Anthracycline-induced Cardiotoxicity Research Articles

A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity

BackgroundAntineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.MethodsThe effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines’s interaction with key genes.ResultsThe ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.ConclusionThis study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.

Natural Products for Preventing and Managing Anthracycline-Induced Cardiotoxicity: A Comprehensive Review.

Doxorubicin (DOX) is an anthracycline anticancer agent that is highly effective in the treatment of solid tumors. Given the multiplicity of mechanisms involved in doxorubicin-induced cardiotoxicity, it is difficult to identify a precise molecular target for toxicity. The findings of a literature review suggest that natural products may offer cardioprotective benefits against doxorubicin-induced cardiotoxicity, both in vitro and in vivo. However, further confirmatory studies are required to substantiate this claim. It is of the utmost importance to direct greater attention towards the intricate signaling networks that are of paramount importance for the survival and dysfunction of cardiomyocytes. Notwithstanding encouraging progress made in preclinical studies of natural products for the prevention of DOX-induced cardiotoxicity, these have not yet been translated for clinical use. One of the most significant obstacles hindering the development of cardioprotective adjuvants based on natural products is the lack of adequate bioavailability in humans. This review presents an overview of current knowledge on doxorubicin DOX-induced cardiotoxicity, with a focus on the potential benefits of natural compounds and herbal preparations in preventing this adverse effect. As literature search engines, the browsers in the Scopus, PubMed, Web of Science databases and the ClinicalTrials.gov register were used.

An update of the molecular mechanisms underlying anthracycline induced cardiotoxicity.

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment.

Exploring Anthracycline-Induced Cardiotoxicity from the Perspective of Protein Quality Control.

Anthracyclines are effective anticancer drugs; however, their use is restricted because of their dose-dependent, time-dependent and irreversible myocardial toxicity. The mechanism of anthracycline cardiotoxicity has been widely studied but remains unclear. Protein quality control is crucial to the stability of the intracellular environment and, ultimately, to the heart because cardiomyocytes are terminally differentiated. Two evolutionarily conserved mechanisms, autophagy, and the ubiquitin-proteasome system, synergistically degrade misfolded proteins and remove defective organelles. Recent studies demonstrated the importance of these mechanisms. Further studies will reveal the detailed metabolic pathway and metabolic control of the protein quality control mechanism integrated into anthracycline-induced cardiotoxicity. This review provides theoretical support for clinicians in the application and management of anthracyclines.

Interrogating early molecular events of doxorubicin-induced cardiotoxicity at single-cell level to identify new cardioprotective agents

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Leducq Foundation Background Doxorubicin (DOX) is a highly effective chemotherapeutic agent widely used for treating various types of malignancies. Unfortunately, its clinical implication is hampered by cardiotoxic side effects which are responsible for increased mortality among cancer survivors compared to the general population. Preclinical and clinical studies have highlighted potential mechanisms of anthracycline-induced cardiotoxicity (AIC), but the core molecular basis remains largely unknown. More importantly, only a few studies have focused on the characterization of the molecular events that distinguish the early reversible phase of AIC from an advanced and irreversible state of the disease. Aim We aim to provide an unbiased and in-depth profile of early transcriptional changes induced by DOX at single cell resolution, to identify new druggable targets for the development of cardioprotective agents to prevent AIC. Methods Based on our previously established murine model of AIC, BALB/c mice were injected with saline (Vehicle) or DOX (3 weekly injections of 4 mg/kg), and hearts were collected at either 3 days (acute cardiotoxicity) or 6 weeks after the first injection (chronic cardiotoxicity). Nuclei were isolated from frozen hearts for single-nuclei transcriptomic (snRNAseq; 10x Genomics, Chromium Single Cell 3' v3.1). Seurat pipeline was mainly used for downstream bioinformatic analysis. Results Echocardiography revealed DOX-induced systolic dysfunction at 6 weeks, confirming the establishment of AIC. SnRNAseq data from 12 hearts allowed to identify 8 major cell types including cardiomyocytes (CM), endothelial and mural cells, fibroblasts, myeloid cells, B and T lymphocytes and neuronal-like cells. To unravel changes in CM, we performed unbiased subclustering which defined 6 different subpopulations, including a CM_Stressed population, characterized by enrichment of typical cardiac stress markers, such as natriuretic peptide hormone (Nppb) and myosin heavy chain 7 (Myh7). Differential abundance analysis showed enrichment of the CM-Stressed population at both 3 days and 6 weeks, suggesting that DOX drives a transcriptional change toward stress status in CM both at early and late stages of cardiotoxicity. Differential gene expression analysis revealed Golgi associated kinase 1B (Gask1B) to be significantly upregulated at both 3 days and 6 weeks in CM_Stressed. In agreement, preliminary experiments showed that Gask1b gene silencing partially rescued DOX-induced heart dysfunction in zebrafish model and hiPSC-derived CM, identifying Gask1b as a potential new player in DOX cardiotoxicity. Conclusions We generated a single-nucleus dataset of DOX-treated mouse hearts and identified transcriptional changes driven by DOX in CM at early and late stages of the disease. Furthermore, we identified Gask1b gene, whose role in cardiac pathophysiology was previously unappreciated, as a new potential marker and determinant of DOX cardiotoxicity.

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.

USE OF SGLT2–INHIBITORS IN THE TREATMENT OF ANTHRACICLINE CARDIOTOXICITY

Abstract The survival rate of cancer patients has significantly increased in the last 25 years thanks to the extraordinary advances in anti-tumor therapies. However, many chemotherapeutic agents are potentially cardiotoxic. In particular, anthracycline-induced cardiotoxicity is a clinical condition caused by chemotherapy drugs that lead to morpho-functional alterations and cell death of cardiomyocytes; the most typical clinical manifestation of this cardiotoxicity is the development of left ventricular dysfunction, which over time can evolve towards full-blown heart failure. It is therefore characterized by a reversible asymptomatic stage that progresses to an irreversible stage, often difficult to treat. For an early individualization of this toxicity, a dedicated clinic has been established in our center for the monitoring of patients undergoing treatment with cardiotoxic chemotherapy. We describe the case of a 53-year-old patient with preserved biventricular systolic function undergoing neoadjuvant treatment for breast cancer, who at the end of the second infusion of anthracyclines presented with mild exertional dyspnoea associated with radiological signs of pulmonary congestion and an increase in the indices of myocardionecrosis and BNP. The echocardiogram revealed a sudden worsening of the left ventricular systolic function which was 48%. It was therefore decided to hospitalize the patient and initiate infusional diuretic therapy with a rapid clinical and instrumental response. An SGLT2 inhibitor with indication for the treatment of heart failure with moderately reduced ejection fraction was also added to the therapy. At the one-month check-up, there was an almost complete recovery of left ventricular function and a clear symptomatic benefit with associated normalization of laboratory markers of myocardial damage and heart failure, with the possibility for the patient to undergo surgery to remove the left ventricle. tumor mass. This clinical case could represent a starting point to start considering therapy with SGLT2 inhibitors for the prevention and early treatment of cardiac toxicities from some chemotherapeutics, in order to avoid the process of irreversibility of myocardial damage with subsequent poor response to anti-inflammatory therapies. – conventional compensation.

Anthracycline-induced cardiotoxicity – primary preventive options. An overview

Anthracycline-induced cardiotoxicity (AIC) has been known since the 1970s but remains relevant, mainly due to the widespread use of anthracyclines in oncological practice. Currently, AIC is viewed as a prolonged and continuous process that starts with the initial dose at molecular and cellular levels and advances, ultimately resulting in cardiomyopathy and heart failure. Many contemporary studies aim to discover methods for early detection of anthracycline-related myocardial injury. Additionally, ongoing research focuses on agents for primary prevention of AIC, examining their effectiveness, place, and timing of administration. This review aims to present the available preventive options, interconnecting them with their mechanisms of action and the mechanisms of AIC. According to current recommendations, primary prevention is indicated for high- and very high-risk patients and includes general measures to lower cardiovascular risk, neurohormonal therapy, and statins. Regular cardiology assessments are a crucial component of heart damage prevention. Evidence of mild myocardial injury (deteriorated Global Longitudinal Strain and troponin release) justifi es cardioprotective measures. Some aspects remain unanswered, including whether early cardioprotection is required, as well as the role and effi cacy of sacubitril/valsartan and sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) for AIC prevention. Physical activity is a promising method to reduce the cardiac damaging effects of anthracyclines. 

Assessment of Native Myocardial T1 Mapping for Early Detection of Anthracycline-Induced Cardiotoxicity in Patients with Cancer: a Systematic Review and Meta-analysis

Anthracycline antibiotic is one of the most effective anti-tumor drugs used to manage certain types of breast cancers, lymphomas, and leukemias. However, anthracyclines induce a dose-dependent cardiotoxicity that may progress to heart failure. Thus, using a sensitive predictor of early cardiac dysfunction in patients treated with anthracyclines can help detect subclinical cardiac dysfunction early and help initiate interventions to protect these patients. Among parameters of myocardial measure, cardiac magnetic resonance (CMR)-measured native myocardial T1 mapping is considered a sensitive and accurate quantitative measure of early subclinical cardiac changes, particularly cardiac inflammation and fibrosis. However, to understand the quality and the validity of the current evidence supporting the use of these measures in patients treated with anthracyclines, we aimed to conduct a systematic review of clinical studies of this measure to detect early myocardial changes in cancer patients treated with anthracyclines. The primary outcome was the level of native T1 mapping. We performed fixed-effects meta-analyses and assessed certainty in effect estimates. Of the 1780 publications reviewed (till 2022), 23 were retrieved, and 9 articles met the inclusion criteria. Our study showed that exposure to anthracycline was associated with a significant elevation of native myocardial T1 mapping from baseline (95% CI 0.1121 to 0.5802; p = 0.0037) as well as compared to healthy control patients (95% CI 0.2925 to 0.7448; p < 0.0001). No significant publication bias was noted on the assessment of the funnel plot and Egger’s test. According to the Q test, there was no significant heterogeneity in the included studies (I2 = 0.0000% versus healthy controls and I2 = 14.0666% versus baseline). Overall, our study suggests that native myocardial T1 mapping is useful for detecting anthracycline-induced cardiotoxicity in patients with cancer.

Abstract PO2-20-06: Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience

Abstract Background Cancer therapy related cardiac dysfunction (CTRCD) is a significant side effect of several chemotherapies, targeted agents, and immunotherapies integral to treatment. Anthracyclines are an example of a commonly used chemotherapy drug class that can cause irreversible early and late onset heart failure. CTRCD often leads to dose reductions and treatment delays or cessation, limiting treatment success and contributing to increased mortality and life-long morbidity in oncology survivors. In Australia, there are currently no multi-centre, longitudinal studies examining CTRCD in adult oncology patients. Trial design The Australian Cardiology-Oncology Registry (ACOR) is a prospective observational non-interventional study involving 14 sites across Australia. Patient information is obtained from hospital medical records and de-identified upon entry into the registry. Patient demographics, medical history, cancer diagnosis, treatment, cardiac evaluations, and the management of demonstrated CTRCD are recorded. Data is collected at baseline (prior to treatment), and then at six-monthly intervals thereafter. Additionally, patients who develop anthracycline-induced cardiotoxicity (ACT) will be asked to participate in the biobanking study, which will involve a one-off 12mL peripheral blood draw that will be processed at an external site for whole genome exome sequencing and the development of pluripotent derived stem cell cardiomyocytes. Eligibility criteria Inclusion Criteria • Adult oncology patients (&amp;gt;18+ years of age) treated with cardiotoxic therapies within the last 5-years Exclusion Criteria • Diagnosis of Trisomy 21 • Patients being treated with palliative intent Specific aims Chris O’Brien Lifehouse aims to use the ACOR to explore the epidemiology, clinical presentation, and management of CTRCD amongst adult oncology patients receiving cardiotoxic therapies. In addition, a biobanking sub-study will attempt to identify gene polymorphisms predisposing individuals to developing ACT. It is hoped that such longitudinal data collection can lead to the introduction of an ACT susceptibility genetic screening test allowing for the inclusion of patient risk stratification prior to anthracycline exposure in routine cancer treatment. Statistical methods Descriptive statistics will be used for variables for quantitative analysis. Kaplan Meier analyses will be used for survival curves, freedom from cardiac failure since enrolment and freedom from arrhythmia since enrolment. An annual report will be produced. Present accrual and target accrual At the time of submission, 224 adult oncology patients have been recruited to the ACOR via Chris O’Brien Lifehouse with the opening of the biobanking sub-study currently in progress. The ACOR anticipates with full registered site capacity to capture 600 patients annually. Citation Format: Jocelyn Finney, Ben Felmingham, Sanjeev Kumar, Alina Mahmood, Lisa Horvath, David Celermajer, Rachel Conyers. Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-06.

Proteomics Approach to Identify Anthracycline-induced Cardiotoxicity Mechanisms in Human Cardiac Fibroblasts

Doxorubicin-induced cardiotoxicity (DIC) is a major life-threatening side-effect of chemotherapy in cancer patients. DIC leading to heart failure is caused by numerous mechanisms, including impaired mitochondrial function, disruption of calcium homeostasis, and altered gene and protein response that triggers cell death and, eventually, fibrosis. We performed a preliminary investigation of the effect of doxorubicin (DOX) on the cardiac fibroblast proteome using mass-spectrometry. Quantitative analysis showed significantly altered expression of 186 proteins. Nine out of forty-two Dox-upregulated proteins and seventeen out of twenty-four Dox-downregulated proteins showed a reciprocal trend in expression upon inhibiting a structural scaffold protein involved in cardiac calcium channel regulation. Overall, our data suggests the involvement of pathways in regulating mitochondrial energy metabolism, matrix remodeling, cell cycle/arrest, and cell survival via Rho/Rac nuclear exchanger proteins. DIC is multifactorial, and based on our pilot data, modulation of calcium channel regulators may be a promising strategy to mitigate the progression of DIC to heart failure. Research support received from the American Heart Association, NIH and the University of Arkansas for Medical Sciences. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardioprotective Potential of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Cancer Treated With Anthracyclines: An Observational Study

Anthracyclines are pivotal in cancer treatment, yet their clinical utility is hindered by the risk of cardiotoxicity. Preclinical studies highlight the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in mitigating anthracycline-induced cardiotoxicity. Nonetheless, the translation of these findings to clinical practice remains uncertain. This study aims to evaluate the safety and potential of SGLT2i for preventing cardiotoxicity in patients with cancer, without preexisting heart failure (HF), receiving anthracyclines therapy. Using the TriNetX Global Research Network, patients with cancer, without previous HF diagnosis, receiving anthracycline therapy were identified and classified into 2 groups based on SGLT2i usage. A 1:1 propensity score matching was used to control for baseline characteristics between the 2 groups. Patients were followed for 2 years. The primary end point was new-onset HF, and the secondary end points were HF exacerbation, new-onset arrhythmia, myocardial infarction, all-cause mortality, and all-cause hospitalization. Safety outcomes included acute renal failure and creatinine levels. A total of 79,074 patients were identified, and 1,412 were included post-matching (706 in each group). They comprised 53% females, 62% White, with a mean age of 62.5 ± 11.4 years. Over the 2-year follow-up period, patients on SGLT2i had lower rates of new-onset HF (hazard ratio 0.147, 95% confidence interval 0.073 to 0.294) and arrhythmia (hazard ratio 0.397, 95% confidence interval 0.227 to 0.692) compared with those not on SGLT2i. The incidence of all-cause mortality, myocardial infarction, all-cause hospitalization, and safety outcomes were similar between both groups. In conclusion, among patients with cancer receiving anthracycline therapy without preexisting HF, SGLT2i use demonstrates both safety and effectiveness in reducing anthracycline-induced cardiotoxicity, with a decreased incidence of new-onset HF, HF exacerbation, and arrhythmias.

Early Detection and Prediction of Anthracycline-Induced Cardiotoxicity - A Prospective Cohort Study.

In the present study, we aimed to investigate whether early cardiac biomarker alterations and echocardiographic parameters, including left atrial (LA) strain, can predict anthracycline-induced cardiotoxicity (AIC) and thus develop a predictive risk score. The AIC registry is a prospective, observational cohort study designed to gather serial echocardiographic and biomarker data before and after anthracycline chemotherapy. Cardiotoxicity was defined as a reduction in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and <55%. In total, 383 patients (93% women; median age, 57 [46-66] years) completed the 2-year follow-up; 42 (11.0%) patients developed cardiotoxicity (median time to onset, 292 [175-440] days). Increases in cardiac troponin T (TnT) and B-type natriuretic peptide (BNP) and relative reductions in the left ventricular global longitudinal strain (LV GLS) and LA reservoir strain [LASr] at 3 months after anthracycline administration were independently associated with subsequent cardiotoxicity. A risk score containing 2 clinical variables (smoking and prior cardiovascular disease), 2 cardiac biomarkers at 3 months (TnT ≥0.019 ng/mL and BNP ≥31.1 pg/mL), 2 echocardiographic variables at 3 months (relative declines in LV GLS [≥6.5%], and LASr [≥7.5%]) was generated. Early decline in LASr was independently associated with subsequent cardiotoxicity. The AIC risk score may provide useful prognostication in patients receiving anthracyclines.

Prevention and treatment of anthracycline-induced cardiotoxicity: A bibliometric analysis of the years 2000–2023

AimsThis study aimed to evaluate the global research trend in the prevention and treatment of cardiotoxicity caused by anthracyclines from 2000 to 2023, and to explore international cooperation, research hotspots, and frontier trends. MethodsThe articles on the prevention and treatment of anthracycline-induced cardiotoxicity published from 2000 to 2023 were searched by Web of Science. The bibliometrics software CiteSpace was used for visual analysis of countries, institutions, journals, authors, cited authors, cited references, and keywords. ResultsThis study analyzed the current status of global research on the prevention and treatment of cardiotoxicity caused by anthracyclines. A total of 3,669 papers were searched and 851 studies were included. The number of publications increased gradually throughout the years. Cardiovascular Toxicology (15) is the journal with the most publications. Circulation (547) ranked first among cited journals. In this field, the country with the most publications is the United States (229), and the institution with the most publications is Charles Univ Prague (18). In the analysis of the authors, Tomas S (10) ranked first. Cardinale D (262) ranked first among cited authors. In the ranking of cited literature frequency, the article ranked first is “Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy” (121). The keywords “heart failure” (215) and “oxidative stress” (212) were the most frequent. “Enalapril”, “inflammation”, “cell death”, “NF-κB” and “Nrf2” were the advanced research contents in 2019–2023. ConclusionsThis study provided valuable information for cardio-oncology researchers to identify potential collaborators and institutions, discover hot topics, and explore new research directions. The prevention and treatment of anthracycline-induced cardiotoxicity focuses on early detection and timely treatment. The results of the current clinical studies on the treatment of anthracycline-induced cardiotoxicity are contradictory, and more studies are needed to provide more reliable clinical evidence in the future.

Abstract LB180: Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison

Abstract Introduction. Cardiotoxicity is an important side effect limiting the clinical use of all anthracyclines, including doxorubicin (DOX). DOX targets topoisomerase II alpha (Top2α) and beta (Top2β), two enzymes that regulate DNA topology. Top2β is present in cardiomyocytes and has been proposed as a major contributor to DOX-induced cardiotoxicity. Annamycin (ANN), a novel clinically evaluated DOX analog, displays suppressed or no cardiotoxic properties in preclinical in vivo experiments. The objective of this study was to directly assess and compare the potency of DOX and ANN against Top2α and Top2β and determine their impact on physiology of human cardiomyocytes and mice hearts following chronic exposure. Our initial data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Methods. The potency of ANN and DOX to inhibit Top2 was tested in DNA relaxation assays using recombinant Top2α and Top2β with kinetoplast as the DNA substrate. ANN and DOX cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models. Cardiotoxicity of liposome formulated ANN (L-ANN) is currently being examined in ongoing clinical studies of subjects with acute myeloid leukemia (NCT05319587) or soft tissue sarcoma with metastases to the lungs (NCT04887298). Results. The nanomolar range potency of ANN in tested cancer cell lines was 2-10 times greater than that of DOX. The DNA relaxation assay demonstrated high potency of ANN against recombinant Top2α and Topβ with IC50 values 0.23±0.06 and 0.22± 0.06 µM, respectively, whereas the IC50 for DOX was 0.65± 0.22 and 0.34± 0.31µM, respectively. Importantly, ANN did not significantly affect electric potential, contractility, and viability of human cardiomyocytes up to highest tested dose of 1,500 nM (72h exposure). In contrast, DOX caused a dramatic change in heart beating rate and decreased in contractility and field potential amplitude. In rat cardiomyocyte culture (H92C), ANN was 14-fold less cytotoxic than DOX (IC50 1,264 nM for ANN vs. 88 nM for DOX). No cardiotoxicity of L-ANN was detected in myocardium of nude mice exposed weekly for 12 weeks to therapeutic doses of L-ANN (4 mg/kg, 40% of LD10). Finally, data from ongoing clinical trials revealed no drug related cardiac events in patients receiving L-ANN (confirmed by an independent review of the Duke’s ECHO core laboratory, USA). Conclusions. Our preclinical studies demonstrate non-cardiotoxic properties of ANN. These data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Interestingly, ANN appeared to be a significantly more potent inhibitor of Top2β than DOX, suggesting that Top2β may not be a universal mediator of cardiotoxicity of anthracyclines. Additional studies are needed to reevaluate the role of Top2β in anthracycline-induced cardiotoxicity. Citation Format: Rafal J. Zielinski, Krzysztof Grela, Roberto Cardenas-Zuniga, Stanislaw Skora, Izabela Fokt, Mihai Gagea, Wolfram Dempke, Waldemar Priebe. Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB180.

Network Pharmacology along with Molecular Docking to Explore the Mechanism of Danshen Injection against Anthracycline-induced Cardiotoxicity and Transcriptome Validation.

Although anthracyclines have demonstrated efficacy in cancer therapy, their utilization is constrained by cardiotoxicity. In contrast, Danshen injection (DSI), derived from Salvia miltiorrhiza, has a longstanding tradition of being employed to ameliorate cardiovascular ailments, including anthracycline- induced cardiotoxicity (AIC). Nonetheless, there is a notable dearth of comprehensive systematic investigation into the molecular mechanisms underlying DSI's effects on AIC. Consequently, this study was undertaken to explore the underlying mechanism by which DSI acted against AIC. Employing network pharmacology approach, the current investigation undertook a comprehensive analysis of the impact of DSI on AIC, which was further validated by transcriptome sequencing with in vitro AIC model. Additionally, molecular docking was conducted to evaluate the binding of active ingredients to core targets. A total of 3,404 AIC-related targets and 12 active ingredients in DSI, including chrysophanol, luteolin, tanshinone IIA, isoimperatorin, among others, were collected by differentially expressed analysis and database search, respectively. The network pharmacology and enrichment analysis suggested 102 potential targets and 29 signaling pathways associated with the protective effect of DSI on AIC. Three core targets (CA12, NOS3, and POLH) and calcium signaling pathways were further validated by transcriptomic analysis of the in-vitro model. The high affinity of the active ingredients binding to corresponding targets was confirmed by molecular docking. The present study suggested that DSI might exert a cardioprotective effect on AIC via the inhibition of CA12, NOS3, and POLH, as well as the modulation of calcium signaling. Further experiments are warranted to verify the findings.

Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline-induced cardiotoxicity.

Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS=LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35±5.03vs. 25.04±4.10, p<.001), LVGLS (-22.77±2.45vs. -20.44±2.62, p<.001), and LAVGLS (51.12±5.63vs. 45.61±5.22, p<.001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30±4.73vs. 57.08±5.83, p<.001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of>19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC),.842; p<.001), a ΔLVGLS of>13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC,.763; p<.001), and a ΔLAVGLS of>16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC,.905; p<.001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905vs..763, p=.027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9%vs. 74.2%, p=.002) and maintained sensitivity in predicting LV cardiotoxicity. LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.

Exploring the effects of calycosin on anthracycline-induced cardiotoxicity: a network pharmacology, molecular docking, and experimental study.

Chemotherapy with anthracyclines can cause cardiotoxicity, possibly leading to stopping treatment in some cancer patients. In cardio-oncology research, preventing and minimizing anthracycline-induced cardiotoxicity (AIC) is a hot issue. For the treatment of AIC, calycosin (CA), an isoflavone component in astragali radix (AR), has become a research focus. However, the elaborate mechanisms of calycosin treating AIC remain to be unrevealed. To explore the effects of CA on AIC through multiple dimensions concerning network pharmacology, molecular docking, and experimental evaluations. The study evaluated calycosin's potential targets and mechanisms for treating AIC using network pharmacology and molecular docking. The candidate genes/targets of CA and AIC were screened using the online-available database. Protein-protein interactions (PPI) between the common targets were constructed using the STRING platform, and the results were then visualized using Cytoscape. Molecular docking was used to evaluate the strength of the binding force between CA and the common targets. The possible pharmacological mechanisms of CA were explained by pathway enrichment and GSEA. Subsequently, the candidate targets were identified in vitro experiments. Network pharmacology effectively discovered the CA's multitarget intervention in AIC, including TNF, ABCC1, TOP2A, ABCB1, and XDH. CA binds to the ATP-binding cassette subfamily B member 1(ABCB1) had the highest binding energy (-7.5 kcal/mol) according to the molecular docking analysis and was selected and visualized for subsequent analysis. In vitro experiments showed that ABCB1 exhibited significant time-curve changes under different doses of doxorubicin (DOX) compared with DMSO control experiments. The anti-AIC pharmacological mechanism of CA were revealed by highlighting the biological processes of oxidative stress (OR) and inflammation. We employed a practicable bioinformatics method to connect network and molecular docking to determine the calycosin's therapeutic mechanism against AIC and identified some bioinformatics results in in vitro experiments. The results presented show that CA may represent an encouraging treatment for AIC.

Is There a Mitochondrial Protection via Remote Ischemic Conditioning in Settings of Anticancer Therapy Cardiotoxicity?

To provide an overview of (a) protective effects on mitochondria induced by remote ischemic conditioning (RIC) and (b) mitochondrial damage caused by anticancer therapy. We then discuss the available results of studies on mitochondrial protection via RIC in anticancer therapy-induced cardiotoxicity. In three experimental studies in healthy mice and pigs, there was a RIC-mediated protection against anthracycline-induced cardiotoxicity and there was some evidence of improved mitochondrial function with RIC. The RIC-mediated protection was not confirmed in the two available studies in cancer patients. In adult cancer patients, RIC was associated with an adverse outcome. There are no data on mitochondrial function in cancer patients. Studies in tumor-bearing animals are needed to determine whether RIC does not interfere with the anticancer properties of the drugs and whether RIC actually improves mitochondrial function, ultimately resulting in improved cardiac function.

Early detection of anthracycline-induced cardiotoxicity using [68Ga]Ga-FAPI-04 imaging.

Anthracycline-induced cardiotoxicity (AIC), whose major manifestation is diffuse myocardial fibrosis, is an important clinical problem in cancer therapy. Therefore, early identification and treatment are clinically important. This study aims to explore the feasibility of using 68Ga-labelled fibroblast activation protein (FAP) inhibitor ([68Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) for the early identification of the fibrotic process and guidance of antifibrosis therapy in AIC. An AIC rat model was induced by the intravascular administration of doxorubicin (DOX) once per week for 1, 2, 3 and 6weeks (2.5mg/kg/injection, groups 1-4), whereas intravascular saline was administered to control rats. Experimental and control groups (n = 4) underwent [68Ga]Ga-FAPI PET/CT following disease induction. Groups 5 and 6 received DOX injections for 3 and 6weeks, treated with angiotensin-converting enzyme (ACE) inhibitor starting at 3weeks, treated with enalapril (20mg/kg, gastric gavage) daily and underwent echocardiography and [68Ga]Ga-FAPI PET/CT at 3weeks after treatment. Rat hearts were subjected to haematoxylin and eosin staining, FAP immunohistochemistry, Sirius red staining and Masson's trichrome staining to investigate the pathological changes and deposition of collagen fibres. Rat blood was sampled weekly for the enzyme-linked immunosorbent assay of various markers of myocardial injury, such as plasma cardiac troponin I, B-type natriuretic peptide and angiotensin II. [68Ga]Ga-FAPI-04 uptake by the heart was significantly higher in the cardiotoxicity group than in the control group at weeks 3 (SUVmax: 1.21 ± 0.23 vs 0.67 ± 0.01, P < 0.05) and 6 (SUVmax: 1.48 ± 0.28 vs 0.67 ± 0.08, P < 0.001), whereas left ventricle ejection fraction (LVEF) did not significantly differ between normal and AIC rats at week 3. FAP+ expression began to increase starting at week 3, before irreversible fibrotic changes were detected, until week 6. After 3weeks of enalapril treatment, [68Ga]Ga-FAPI-04 accumulation decreased in groups 5 and 6 (SUVmax decreased from 1.21 ± 0.23 to 0.77 ± 0.08 and 1.48 ± 0.28 to 1.09 ± 1.06, P < 0.05). Cardiac function was preserved (LVEF was 75.7% ± 7.38% in group 3 vs 74.5% ± 2.45% in group 5, P > 0.05) and improved (LVEF increased from 51.6% ± 9.03% in group 4 to 65.2% ± 4.27% in group 6, P < 0.05), and myocardial fibrosis attenuated (from 6.5% ± 1.2% in group 4 to 4.31% ± 0.37% in group 6, P < 0.01). [68Ga]Ga-FAPI PET/CT can be used for the early detection of active myocardial fibrosis in AIC and the evaluation of the efficacy of therapeutic interventions. Early treatment guided by [68Ga]Ga-FAPI PET/CT may reduce anthracycline-induced myocardial injury and improve heart function.