Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity.
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ABSTRACT:
SUBMITTER: Magdy T
PROVIDER: S-EPMC7923254 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Anthracyclines are a class of chemotherapy drugs that are highly effective for the treatment of human cancers, but their clinical use is limited by associated dose-dependent cardiotoxicity. The precise mechanisms by which individual anthracycline induces cardiotoxicity are not fully understood. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are emerging as a physiologically relevant model to assess drugs cardiotoxicity. Here, we describe an assay platform by coupling hiPSC-CMs and impedance measurement, which allows real-time monitoring of cardiomyocyte cellular index, beating amplitude, and beating rate. Using this approach, we have performed comparative studies on a panel of four anthracycline drugs (doxorubicin, epirubicin, idarubicin, and daunorubicin) which share a high degree of structural similarity but are associated with distinct cardiotoxicity profiles and maximum cumulative dose limits. Notably, results from our hiPSC-CMs impedance model (dose-dependent responses and EC50 values) agree well with the recommended clinical dose limits for these drugs. Using time-lapse imaging and RNAseq, we found that the differences in anthracycline cardiotoxicity are closely linked to extent of cardiomyocyte uptake and magnitude of activation/inhibition of several cellular pathways such as death receptor signaling, ROS production, and dysregulation of calcium signaling. The results provide molecular insights into anthracycline cardiac interactions and offer a novel assay system to more robustly assess potential cardiotoxicity during drug development.
| S-EPMC7956936 | biostudies-literature
Project description:Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus. Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis. Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43-2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11-2.74), and obesity (OR: 1.72; 95% CI: 1.13-2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1-35.8% vs. 16.4%, 95% CI: 13.4-19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9-36.1%), which is similar with the overall result of GLS. Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.
| S-EPMC8511483 | biostudies-literature
Project description:BackgroundAnthracyclines are commonly used chemotherapeutic agents to treat malignant tumors. However, cardiotoxicity is a potentially serious adverse effect of anthracyclines. Beta-blockers may be effective in preventing anthracycline-induced cardiotoxicity (AIC). However, the lack of direct comparisons of various beta-blockers interferes with clinical decision-making. Network meta-analysis (NMA) was performed to assess the effectiveness of beta-blockers for AIC.MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Clinical Trials. The last update was in May 2022. Randomized controlled trials (RCT) of beta-blockers for AIC were included. Four beta-blockers were selected for comparison based on the number of studies. NMA was conducted with STATA 14.0 software.ResultsA total of 10 RCTs (875 patients) met the selection criteria. NMA results showed that carvedilol was superior to bisoprolol [SMD = -0.50, 95% CI (-0.91, -0.10)] and nebivolol [SMD = -1.46, 95%CI (-2.82, -0.11)] in a delay of LVEF. The results of the cumulative probability ordering are as follows: carvedilol (83.8%) > metoprolol (71.8%) > bisoprolol (43.9%) > placebo (40.9%) > nebivolol (9.5%).ConclusionBased on the available evidence, carvedilol is the best beta-blocker for AIC, followed by metoprolol. However, additional studies with large samples should be conducted to confirm our findings.
| S-EPMC9403514 | biostudies-literature
Project description:Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long-term complications. Cancer treatment-related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio-Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline-induced cardiotoxicity (AIC), which can lead to heart failure. Early-onset cardiotoxicity appears within a year of treatment, whereas late-onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.
| S-EPMC7877852 | biostudies-literature
Project description:ObjectivesTo identify anthracycline-induced acute (within 1 month) and early-onset chronic progressive (within 1 year) cardiotoxicity in children younger than 16 years of age with childhood malignancies at a tertiary care centre of Pakistan.DesignProspective cohort study.SettingAga Khan University, Karachi, Pakistan.Participants110 children (aged 1 month-16 years).InterventionAnthracycline (doxorubicin and/or daunorubicin).Outcome measurementsAll children who received anthracycline as chemotherapy and three echocardiographic evaluations (baseline, 1 month and 1 year) between July 2010 and June 2012 were prospectively analysed for cardiac dysfunction. Statistical analysis including systolic and diastolic functions at baseline, 1 month and 1 year was carried out by repeated measures analysis of variance.ResultsMean age was 74±44 months and 75 (68.2%) were males. Acute lymphoblastic leukaemia was seen in 70 (64%) patients. Doxorubicin alone was used in 59 (54%) and combination therapy was used in 35 (32%). A cumulative dose of anthracycline <300 mg/m(2) was used in 95 (86%). Fifteen (14%) children developed cardiac dysfunction within a month and 28 (25%) children within a year. Of these 10/15 (66.6%) and 12/28 (43%) had isolated diastolic dysfunction, respectively, while 5/15 (33.3%) and 16/28 (57%) had combined systolic and diastolic dysfunction. Seven (6.4%) patients expired due to severe cardiac dysfunction. Eight of 59 (13.5%) children showed dose-related cardiotoxicity (p=<0.001). Cardiotoxicity was also high when the combination of doxorubicin and daunorubicin was used (p=0.004).ConclusionsIncidence of anthracycline-induced cardiotoxicity is high. Long-term follow-up is essential to diagnose its late manifestations.
| S-EPMC3840341 | biostudies-literature
Project description:Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional and newer anti-neoplastic therapies can cause short- and long-term cardiotoxicity. The clinical implications of this cardiotoxicity become more important with the increasing use of cardiotoxic drugs. The implications are especially serious among patients predisposed to adverse cardiac effects, such as youth, the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic radiation. However, the optimal strategy for preventing and managing chemotherapy-induced cardiotoxicity remains unknown. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use. The only United States Food and Drug Administration and European Medicines Agency approved treatment for preventing anthracycline-related cardiomyopathy is dexrazoxane. We advocate administering dexrazoxane during cancer treatment to limit the cardiotoxic effects of anthracycline chemotherapy.
| S-EPMC7048046 | biostudies-literature
Project description:Cardiac side effects are a major drawback of anticancer therapies, often requiring the use of low and less effective doses or even discontinuation of the drug. Among all the drugs known to cause severe cardiotoxicity are anthracyclines that, though being the oldest chemotherapeutic drugs, are still a mainstay in the treatment of solid and hematological tumors. The recent expansion of the field of Cardio-Oncology, a branch of cardiology dealing with prevention or treatment of heart complications due to cancer treatment, has greatly improved our knowledge of the molecular mechanisms behind anthracycline-induced cardiotoxicity (AIC). Despite excessive generation of reactive oxygen species was originally believed to be the main cause of AIC, recent evidence points to the involvement of a plethora of different mechanisms that, interestingly, mainly converge on deregulation of mitochondrial function. In this review, we will describe how anthracyclines affect cardiac mitochondria and how these organelles contribute to AIC. Furthermore, we will discuss how drugs specifically targeting mitochondrial dysfunction and/or mitochondria-targeted drugs could be therapeutically exploited to treat AIC.
| S-EPMC7080657 | biostudies-literature
Project description:BackgroundDoxorubicin and other anthracycline derivatives inhibit topoisomerase II and is an important class of cytotoxic chemotherapy in cancer treatment. The use of anthracycline is limited by dose-dependent cardiotoxicity, which may manifest initially as asymptomatic cardiac dysfunction with subsequent progression to congestive heart failure. Despite baseline assessment and periodic monitoring of cardiac function for patients receiving anthracycline agents, there are unmet needs in prediction and prevention of anthracycline-induced cardiotoxicity (AIC).Case summaryA 35-year-old African American female was found to have a 9-cm high-grade osteosarcoma of right femur and normal baseline cardiac function with left ventricular ejection fraction of approximately 60%-70% determined by transthoracic and dobutamine stress echocardiogram. She underwent perioperative doxorubicin and cisplatin chemotherapy with 3 cycles before surgery and 3 cycles after surgery, and received a total of 450 mg/m2 doxorubicin at the end of her treatment course. She was evaluated regularly during chemotherapy without any cardiac or respiratory symptoms. Approximately two months after her last chemotherapy, the patient presented to the emergency department with dyspnea for one week and was intubated for acute hypoxic respiratory failure. Echocardiogram showed an ejection fraction of 5%-10% with severe biventricular failure. Despite attempts to optimize cardiac function, the patient's hemodynamic status continued to decline, and resuscitation was not successful on the seventh day of hospitalization. The autopsy showed no evidence of osteosarcoma, and the likely cause of death was cardiac failure with the evidence of pulmonary congestion, liver congestion, and multiple body cavity effusions.ConclusionWe present a case of 35-year-old African American female developing cardiogenic shock shortly after receiving a cumulative dose of 450 mg/m2 doxorubicin over 9 mo. Cardiac monitoring and management of patients receiving anthracycline chemotherapy have been an area of intense research since introduction of these agents in clinical practice. We have reviewed literature and recent advances in the prediction and prevention of AIC. Although risk factors currently identified can help stratify patients who need closer monitoring, there are limitations to our current understanding and further research is needed in this field.
| S-EPMC7821007 | biostudies-literature
Project description:Breast cancer has become the most common cancer in the US and worldwide. While advances in early detection and treatment have resulted in a 40% reduction in breast cancer mortality, this reduction has not been achieved uniformly among racial groups. A large percentage of non-metastatic breast cancer mortality is related to the cardiovascular effects of breast cancer therapies. These effects appear to be more prevalent among patients from historically marginalized racial/ethnic backgrounds, such as African American and Hispanic individuals. Anthracyclines, particularly doxorubicin and daunorubicin, are the first-line treatments for breast cancer patients. However, their use is limited by their dose-dependent and cumulative cardiotoxicity, manifested by cardiomyopathy, ischemic heart disease, arrhythmias, hypertension, thromboembolic disorders, and heart failure. Cardiotoxicity risk factors, such as genetic predisposition and preexisting obesity, diabetes, hypertension, and heart diseases, are more prevalent in racial/ethnic minorities and undoubtedly contribute to the risk. Yet, beyond these risk factors, racial/ethnic minorities also face unique challenges that contribute to disparities in the emerging field of cardio-oncology, including socioeconomic factors, food insecurity, and the inability to access healthcare providers, among others. The current review will address genetic, clinical, and social determinants that potentially contribute to this disparity.
| S-EPMC10452913 | biostudies-literature
Project description:Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance toward improving patient care and our understanding of the molecular mechanisms involved in ACT. Human-induced pluripotent stem cell-derived cardiomyocytes represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests.
| S-EPMC6590110 | biostudies-literature