiotoxicity: a Systematic Review and Meta-analysis.

The evidence supporting the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and beta-blockers for the prevention of anthracycline-induced cardiomyopathy is controversial. We performed a meta-analysis to assess the effectiveness of these drugs in preventing cardiotoxicity. The meta-analysis included prospective, randomized studies in adults receiving anthracycline chemotherapy and compared the use of RAAS inhibitors or beta-blockers versus placebo with a follow-up of 6 to 18 months. The primary outcome was change in left ventricular ejection fraction (LVEF) during chemotherapy. Secondary outcomes were the incidence of heart failure, all-cause mortality, and changes in end-diastolic measurement. Heterogeneity was assessed by stratification and meta-regression. A significance level of p < 0.05 was adopted. The search resulted in 17 studies, totaling 1,530 patients. The variation (delta) in LVEF was evaluated in 14 studies. Neurohormonal therapy was associated with a lower delta in pre- versus post-therapy LVEF (weighted mean difference 4.42 [95% confidence interval 2.3 to 6.6]) and higher final LVEF (p < 0.001). Treatment resulted in a lower incidence of heart failure (risk ratio 0.45 [95% confidence interval 0.3 to 0.7]). There was no effect on mortality (p = 0.3). For analysis of LVEF, substantial heterogeneity was documented, which was not explained by the variables explored in the study. The use of RAAS inhibitors and beta-blockers to prevent anthracycline-induced cardiotoxicity was associated with less pronounced reduction in LVEF, higher final LVEF, and lower incidence of heart failure. No changes in mortality were observed. (CRD PROSPERO 42019133615).

Heart failure with reduced ejection fraction in young women: Management and outcomes in Reunion island

Heart failure with reduced ejection fraction (HFrEF) is a public health problem in France and around the world, with an increasing prevalence and a high mortality-rate. There is no data about HFrEF in young women in Reunion Island. We sought to describe characteristics, management, and evolution of HFrEF in young women in Reunion Island. We retrospectively enrolled all 18- to 44-year-old women, hospitalized between 01/01/2014 and 12/31/2019 with a new diagnosis of cardiac failure with left ventricular ejection fraction (LVEF) ≤ 45%. One hundred and thirty patients were included. Thirty-six patients (28%) had an ischemic cardiopathy, 88 (68%) a non-ischemic dilated cardiomyopathy. Among them, 40 (45%) had a peripartum cardiomyopathy, 27 (30%) an idiopathic cardiomyopathy, 5 (6%) an anthracycline-induced cardiomyopathy. Mean age was 36 ± 6 years, mean LVEF 29 ± 10%. Most frequent cardiovascular risk factors were: tobacco use (44%), hypertension (32%), and diabetes (25%). Obesity (39%) was particularly represented regardless of the type of cardiopathy. At discharge, 83% of patients were treated with beta-blockers and 86% with angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. Fifty-three patients (49%) had a complete LVEF recovery (≥ 50%) after one year, with a significantly higher rate in peripartum cardiomyopathy (71%) than in non-peripartum dilated cardiomyopathy (33%, P = 0.02). The overall one-year mortality-rate was 11%, significantly higher in non-peripartum dilated cardiomyopathy (19%) than peripartum cardiomyopathy (3%) and ischemic cardiopathy (8%). One patient underwent cardiac transplantation after a myocardial infarction. HFrEF has a high mortality-rate in young women in Reunion Island. In these young patients, dilated cardiomyopathy is frequent, but ischemic cardiopathy has a particularly high incidence due to the high prevalence of cardiovascular risk factors.

Anthracycline-induced cardiomyopathy in the long-term period after chemotherapy: clinical case

Background. As is known, the treatment of the oncological process leads either to the occurrence of cardiovascular pathology, or to an increase in the risk of death from cardiovascular diseases. Currently, the concept of ˝cardiovascular toxicity˝ has been introduced, which is associated with the treatment of cancer (CTR-CVT). Systemic drug anthracycline-containing anticancer therapy can cause a number of cardiovascular complications, such as myocardial systolic dysfunction, coronary heart disease, cardiac arrhythmias, arterial hypertension. Particular attention is paid to anthracycline drugs, because they are still included in combinations of many adjuvant therapy regimens and first-line treatment of both the most common cancers and rarer ones.&#x0D; Clinical Case Description. The article presents a clinical case of a patient who received adjuvant polychemotherapy for breast cancer in 2017 with AC 4 D 4 regimen, in which chronic anthracycline-induced cardiomyopathy manifested years after completion of antitumor therapy. The development of anthracycline cardiomyopathy is possible even in patients with initially low cardiac risk.&#x0D; Conclusion. The clinical case highlights the importance of monitoring patients after the end of anthracycline antitumor therapy, in particular, they are shown to periodically perform an echocardiographic study in order to detect delayed asymptomatic myocardial dysfunction.

697 SGLT2-INHIBITORS PREVENT LEFT VENTRICULAR DISFUNCTION INDUCED BY ANTHRACYCLINE CHEMOTERAPY IN MOUSE MODEL: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background No human studies evaluating the efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2-i) in preventing left ventricular dysfunction induced by anthracycline chemotherapy are available. Current evidence on this topic is based on few studies conducted on mouse models. Objective We investigated this issue through a meta-analysis of echocardiography studies that reported data on difference in left ventricular function between animals assuming SGLT2-i and controls in mouse models of anthracycline-induced cardiomyopathy. Methods The PubMed, OVID-MEDLINE and Cochrane library databases were systematically analysed to search English-language articles published from inception to 31 July 2022. Studies were identified by using Me-SH terms and crossing the following terms: “ sodium glucose cotransporter 2 inhibitors”, “gliflozin”, “anthracycline”, “cardiotoxicity”, “systolic dysfunction” and “echocardiography”. Results The meta-analysis included a total of 106 mice (Sprague Dawley and C57Bl/6 species) with anthracycline-induced cardiomyopathy from 7 studies, 60 mice assuming a SGLT2-i (Empagliflozin:4 studies, Dapagliflozin:2, Canagliflozin:1) and 46 controls. Compared with controls, left ventricle systolic function was significantly better in the pooled SGLT2-i group. Precisely, both fractional shortening (FS: 44,7±3,7 vs 32,6±3,3) and left ventricle ejection fraction (LVEF: 78,2±3,4 vs 64,2±4,9) were higher in the pooled SGLT2-i group than in the controls group, with standard mean difference (SMD) respectively being 2,42±0,56 for FS (CI: 1,326-3,510, p value &amp;lt;0.001) and 2,46±0,61 for LVEF (CI: 1,267-3,656, p value &amp;lt;0.001). Figure 1. Conclusions Our study shows a favourable effect of SGLT2-i in the prevention of left ventricular dysfunction induced by anthracycline chemotherapy in mouse models, suggesting that this pharmacological strategy should also be tested in clinical studies involving human subjects.

Early myocardial oedema can predict subsequent cardiomyopathy in high-dose anthracycline therapy.

This study aims to assess subclinical changes in functional and morphologic myocardial MR parameters very early into a repetitive high-dose anthracycline treatment (planned cumulative dose >650mg/m2 ), which may predict subsequent development of anthracycline-induced cardiomyopathy (aCMP). Thirty sarcoma patients with previous exposition of 300-360mg/m2 doxorubicin-equivalent chemotherapy who were planned for a second treatment of anthracycline-based chemotherapy (360mg/m2 doxorubicin-equivalent) were recruited. Enrolled individuals received three CMR studies (before treatment, 48h after first anthracycline treatment and upon completion of treatment). Native T1 mapping (MOLLI 5s(3s)3s), T2 mapping, and extracellular volume (ECV) maps were acquired in addition to a conventional CMR with SSFP-cine imaging at 1.5T. Patients were given 0.2mmol/kg gadoteridol for ECV quantification and LGE imaging. Blood samples for cardiac biomarkers were obtained before each scan. Development of relevant aCMP was defined as drop of left ventricular ejection fraction (LVEF) by >10% compared with baseline. Twenty-three complete datasets were available for analysis. Median treatment time was 20.7±3.0weeks. Eight patients developed aCMP with LVEF reduction >10% until end of chemotherapy. Baseline LVEF was not different between patients with and without subsequent aCMP. Patients with aCMP had decreased LV mass upon completion of therapy (99.4±26.5g vs. 90.3±24.8g; P=0.02), whereas patients without aCMP did not show a change in LV mass (91.5±20.0g vs. 89.0±23.6g; P>0.05). On strain analysis, GLS (-15.3±1.3 vs. -13.4±1.6; P=0.02) and GCS (-16.7±2.1 vs. -14.9±2.6; P=0.04) were decreased in aCMP patients upon completion of therapy, whereas non-aCMP individuals showed no change in GLS (-15.4±3.3 vs. -15.4±3.4; P=0.97). When assessed 48h after first dose of anthracyclines, patients with subsequent aCMP had significantly elevated myocardial T2 times compared with before therapy (53.0±2.8ms vs. 49.3±5.2ms, P=0.02) than patients who did not develop aCMP (50.7±5.1ms vs. 51.1±3.9ms, P>0.05). Native T1 times decreased at 48h after first dose irrespective of development of subsequent aCMP (1020.2±28.4ms vs. 973.5±40.3ms). Upon completion of therapy, patients with aCMP had increased native T1 compared with baseline (1050.8±17.9ms vs. 1022.4±22.0ms; P=0.01), whereas non-aCMP patients did not (1034.5±46.6ms vs. 1018.4±29.7ms; P=0.15). No patient developed new myocardial scars or compact myocardial fibrosis under chemotherapy. Cardiac biomarkers were elevated independent of development of aCMP. With high cumulative anthracycline doses, early increase of T2 times 48h after first treatment with anthracyclines can predict the development of subsequent aCMP after completion of chemotherapy. Early drop of native T1 times occurs irrespective of development of aCMP in high-dose anthracycline therapy.

Abstract 14988: Longitudinal Strain for Early Identification of Anthracycline-Induced Cardiomyopathy in Pediatrics

Introduction: Anthracycline-induced cardiomyopathy (ACM) affects pediatric cancer survivors and echocardiogram (echo) surveillance is required. In adults, a decline in global longitudinal strain (LS) &gt;15% is a pre-clinical marker of ACM. There is utility in determining change in strain associated with pre-clinical ACM in pediatrics. Methods: We queried our institutional database to identify patients &lt;19 yo, with acute myeloid leukemia (AML), Ewing’s sarcoma or osteosarcoma, who received anthracyclines (1/1/2008 - 12/31/2020), and developed sub-acute or chronic ACM (LVEF &lt;55% greater than 30 days post anthracycline completion). Echo at baseline (time of cancer diagnosis) and pre-ACM (within 2 years of first documented LVEF &lt;55%) were compared for strain differences. Four-chamber LS, mid-chamber circumferential strain (CS) and left atrial strain (LAS) were analyzed using TomTec software. Results: Twenty-two patients were eligible for analysis from 428 meeting inclusion criteria (Figure 1). Demographics are shown in Table 1. There was a significant decline in LS from baseline to pre-ACM echo (-20.7 +/-2.98 vs -18.2 +/-3.74; p=0.026) amounting to a mean absolute LS decline of 2.5% and relative decline of 12.4% from baseline. Differences in CS (25.15 +/-4.89 vs 23.44 +/-5.11; p=0.35), LAS (43.09 +/-10.48 vs 45.23 +/-13.43; p=0.54) and heart rate (99.55 +/-19.88 vs 90.24 +/-26.47; p=0.09) were not significant. Conclusions: A significant decrease in LS occurs following anthracyclines pre-dating the diagnosis of subacute or chronic ACM in children. Prospective research with established imaging protocols may validate the role of strain in surveillance for pediatric ACM.

Abstract 13359: Added Benefit of Parametric Mapping in Anthracycline-Induced Cardiomyopathy - Avoiding a Misdiagnosis

Case Presentation A 72 year old man presented with progressive dyspnea on exertion, only able to climb 4 stairs prior to symptom onset. He had a history of diffuse large B-cell lymphoma for which he had completed chemotherapy with cyclophosphamide, doxorubicin, rituximab, vincristine, and prednisone a year prior to presentation with recent PET scan showing complete remission. EKG showed rate-controlled atrial fibrillation. TTE confirmed a severely reduced systolic function with LVEF 25% and global hypokinesis. Coronary angiogram revealed no obstructive disease. Cardiac MRI (CMR) was then performed with no evidence of myocardial infarction, infiltration, or scarring on delayed gadolinium enhancement (DGE). T2 mapping, DIR, and TIR sequencing did not show any myocardial edema. However, baseline pre-contrast T1 relaxation time was increased at 1140-1153ms [Figure 1A] with a calculated ECV [Figure 1B] elevated at 37-40%, concerning for anthracycline-induced cardiomyopathy (AIC). Discussion Anthracyclines, such as doxorubicin, are important chemotherapeutic agents; however, their utility is often limited by development of progressive cardiotoxicity. Cumulative dose-dependent exposure can lead to apoptotic myocyte loss, myocardial fibrosis, and dysmotility. DGE usually identifies focal myocardial fibrosis; however, anthracycline-induced fibrosis is frequently diffuse and can be missed by qualitative analysis and DGE burden assessment. Diffuse fibrosis is better demonstrated with use of hematocrit adjusted ECV and pre-/post-T1 mapping. CMR provides additional information about decrease in the LV mass, aortic stiffness, myocardial strain, early fibrosis detection, and myocardial edema that can aid in early detection of cardiotoxicity during anthracycline therapy. Use of CMR parametric imaging is complementary and essential in accurately diagnosing AIC in patients with prior exposure and merits widespread consideration in cardio-oncology.

Review of potential predictors of anthracycline-induced cardiotoxicity from the position of disease pathogenesis

Cardiotoxicity of anthracycline chemotherapy drugs is one of the main interdisciplinary problems in the research area of cardio-oncology. As is known, the high antitumor efficacy of anthracycline antibiotics is significantly leveled by the development of disabling and lethal heart lesions. However, the pathogenesis of toxic heart disease, as well as diagnostic criteria and markers of anthracycline-induced cardiomyopathy are not fully understood. The article provides a detailed review of potential markers of anthracycline cardiotoxicity from the position of disease pathogenesis. The scheme of pathogenetic development of anthracycline-induced cardiomyopathy is proposed in this article. The main methods of diagnostics of toxic damage of the heart that are currently used in clinical researches of domestic and foreign scientists are reviewed.