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Human-induced pluripotent stem cells (hiPSCs) are discussed as disease modeling for optimization and adaptation of therapy to each individual. However, the fundamental question is still under debate whether stem-cell-based disease modeling and drug discovery are applicable for recapitulating pathological processes under in vivo conditions. Drug treatment and exposure to different chemicals and environmental factors can initiate diseases due to toxicity effects in humans. It is well documented that drug-induced cardiotoxicity accelerates the development of heart failure (HF). Until now, investigations on the understanding of mechanisms involved in HF by anticancer drugs are hindered by limitations of the available cellular models which are relevant for human physiology and by the fact that the clinical manifestation of HF often occurs several years after its initiation. Recently, we identified similar genomic biomarkers as observed by HF after short treatment of hiPSCs-derived cardiomyocytes (hiPSC-CMs) with different antitumor drugs such as anthracyclines and etoposide (ETP). Moreover, we identified common cardiotoxic biological processes and signal transduction pathways which are discussed as being crucial for the survival and function of cardiomyocytes and, therefore, for the development of HF. In the present review, I discuss the applicability of the in vitro cardiotoxicity test systems as modeling for discovering preventive mechanisms/targets against cardiotoxicity and, therefore, for novel HF therapeutic concepts.

Higenamine (HG) is a natural benzylisoquinoline alkaloid isolated from Aconitum with positive inotropic and chronotropic effects. This study aimed to investigate the possible cardioprotective effects of HG combined with [6]-gingerol (HG/[6]-GR) against DOX-induced chronic heart failure (CHF) by comprehensive approaches. DOX-induced cardiotoxicity model in rats and H9c2 cells was established. Therapeutic effects of HG/[6]-GR on haemodynamics, serum indices and histopathology of cardiac tissue were analysed. Cell mitochondrial energy phenotype and cell mitochondrial fuel flex were measured by a Seahorse XFp analyser. Moreover, UHPLC-Q-TOF/MS was performed to explore the potential metabolites affecting the therapeutic effects and pathological process of CHF. To further investigate the potential mechanism of HG/[6]-GR, mRNA and protein expression levels of RAAS and LKB1/AMPK/Sirt1-related pathways were detected. The present data demonstrated that the therapeutic effects of HG/[6]-GR combination on CHF were presented in ameliorating heart function, down-regulation serum indices and alleviating histological damage of heart tissue. Besides, HG/[6]-GR has an effect on increasing cell viability of H9c2 cells, ameliorating DOX-induced mitochondrial dysfunction and elevating mitochondrial OCR and ECAR value. Metabolomics analyses showed that the therapeutic effect of HG/[6]-GR combination is mainly associated with the regulation of fatty acid metabolites and energy metabolism pathways. Furthermore, HG/[6]-GR has an effect on down-regulating RAAS pathway-related molecules and up-regulating LKB1/AMPKα/Sirt1-related pathway. The present work demonstrates that HG/[6]-GR prevented DOX-induced cardiotoxicity via the cardiotonic effect and promoting myocardial energy metabolism through the LKB1/AMPKα/Sirt1 signalling pathway, which promotes mitochondrial energy metabolism and protects against CHF., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.

Recent clinical investigations indicate that anthracycline-based chemotherapies induce early decline in heart mass in cancer patients. Heart mass decline may be caused by a decrease in cardiac cell number because of increased cell death or by a reduction in cell size because of atrophy. We previously reported that an anthracycline, doxorubicin (DOX), induces apoptotic death of cardiomyocytes by activating cyclin-dependent kinase 2 (CDK2). However, the signaling pathway downstream of CDK2 remains to be characterized, and it is also unclear whether the same pathway mediates cardiac atrophy. Here we demonstrate that DOX exposure induces CDK2-dependent phosphorylation of the transcription factor forkhead box O1 (FOXO1) at Ser-249, leading to transcription of its proapoptotic target gene, Bcl-2-interacting mediator of cell death (Bim). In cultured cardiomyocytes, treatment with the FOXO1 inhibitor AS1842856 or transfection with FOXO1-specific siRNAs protected against DOX-induced apoptosis and mitochondrial damage. Oral administration of AS1842856 in mice abrogated apoptosis and prevented DOX-induced cardiac dysfunction. Intriguingly, pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely because of repression of muscle RING finger 1 (MuRF1), a proatrophic FOXO1 target gene. In conclusion, DOX exposure induces CDK2-dependent FOXO1 activation, resulting in cardiomyocyte apoptosis and atrophy. Our results identify FOXO1 as a promising drug target for managing DOX-induced cardiotoxicity. We propose that FOXO1 inhibitors may have potential as cardioprotective therapeutic agents during cancer chemotherapy., (© 2020 Xia et al.)

In the present study, we explored SA's activity against DOX-induced cardiotoxicity and revealed its underlying mechanisms. Male Wistar rats (weight, 190-210g; n = 6) were randomly divided into four groups: group I, normal control; group II, DOX 15 mg/kg via intraperitoneal (ip) route; group III, administered DOX+SA 20 mg/kg; and group IV, administered DOX+captopril (CAP 30 mg/kg). SA and CAP were administered orally for seven days, and DOX (15 mg/kg) was injected intraperitoneally an hour before SA treatment on the fifth day. Forty-eight hours after DOX administration, animals were anesthetized and sacrificed for molecular and histology experiments. SA significantly mitigated the myocardial effects of DOX, and following daily administration, it reduced serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB to near normal values. Levels of oxidative stress markers, glutathione-peroxidase, superoxide dismutase, and catalase, in the cardiac tissue were significantly increased, whereas malondialdehyde levels decreased after SA treatment in DOX-administered rats. Furthermore, DOX caused an inflammatory reaction by elevating the levels of proinflammatory cytokines, tumor necrosis factor- α (TNF- α ), interleukin-1 β (IL-1 β ), and endothelin- (ET-) 1, as well as nuclear factor kappa-B (NF- κ B) expression. Daily administration of SA significantly repressed TNF- α , IL-1 β , ET-1, and NF- κ B levels. caspase-3 and Bax expression, bcl-2-like protein and caspase-3 activities and levels. Overall, we found that SA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptotic damage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Yousef A. Bin Jardan et al.)

Background: Due to growing long-term survival rate of oncologic patients, there is increased interest in cardiotoxicity of oncologic treatment among medical professionals. It is concerning both paediatric and adult patients. When prescribing oncologic treatment, there should be focus on the efficacy and safety of the used drugs. Nowadays, the main problem is early dia-gnosis of cardiotoxicity., Purpose: In our work we wanted to investigate whether the increase in bio-markers after the cytostatic therapy with anthracyclines can predict further increase in the left ventricular volume and decrease of the left ventricular ejection fraction., Materials and Methods: We were monitoring 36 patients with the dia-gnosis of non-Hodgkins lymphoma who received therapy with anthracyclines. After the therapy we were measuring the cardiac bio-markers NT-proBNP and high-sensitivity troponin I and performed echocardiography., Results: In our group of patients there is a statistically significant correlation between increased levels of troponin I, NT-proBNP and increment of the left ventricular volume measured before the treatment and 3 months after the treatment. There is also a significant inverse correlation between the left ventricular volume and left ventricular ejection fraction. There was no relationship between higher cumulative doses of anthracyclines and the increment of the left ventricular volume. There is a significant correlation between higher cumulative doses of anthracyclines and higher levels of troponin I., Conclusion: The measurement of bio-markers troponin I and NT-proBNP should be considered for an early dia-gnosis of cardiotoxicity in oncologic patients. Echocardiography is also beneficial for the dia-gnosis in these patients. All efforts after the dia-gnosis should be focused on the therapy with cardioprotective drugs, which can prevent the development of severe heart failure.

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

There is a distinct increase in the risk of heart disease in people exposed to ionizing radiation (IR). Radiation-induced heart disease (RIHD) is one of the adverse side effects when people are exposed to ionizing radiation. IR may come from various forms, such as diagnostic imaging, radiotherapy for cancer treatment, nuclear disasters, and accidents. However, RIHD was mainly observed after radiotherapy for chest malignant tumors, especially left breast cancer. Radiation therapy (RT) has become one of the main ways to treat all kinds of cancer, which is used to reduce the recurrence of cancer and improve the survival rate of patients. The potential cause of radiation-induced cardiotoxicity is unclear, but it may be relevant to oxidative stress. Oxidative stress, an accumulation of reactive oxygen species (ROS), disrupts intracellular homeostasis through chemical modification and damages proteins, lipids, and DNA; therefore, it results in a series of related pathophysiological changes. The purpose of this review was to summarise the studies of oxidative stress in radiotherapy-induced cardiotoxicity and provide prevention and treatment methods to reduce cardiac damage., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Zhang Ping et al.)

Cardiotoxicity is a major drawback of anticancer therapies, often hindering optimal management of cancer. Among the most cardiotoxic agents are anthracyclines (AC) that, despite being cardiotoxic, are highly effective in the treatment of a wide variety of cancers, spanning from hematological malignancies to solid tumors. Modern imaging techniques can identify patients at risk of developing cardiotoxicity, but treatment options are still limited and ineffective, partly because the molecular mechanisms underlying AC cardiac side effects are still incompletely understood. Although AC cardiotoxicity was initially ascribed to the trigger of cell-damaging oxidative stress, antioxidants fail to prevent anthracycline-induced cardiotoxicity (AIC), suggesting the involvement of additional mechanisms. Among these, the cellular recycling process, named autophagy, recently emerged to play a key role in AIC, but whether autophagy activation is beneficial or detrimental in this context is still controversial. This review will summarize recent evidence on the role of autophagy in AIC in the attempt to reconcile the controversial findings in the field. Finally, we will describe major regulator of cardiac autophagy that may represent good candidates for therapeutic intervention in AIC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

T-2 toxin, A trichothecenes mycotoxin, is immunotoxic to animals and humans. Although it is highly cardiotoxic, the pathogenesis of cardiomyopathy caused by T-2 toxin is not entirely clear. Hence, in our research, cardiomyopathy was induced by a single injection of T-2 mycotoxin (0.23 mg/kg s.c., 1 LD 50 ) to Wistar rats. The cardiac tissue was carefully examinated by using basic histopathology, semiquantitative (tissue grading score scales) and imaging (a total number of mast cells - MCs) analyses on days 1, 7, 14, 21, 28 and 60 of the study. The most intensive myocardial alterations (cardiac damage score, CDS = 4.20-4.40), irregular glycogen distribution (glycogen distribution score, GDS = 4.07-4.17), haemorrhagic foci (vascular damage score, VDS = 4.57-4.90), diffuse accumulation and degranulation of MCs were observed on day 28 and 60 after treatment (p < 0.001 vs. control and 1st T-2-toxin-treated group, respectively). Besides, statistically significant positive correlations were obtained regarding myocardial injury, glycogen distribution and intensity of haemorrhage, and a negative correlation was found in the case of MCs. Obtained results are essential and crucial for further in vivo experimental studies, including the development of medications able to reduce T-2 toxin-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Xiaoxue Yu et al.)

Doxorubicin (DOX) is commonly used for the treatment of many types of cancers but its cardiotoxicity, owing to free radical formation, limits its clinical use. Hesperidin (HES), a flavanone glycoside, has been shown to exert multiple pharmacological actions including cardioprotective effects. Herein, we aim to formulate HES loaded solid lipid nanoparticles (SLNs) using supercritical antisolvent (SAS) technology to improve the oral delivery of HES. Process parameters were optimized to produce small size (175.3 ± 3.6 nm) HES-SLNs with high encapsulation efficiency (87.6 ± 3.8 %). DSC and XRD showed that HES is amorphously dispersed in SLNs. Compared to HES, HES-SLNs resulted in a nearly 20-fold increase in aqueous solubility and a nearly 5-fold increase in apparent permeability. Pharmacokinetics in rats revealed nearly 4.5-fold higher bioavailability of HES from SLN formulation compared to HES suspension. Data showed that HES-SLN significantly attenuated DOX-induced cardiotoxicity through lowering creatine kinase-muscle/brain, cardiac troponin I and improving histopathological scores as compared to the DOX group. HES-SLN also decreased malondialdehyde, increased catalase and superoxide dismutase of rats' heart to levels relatively comparable to control. Marked reductions in caspase-3 were also observed following HES-SLN treatment. Conclusively, these results describe a cardioprotective effect for HES-SLN against DOX-induced cardiotoxicity likely facilitated via suppression of oxidative stress and apoptosis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model., Competing Interests: The author declare no conflict of interest, The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, mostly in pediatric cases. Here, we demonstrate that DXR alters the mitochondrial membrane composition associated with bioenergetic impairment and cell death in human cancer cells. The remodeling of the mitochondrial membrane was explained by phosphatidylserine decarboxylase (PSD) inhibition by DXR. PSD catalyzes phosphatidylethanolamine (PE) synthesis from phosphatidylserine (PS), and DXR altered the PS/PE ratio in the mitochondrial membrane. Moreover, we observed that DXR localized to the mitochondrial compartment and drug uptake was rapid. Evaluation of other topoisomerase II inhibitors did not show any impact on the mitochondrial membrane composition, indicating that the DXR effect was specific. Therefore, our findings revealed a side molecular target for DXR and PSD, potentially involved in DXR anti-cancer properties and the associated toxicity.

Advances in cancer treatment have led to significant improvements in long-term survival in many types of cancer, but heart dysfunction and heart failure, associated with cancer treatment, have also increased. Anthracyclines are the main cause of this type of cardiotoxicity. In this study, we describe a combined experimental and cell morphology analysis approach for the high-throughput measurement and analysis of a cardiomyocyte cell profile, using partial least square linear discriminant analysis (PLS-LDA) as the pattern recognition algorithm. When screening a small-scale natural compound library, rosmarinic acid (RosA), as a candidate drug, showed the same cardioprotective effect as the positive control. We investigated the protective mechanism of RosA on a human cardiomyocyte cell line (AC16) and human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We showed that RosA pretreatment suppressed doxorubicin (Dox)-induced cell apoptosis and decreased the activity of caspase-9. RosA promotes the expression of Heme oxygenase-1 (HO-1) and reduces the production of reactive oxygen species (Ros), which is induced by Dox. Meanwhile, it can also promote the expression of cardiac-development-related protein, including histone deacetylase 1 (HDAC1), GATA binding protein 4 (GATA4) and troponin I3, cardiac type (CTnI). Collectively, our data support the notion that RosA is a protective agent in hiPSC-CMs and has the potential for therapeutic use in the treatment of cancer therapy-related cardiac dysfunction and heart failure., Competing Interests: the authors declare no conflict of interest.

Aims: We sought to describe survival outcomes and toxicities of trastuzumab in real-world patients with HER2-positive, metastatic breast cancer (MBC) and compare these to a recent systematic review of clinical trials., Methods: We searched the medical records of three Sydney cancer centers for patients with HER2-positive, MBC starting trastuzumab from January 2001 to March 2017. We recorded patient, tumor, and treatment characteristics; survival times from start of palliative trastuzumab; and rates of cardiac toxicity. Survival distribution was summarized using the following percentiles (represented scenario): 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). Survival times were compared to recent review of HER2-positive MBC randomized trials. Factors associated with survival were assessed with Cox models., Results: Characteristics of the 126 patients were: median age 53 years, ER positive cancer (50%), de-novo metastatic disease (23%), prior adjuvant trastuzumab (15%), liver metastases (37%), and brain metastases (23%). The median duration of first-line trastuzumab was 11 months (interquartile range, (IQR) 5-27). Survival times in months (vs the systematic review) were: 90th percentile 8 (9); 75th percentile 16 (19); and median 34 (33). Follow-up duration was insufficient to estimate the 25th and 10th percentiles, similar to the systematic review. Liver metastases were associated with shorter survival (HR = 1.74, 95% CI, 1.1-2.76, P = .02). Seventy percent of patients had a baseline cardiac assessment. Five patients (3.9%) developed symptomatic cardiac toxicity, similar to clinical trials., Conclusion: Survival and cardiac toxicity rates for women starting trastuzumab in routine practice were comparable to clinical trials. Oncologists can use clinical trial data as a reference point when explaining survival outcomes to women with HER2-positive MBC., (© 2019 John Wiley & Sons Australia, Ltd.)

Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) have revolutionized cancer treatment by recovering the attack of T lymphocytes on the malignant cells. They have improved clinical outcomes dramatically in multiple types of advanced-stage malignancies. Even though the tolerance and safety profiles are generally good, it has been widely reported that ICIs can cause severe or fatal immune-related adverse events (irAEs), since the activated T lymphocytes are not specific for tumor cells. Cardiac irAEs appear to occur less frequently than irAEs in other organ systems but are notorious for high mortality. Here, we aim to identify and characterize the ICI-associated cardiotoxicity and summarize the optional diagnosis and treatment strategies., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Children surviving cancer and chemotherapy are at risk for adverse health events including heart failure that may be delayed by years. Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8-20 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced "late-onset cardiotoxicity" was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3-4 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1-45 mg/kg). Cardiovascular function was unaltered at the lower dosages (1-15 kg/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.

Cancer remains a leading health threat in the United States, and cardiovascular drug toxicity is a primary cause to eliminate a drug from FDA approval. As a result, the demand to develop new anticancer drugs without cardiovascular toxicity is high. Human induced pluripotent stem (iPS) cell-derived tissue chips provide potentially a cost-effective preclinical drug testing platform, including potential avenues for personalized medicine. We have developed a three-dimensional microfluidic device that simultaneously cultures tumor cell spheroids with iPS-derived cardiomyocytes (iPS-CMs) and iPS-derived endothelial cells (iPS-EC). The iPS-derived cells include a GCaMP6 fluorescence reporter to allow real-time imaging to monitor intracellular calcium transients. The multiple-chambered tissue chip features electrodes for pacing of the cardiac tissue to assess cardiomyocyte function such as the maximum capture rate and conduction velocity. We measured the inhibition concentration (IC 50 ) of the anticancer drugs, Doxorubicin (0.1 μM) and Oxaliplatin (4.2 μM), on the tissue chip loaded with colon cancer cells (SW620). We simultaneously evaluated the cardiotoxicity of these anticancer drugs by assessing the drug effect on the spontaneous beat frequency and conduction velocity of iPS-derived cardiac tissue. Consistent with in vivo observations, Doxorubicin reduced the spontaneous beating rate and maximum capture rate at or near the IC 50 (0.04 and 0.22 μM, respectively), whereas the toxicity of Oxaliplatin was only observed at concentrations beyond the IC 50 (33 and 9.9 μM, respectively). Our platform demonstrates the feasibility to simultaneously assess cardiac toxicity and antitumor effects of drugs and could be used to enhance personalized drug testing safety and efficacy. Impact statement Drug development using murine models for preclinical testing is no longer adequate nor acceptable both financially for the pharmaceutical industry as well as for generalized or personalized assessment of safety and efficacy. Innovative solutions using human cells and tissues provide exciting new opportunities. In this study, we report on the creation of a 3D microfluidic device that simultaneously cultures human tumor cell spheroids with cardiomyocytes and endothelial cells derived from the same induced pluripotent stem cell line. The platform provides the opportunity to assess efficacy of anticancer agents while simultaneously screening for potential cardiovascular toxicity in a format conducive for personalized medicine.

Cardiotoxicity is a well-known adverse effect of doxorubicin (Dox) administration, but the underlying molecular mechanism of this effect is not fully understood. Over the past two decades, considerable efforts have focused on the potential molecular targets of cardiotoxicity in the hope that novel targeted therapies will be generated to attenuate Dox-induced cardiotoxicity. Here, we provide a comprehensive overview of genetically modified animals that show enhanced or reduced susceptibility to the cardiotoxic effects of Dox. We focused on the process by which the molecules involved in DNA damage, oxidative stress, apoptosis, autophagy and necrosis are affected in the presence of Dox. We also present a protein-protein interaction network and explain the contribution of the components to the process of Dox-induced cardiotoxicity. More importantly, data from the literature have indicated that PI3Kγ and Rac1 are potential targets with therapeutic advantages in cancer therapy; molecules that target these proteins can simultaneously attenuate Dox-induced cardiotoxicity and enhance its anticancer activity. This review highlights the potential molecular targets that are critical regulators involved in Dox-mediated cardiotoxicity, thus providing further insight into the development of potential treatment strategies to prevent the cardiotoxic effects and enhance the anticancer efficiency of Dox in cancer patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The clinical use of doxorubicin (DOX) is challenged by its incremental dose-related cardiotoxicity., Objective: The aim of the hereby study was to investigate sandalwood essential oil (SEO) against DOX-induced cardiac toxicity., Methods: Male Sprague-Dawley rats were allocated into 4 groups. Groups 1 signified the control, whereas group 2 administered 100 mg/kg/day SEO, both act as control. In group 3, DOX was given intraperitoneal in a dose of 3 mg/kg/ every other day for 2 weeks to induced cardiotoxicity. While group 4 received a combination of SEO and DOX for 2 weeks. DOX prompted variations were assessed by measuring cardiac injury biomarkers, including creatine phosphokinase, cardiac troponin T, and lactate dehydrogenase (LDH), electrocardiogram (ECG) fluctuations, heart rate (HR), and blood pressure (BP) indices. The effect of both DOX and SEO on various antioxidants such as glutathione, superoxide dismutase, and catalase and inflammatory mediators including interleukin-1β, tumor necrosis factor-alpha, and NF-κB was quantified., Results: DOX augmented cardiac injury biomarkers, altered ECG, deceased HR and antioxidants, and finally increased BP indices. Treatment with SEO significantly (p < 0.05) decreased cardiac biomarkers and reversing ECG changes and BP. Moreover, treatment with SEO enhanced HR anomalies and antioxidant activity reduction and precluded the intensive inflammatory response induced by DOX., Conclusion: SEO may have the potential of mitigating cardiac rhythm and BP indices changes induced with DOX. SEO modifications may be due to antioxidant capacity improvement and inflammatory response prohibition of the heart muscle., (© 2019 S. Karger AG, Basel.)

Background: Immune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described., Methods: First, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of ≥90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared., Results: In the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively)., Conclusions: Late CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD., Trial Registration Numbers: NCT03678337, NCT03882580, and NCT03492528., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Aconitine, the natural product extracted from Aconitum species, is widely used for the treatment of various diseases, including rheumatism, arthritis, bruises, fractures and pains. However, many studies have reported cardiotoxicity and neurotoxicity caused by aconitine, but the detailed mechanism underlying aconitine's effect on these processes remains unclear., Materials and Methods: The effects of aconitine on the inflammation, apoptosis and viability of H9c2 rat cardiomyocytes were evaluated by flow cytometry, Western blot, RNA sequencing and bioinformatics analysis., Results: Aconitine suppressed cardiomyocyte proliferation and induced inflammation and apoptosis in a dose- and time-dependent manner. These inflammatory damages could be reversed by a TNFα inhibitor and BNIP3-mediated mitophagy. Consistent with the in vitro results, overexpression of BNIP3 in heart tissue partially suppressed the cardiotoxicity of aconitine by inhibiting apoptosis and the NLRP3 inflammasome., Conclusions: Our findings lay a foundation for the application of a TNFα inhibitor and BNIP3 to aconitine-induced cardiac toxicity prevention and therapy, thereby demonstrating potential for further investigation., (© 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Background and Purpose: Tiotropium bromide (TB) is a long acting muscarinic receptor antagonist used to manage chronic obstructive pulmonary disease (COPD). Recent meta-analyses suggest an increased risk of cardiovascular events with TB. Ca 2+ /calmodulin dependent kinase II (CaMKII) and L-type Ca 2+ channels regulate Ca 2+ concentrations allowing management of Ca 2+ across membranes. Pathological increases in Ca 2+ are initially slow and progressive, however once the cytosolic concentration rises >1-3 μM from ~100 nM, calcium overload occurs and can lead to cell death. Ipratropium bromide, a short acting muscarinic receptor antagonist has previously been found to induce Ca 2+ mediated eryptosis. The aim of this study was to investigate the role of Ca 2+ in Tiotropium bromide mediated cardiotoxicity., Experimental Approach: Isolated Sprague-Dawley rat hearts were perfused with TB (10-0.1 nM) ± KN-93 (400 nM) or nifedipine (1 nM). Hearts were stained to determine infarct size (%) using triphenyltetrazolium chloride (TTC), or snap frozen to determine p-CaMKII (Thr 286 ) expression. Cardiomyocytes were isolated using a modified Langendorff perfusion and enzymatic dissociation before preparation for Fluo 3-AM staining and flow cytometric analysis., Key Results: TB increased infarct size compared to controls by 6.91-8.41%, with no effect on haemodynamic function. KN-93/nifedipine with TB showed a 5.90/7.38% decrease in infarct size compared to TB alone, the combined use of KN-93 with TB also showed a significant increase in left ventricular developed pressure whilst nifedipine with TB showed a significant decrease in coronary flow. TB showed a 42.73% increase in p-CaMKII (Thr 286 ) versus control, and increased Ca 2+ fluorescence by 30.63% in cardiomyocytes., Conclusions and Implications: To our knowledge, this is the first pre-clinical study to show that Tiotropium bromide induces Ca 2+ signalling via CaMKII and L-type Ca 2+ channels to result in cell damage. This has significant clinical impact due to long term use of TB in COPD patients, and warrants assessment of cardiac drug safety., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Immunotherapy drugs are associated with a multitude of immune-related adverse events. We describe a case of cardiac tamponade in a patient with stage IV lung adenocarcinoma, with almost 100% expression of PDL-1, treated with pembrolizumab. The patient is a 62-year-old male who developed worsening shortness of breath after five cycles of pembrolizumab. He was diagnosed with large pericardial effusion on computed tomography chest. Echocardiogram confirmed tamponade physiology. He was treated with discontinuation of pembrolizumab and urgent pericardial window followed by high dose prednisone with tapering. The patient responded very well to the treatment. We have comprehensively reviewed cases of pericardial effusion secondary to either immune mediated mechanisms or pseudoprogression.

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H 1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H 1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA 2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H 1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H 1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K + channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism., (© 2019 John Wiley & Sons Ltd.)

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher C max and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.

Hydrogen sulfide (H 2 S), as an environmental gas pollutant, has harmful effects on many tissues and organs, including myocardium. However, the underlying mechanisms of H2S-induced myocardia toxicity remain poorly understood. The present study was designed to investigate the effect of H 2 S on myocardia injury in broilers from the perspective of apoptosis. 30 ppm H2S was administered in the broiler chamber for 2, 4 and 6 week, respectively, and the myocardial samples in control groups and H2S groups were collected immediately after euthanized broilers. Transmission electron microscope, test kits, qRT-PCR and western blot were performed. Results showed that H 2 S exposure decreased the activities of catalase (CAT) and total antioxidant capability (T-AOC), whereas the content of hydrogen peroxide (H 2 O 2 ) and the activity of inducible nitric oxide synthase (iNOS) enhanced. Besides, we found the excessive expression of mitochondrial fission genes (Drp1 and Mff) by H 2 S, the dynamic balance of mitochondrial fission and fusion is destroyed. Furthermore, the levels of pro-apoptotic gene (including CytC, Cas3, Cas8, Cas9, TNF-α and Bax) increased after H 2 S exposure, as well as the expression level of anti-apoptotic gene bcl-2 decreased. At the same time, the activities of ATPase (including Na + -K + -ATPase, Ca 2+ -ATPase, Mg 2+ -ATPase and Ca 2+ -Mg 2+ -ATPase) weakened under H 2 S exposure. Therefore, we conclude that H 2 S induced oxidative stress and then leaded to excessive mitochondrial fission, which involved in apoptosis and damage broiler myocardia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent developments of novel targeted therapies are contributing to the increased long-term survival of cancer patients; however, drug-induced cardiotoxicity induced by cancer drugs remains a serious problem in clinical settings. Nevertheless, there are few in vitro cell-based assays available to predict this toxicity, especially from the aspect of morphology. Here, we developed a simple two-dimensional (2D) morphological assessment system, 2DMA, to predict drug-induced cardiotoxicity in cancer patients using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with image-based high-content analysis in a high-throughput manner. To assess the effects of drugs on cardiomyocytes, we treated iPSC-CMs with 28 marketed pharmaceuticals and measured two key parameters: number of cell nuclei and sarcomere morphology. Drugs that significantly perturbed these two parameters at concentrations ≤30 times the human C max value were regarded as positive in the test. Based on these criteria, the sensitivity and specificity of the 2DMA system were 81% and 100%, respectively. Moreover, the translational predictability of 2DMA was comparable with that of a three-dimensional cardiotoxicity assay. RNA sequencing further revealed that the expression levels of several genes related to sarcomere components decreased following treatment with sunitinib, suggesting that inhibition of the synthesis of proteins that comprise the sarcomere contributes to drug-induced sarcomere disruption. Based on these features, the 2DMA system provides mechanistic insight with high predictability of cancer drug-induced cardiotoxicity in humans, and could thus contribute to the reduction of drug attrition rates at early stages of drug development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was closely involved in doxorubicin- (DOX-) induced cardiotoxicity. MicroRNA-200a (miR-200a) could target Keap1 mRNA and promote degradation of Keap1 mRNA, resulting in Nrf2 activation. However, the role of miR-200a in DOX-related cardiotoxicity remained unclear. Our study is aimed at investigating the effect of miR-200a on DOX-induced cardiotoxicity in mice. For cardiotropic expression, male mice received an injection of an adeno-associated virus 9 (AAV9) system carrying miR-200a or miR-scramble. Four weeks later, mice received a single intraperitoneal injection of DOX at 15 mg/kg. In our study, we found that miR-200a mRNA was the only microRNA that was significantly decreased in DOX-treated mice and H9c2 cells. miR-200a supplementation blocked whole-body wasting and heart atrophy caused by acute DOX injection, decreased the levels of cardiac troponin I and the N-terminal probrain natriuretic peptide, and improved cardiac and adult cardiomyocyte contractile function. Moreover, miR-200a reduced oxidative stress and cardiac apoptosis without affecting matrix metalloproteinase and inflammatory factors in mice with acute DOX injection. miR-200a also attenuated DOX-induced oxidative injury and cell loss in vitro. As expected, we found that miR-200a activated Nrf2 and Nrf2 deficiency abolished the protection provided by miR-200a supplementation in mice. miR-200a also provided cardiac benefits in a chronic model of DOX-induced cardiotoxicity. In conclusion, miR-200a protected against DOX-induced cardiotoxicity via activation of the Nrf2 signaling pathway. Our data suggest that miR-200a may represent a new cardioprotective strategy against DOX-induced cardiotoxicity., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Xiaoping Hu et al.)

Aims: Doxorubicin (DOX), a widely used powerful chemotherapeutic component for cancer treatment, can give rise to severe cardiotoxicity that limits its clinical use. Pyroptosis is characterized by proinflammation and has been defined as a new type of programmed cell death in recent years. However, whether the DOX-induced cardiotoxicity is related to pyroptosis, and if so, which genes are involved in this process is largely unknown. In this study, we sought to identify the effect of DOX on cardiomyocyte pyroptosis and further reveal the underlying regulatory mechanism., Methods and Results: In vitro and in vivo experiments showed that DOX treatment induced cardiomyocyte pyroptosis as evidenced by increased cell death and upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-3, IL-1β, IL-18 and GMDSD-N. Inhibition of NLRP3 rescued the DOX-induced pyroptosis. qRT-PCR showed that TINCR lncRNA was upregulated by DOX treatment and knockdown of TINCR reversed the DOX-induced pyroptosis both in vitro and in vivo. Mechanistic investigations revealed that TINCR increased NLRP3 level via recruiting IGF2BP1 to enhance NLRP3 mRNA. And the effect of TINCR on cardiomyocyte pyroptosis was attenuated by the inhibition of NLRP3 or IGF2BP1. Finally, TINCR was not involved in DOX-induced pyroptosis in cancer cells., Conclusion: TINCR mediates the DOX-induced cardiotoxicity and pyroptosis in an IGF2BP1-dependent manner. Therefore, TINCR may serve as a promising therapeutic target to overcome the cardiotoxicity of chemotherapy for cancer therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell-derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell-derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.

The aim of this study was to evaluate the frequency of severe cardiac complications and to assess the ability of various factors to predict these complications in severe aplastic anaemia (SAA) patients after haploidentical transplantation. A retrospective study was conducted in 216 consecutive SAA patients who underwent haploidentical transplantation from 2006 to 2017. All patients received a unified regimen including busulfan, cyclophosphamide (CTX) and antithymocyte globulin at a single centre. A total of 12 (5.6%) patients developed grade III or IV cardiac toxicity. Patients with cardiotoxicity had significantly poorer overall survival (OS) than did those without cardiotoxicity (12.5 vs. 89.6%, P < 0.001). A multivariable model identified four independent adverse predictors of severe cardiotoxicity: pre-transplant ECOG score ( ≥ 2), abnormal ST-T wave on 12-lead ECG, hyperlipaemia and recalculated CTX dose ( ≥ 1.8 g/m 2 /d). The incidences of severe cardiotoxicity were 50.0%, 6.0% and 1.3% in the high- (3-4 factors), intermediate- (2 factors) and low-risk (0-1 factor) groups, respectively (P < 0.001). The corresponding OS rates were 49.0%, 80.4% and 90.3%, respectively (P < 0.001), at final follow-up. Therefore, patients with high-risk scores had the poorest outcomes and should be monitored closely. Reduced intensity conditioning might be recommended for these patients.

Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin-like growth factor receptor type II α (IGF-IIRα) which is a novel stress-inducible protein was explored in doxorubicin-induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD-TG [IGF-IIRα]) overexpressing IGF-IIRα specifically in heart, we found that IGF-IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin-induced cardiac stress. Overexpression of IGF-IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p-Akt and estrogen receptor β/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin-I, and apoptosis-inducing agents such as p53, Bax, and cytochrome C, respectively. IGF-IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF-IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF-IIRα is a novel stress-induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin-induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy., (© 2019 Wiley Periodicals, Inc.)

Doxorubicin (DOX) is an antitumor drug widely used in hematological tumors and various solid tumors. However, the cardiotoxicity elicited by DOX severely limits its clinical treatment. Dimethyl itaconate (DI), a common form of itaconate, is found many potential targets for prevent heart injury. Here we employed wild type and Nrf2 knockout mice and induced a cardiotoxicity model by administration of DOX to clarify the effects of DI. After treatment with DI, we found that it could effectively alleviate the cardiotoxicity by analyzing morphology, LDH levels and heart weight/body weight ratio changes. Meanwhile we demonstrated that RIP3, a key protein of necrosis, was significantly decreased in DI treated group. Further we observed that treatment with DI could suppress oxidative stress by altering Nrf2/HO-1. Compared with vehicle group, DI could increase the tissue SOD and GSH, and reduce MDA levels, then DHE staining revealed that the level of ROS in DI group reduced by half. Finally, transmission electron microscope (TEM) data showed that treatment with DI obviously decreased the mitochondrial damage. While Nrf2 was ablated in mice, the protective effects of DI were vanished and SOD, GSH, MDA became unchanged related to vehicle group. This report provides the evidence for the protective effects of DI treatment in cardiotoxicity induced by DOX. On mechanisms, DI could reduce the oxidative stress by altering Nrf2/HO-1 pathway and prevent mitochondrial from damage. Taken together, these findings of this paper will afford the new therapeutic targets in DOX related cardiotoxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus. This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy. We found that AS-IV supplementation alleviates body weight loss, myocardial injury, apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro. NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4., (Copyright © 2019. Published by Elsevier B.V.)

Doxorubicin (DOX) is a potent anti-neoplastic agent with cumulative cardiotoxicity. DOX-induced cardiotoxicity has been shown to depend on the different dosing times. However, the basis for determining the dosing time to minimize DOX-induced cardiotoxicity and the underlying mechanisms remain incompletely understood. Here we first showed that SIRT3, the major mitochondrial deacetylase, is negatively correlated to DOX-induced cardiotoxicity through the regulation of ATP production, mitochondrial membrane potential (MMP) level and ROS level in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we used in vivo experiments to demonstrate that DOX significantly reduced the SIRT3 expression and the SIRT3 activity as reflected by the increased Ac K68 MnSOD/MnSOD ratio in rats after six weeks of treatment. Notably, the activity of SIRT3 had an obvious diurnal rhythm pattern in the myocardium of healthy rats. More importantly, an obvious lower Ac K68 MnSOD/MnSOD ratio was observed in rat hearts with DOX administrated at Zeitgeber time (ZT) 9 (ZT 0 was the time lights were turned on) than ZT1, which represent the peak and trough of SIRT3 activity. Moreover, DOX ZT9 reduced the body weight loss, extended the survival period, improved the heart function and alleviated the myocardial lesions compared to DOX ZT1. Mechanistic investigations demonstrated that DOX ZT1 significantly reduced ATP production, oxygen consumption rate (OCR) at various respiration states, MMP level and MnSOD activity and enhanced the H 2 O 2 level compared with CON ZT1, whereas there was no significant effect for DOX ZT9 compared with CON ZT9. Taken together, dosing at the peak time of SIRT3 activity reduced DOX-induced cardiotoxicity, which may be related to the increased endogenous tolerance against the mitochondrial dysfunction and oxidative stress caused by DOX., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The present study aimed at investigating the protective effects of nerolidol (NRD) against myocardial infarction (MI) induced by isoproterenol (ISO) in Wistar rats. The rats were randomly divided into five groups, each group consisting of six rats. Group I were treated as control rats, group II received NRD (200 mg/kg b.w.) by intragastric intubation for 21 days, group III received ISO (60 mg/kg b.w) subcutaneously (s.c) for two consecutive days on 22nd and 23rd day, group IV and V received NRD (100 and 200 mg/kg b.w) as in group II and additionally ISO was given for two consecutive days (22nd and 23rd). On 24th day all the rats were sacrificed by cervical dislocation and the blood and heart samples were collected. In the present study, ISO-induced myocardial damage was indicated by the changes in body weight, heart weight and the cardiac and hepatic marker enzymes such as creatine kinase (CK), creatine kinase-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and troponin T and I (cTnT, cTnI) in the serum. In addition, the levels of lipid peroxidation products such as thiobarbituric acid reactive substances (TBARS), conjugated dines (CD), and lipid hydroperoxides (LHPs) increased significantly in the plasma and heart tissue. Activities of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) in erythrocytes and heart tissue and the levels of nonenzymatic antioxidants like vitamin C, vitamin E, and reduced glutathione (GSH) in plasma and heart tissue were decreased in ISO-induced rats. Histopathological observations were also supported with the biochemical parameters. Pretreatment with NRD at different doses (100 and 200 mg/kg b.w) for 21 days prevented the above changes induced by ISO. The 200 mg/kg b.w of NRD was more pronounced than the other dose and brought back all the above parameters near to normalcy., (© 2019 Wiley Periodicals, Inc.)

This study investigated if JAK/STAT signaling pathway mediates doxorubicin (DOX)-induced cell death and fibrosis in left ventricles (LVs) of rats and examined if acylated ghrelin affords protection by modulating this pathway. Male rats (120 ± 5 g) were divided into 6 groups (10 rats each) as follows: control; control + AG (10 ng/kg, s.c.); DOX (an accumulative dose 15 mg/kg, i.p.); DOX + AG, DOX + AG + AG490, a JAK2 inhibitor (5 mg/kg, i.p.); and DOX + AG + [D-Lys3]-GHRP-6; an AG receptor antagonist (3.75 mg/kg, i.p.). All treatments were carried out for 35 days. In rats' LVs, DOX significantly impaired the systolic and diastolic functions, enhanced levels of ROS and MDA, reduced levels of GSH and Bcl-2, and increased mRNA and protein levels of collagen I/III and TGF-β and cleaved caspase-3. In addition, although DOX did not affect JAK1 or JAK2 activity, it significantly increased protein levels of IL-6, decreased STAT3 and p-STAT3 (Tyr701&Ser727), and increased STAT1 and p-STAT1 (Tyr701&Ser727) levels, with a concomitant decrease in ERK1/2 activity and an increase in P38 activity. However, without affecting IL-6 and JAK1/2, AG reversed all of the observed alterations with a significant increase in the levels and activities of JAK2. Similar effects of AG were also seen in control rats. Interestingly, all the beneficial effects afforded by AG were abolished by AG490 and AG + [D-Lys3]-GHRP-6. In conclusion, DOX-induced cardiac toxicity involves stimulation of IL-6, P38, and STAT1 signaling levels whereas the protective effect afforded by AG involves the activation of ERK1/2 and JAK2/STAT3 and inhibition of STAT1.

Objectives: Cardiotoxicity is an important side effect in patients receiving chemotherapy and the application of anthracycline drugs for gastric cancer treatment is uncommon. The purpose of this study was to determine the incidence rate of and risk factors for cardiotoxicity in gastric cancer patients treated with fluorouracil-based chemotherapy., Materials and Methods: We retrospectively enrolled patients with locally advanced or metastatic gastric cancer from 2011 to 2016. Patients were treated with multiple cycles of fluorouracil-based chemotherapy at Peking University First Hospital. The incidence of cardiotoxicity and patients' clinical data were obtained from hospital clinical databases and manually reviewed., Results: A total of 129 patients were eligible for and were enrolled in this study. A median of 6 chemotherapy cycles were administered (range 1-18 cycles). Cardiotoxicity was observed in 38 of 129 patients (29.5%). Twelve patients (9.3%) exhibited toxicity greater than grade 2, and 2 (1.6%) patients died of cardiac toxicity. The only independent risk factor for serious cardiotoxicity identified by multivariable analysis was a history of cardiac disease (OR 4.108, 95% CI 2.778-6.074, P < 0.001)., Conclusions: Chemotherapy-related cardiotoxicity may be underestimated in Chinese gastric cancer patients. Close monitoring for cardiotoxicity and enhanced cardiac management are recommended for patients who receive fluorouracil-based chemotherapy, especially for patients with high-risk factors for serious cardiotoxicity. New strategies, such as identifying the administration schedule of fluorouracil with minimal cardiotoxicity, and cardio-oncology, are necessary to prevent and treat chemotherapy-induced cardiotoxicity.

The toxic effects of different atrazine concentrations on tadpoles and adult male African clawed frogs (Xenopus laevis) were assessed in a controlled laboratory environment following 90 days' exposure. The aim was to elucidate the danger of atrazine exposure on the cardiac tissue relative to its critical function of rhythmic contractility, fundamental for optimal blood circulation and homeostasis. Tadpoles and adult frogs were exposed to 0 μg/L (control), 0.01 μg L -1 , 200 μg L -1 and 500 μg L -1 concentrations of atrazine for 90 days. Mortality was concenration-dependent and significantly increased in juvenile group (77%, 43%, 23% and 0 respectively for 500 μg L -1 , 200 μg L -1 , 0.01 μg L -1 , and control group). While the mean juvenile heart area decreased concentration-dependently, adult frog mean heart area significantly increased in the 200 μg L -1 group only and mean heart weight change was variable across all exposure levels. Light microscopy of hematoxylin and eosin (H&E) and Mallory-Heidenhain rapid one-step staining techniques on cardiac tissue sections of the juvenile and adult frogs revealed shrinkage of cardiac muscle cells into thin wavy myocytes. Additionally, disorganized branching of muscle fibres with reduced striations were observed in 0.01 μg L -1 and 200 μg L -1 but hypertrophied myocytes, thickened intensely staining myofibrils in the 500 μg L -1 group in juvenile and adult frogs. Significant increase in the mean percentage area of connective tissue in all the treated groups (p < 0.036) were also recorded. Immunohistochemistry analysis showed decreased eNOS localization in cardiac tissue in 200 μg L -1 and 500 μg L -1 of both juvenile and adult group, suggestive of decreased cardiac contractility due to atrazine exposure. The results indicate that environmentally relevant atrazine concentrations cause significant mortality in tadpoles while concentrations ≥200 μg L -1 adversely affect cardiac muscle morphology and may induce functional perturbations in cardiac tissue contractility and consequent dysfunction which generally may have an adverse impact on their survival and longevity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration., Methods: The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations., Results: Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is clinically employed to treat cancers especially for breast cancer and lung cancer. But its clinical applications are limited by the dose-dependent cardiac toxicity. Resveratrol (Res), a polyphenolic antitoxin, has been proved to be capable of improving the cardiomyocyte calcium cycling by up-regulating SIRT-1-mediated deacetylation to inhibit DOX-induced cardiotoxicity. Purpose: The objective of this study was to develop a solid lipid nanoparticle (SLN) loaded with Res to trigger inhibition of DOX-induced cardiotoxicity. Methods: Res-SLN was prepared by emulsification-diffusion method followed by sonication and optimized using central composite design/response surface method. The Res-SLN was further evaluated by dynamic light scattering, transmission electron microscopy for morphology and high performance liquid chromatography for drug loading and release profile. And the Res distribution in vivo was determined on rats while the effect of inhibit DOX-induced cardiotoxicity was investigated on mice. Results: Res-SLN with homogeneous particle size of 271.13 nm was successfully formulated and optimized. The prepared Res-SLN showed stable under storage and sustained release profile, improving the poor solubility of Res. Heart rate, ejection fractions and fractional shortening of Res-SLN treating mice were found higher than those on mice with cardiac toxicity induced by single high-dose intraperitoneal injection of DOX. And the degree of myocardial ultrastructural lesions on mice was also observed. Conclusion: Res-SLN has a certain therapeutic effect for protecting the myocardium and reducing DOX-induced cardiotoxicity in mice., Competing Interests: The authors report no conflicts of interest in this work.

Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.

The aim of the present study was to determine the protective and therapeutic effects of linalool (LIN) against doxorubicin (DOX)-induced cardiotoxicity in rats histologically and biochemically. In experiments, 64 male Wistar albino rats were randomly divided into eight groups ( n = 8). These groups were control (C) (0.9% saline solution), DOX (20 mg/kg DOX), LIN50 (50 mg/kg LIN), LIN100 (100 mg/kg LIN), DOX + LIN50 (20 mg/kg DOX and 50 mg/kg LIN), DOX + LIN100 (20 mg/kg DOX and 100 mg/kg LIN), LIN50 + DOX (50 mg/kg LIN and 20 mg/kg DOX), and LIN100 + DOX (100 mg/kg LIN and 20 mg/kg DOX). It was determined that necrosis and extensive inflammatory cell infiltration were observed in the DOX group. It was determined that histopathological changes significantly decreased in groups treated with LIN after DOX administration. While the caspase-3 immunostaining was highly evident in DOX group apoptotic cells ( p < 0.001, for all), the intensity of caspase-3 immunostaining in the treatment groups decreased ( p < 0.05). While DOX administration resulted in a significant increase in malondialdehyde (MDA) levels and plasma Creatine kinase (CK) and lactate dehydrogenase (LDH) levels in cardiac tissue when compared to the C groups, it was observed that DOX + LIN administration led to a significant decrease in MDA, plasma CK and LDH levels and a significant increase in glutathione (GSH), superoxide dismutase, and catalase enzyme levels. Finally, it was concluded that DOX led to heavy cardiotoxicity and DOX + LIN administration could remove cardiomyopathy symptoms.

The cardiotoxic adverse effect of doxorubicin (DOX) is the major factor limiting its use. Recently, mesenchymal stem cells (MSCs) have been implicated in the preclinical studies of treatment of DOX-induced cardiotoxicity. The question is MSCs pretreated with platelet-rich plasma (PRP) have a better influence on DOX-induced cardiotoxicity compared to the influence of MSCs alone. Twenty-four Wistar rats were categorized into control, DOX-treated, MSC-treated, and PRP/MSC-treated groups. DOX was injected for two consecutive weeks. Light microscopic, biochemical markers (interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α), and creatine kinase-MB (CK-MB)), immunohistochemical (Bax, Bcl2, vascular endothelial growth factor (VEGF), and cardiac troponin-I (CT-I)), and oxidative/antioxidative markers (malondialdehyde (MDA)/superoxide dismutase (SOD)) were measured. Degenerative cardiac changes were detected in the DOX-treated group with complete loss of the architecture and coagulative necrosis. These changes were accompanied with the elevation of the serum level of CK-MB and loss of CT-I immunoreactivity. The major factors in the DOX-induced cardiotoxicity were the oxidative stress (elevated MDA/decreased SOD), inflammation (elevated TNF-α/decreased IL-10), and cardiac apoptosis (lower Bcl2, higher Bax, and lower Bcl2/Bax ratio). MSCs and PRP/MSCs attenuate DOX-induced cardiotoxicity. Better attenuation was observed in the PRP/MSC-treated group. PRP/MSC combination reduced greatly the MDA and TNF-α and increased IL-10, Bcl2/Bax ratio, and VEGF. PRP had no significant influence over the Bcl2, Bax, and SOD. In conclusion, DOX in its toxic dose induced myocardial injury. This destructive effect is related to oxidative stress, inflammation, and cardiac apoptosis. PRP/MSC possesses a better attenuation over the DOX-induced toxicity compared to MSC alone.

Cisplatin is a powerful chemotherapeutic agent. Cardiotoxicity is one of its major adverse effects. Ginger is a commonly used element in herbal medicine due to its anti-oxidant potentials. This study was planned to assess the histological changes induced by cisplatin in the cardiac muscle and to clarify the possible protective influence of ginger intake. Forty rats were divided into four groups. Control; given normal saline. Ginger; received oral ginger (500 mg/kg/day) for 12 days. Cisplatin; given cisplatin (2 mg/kg/day) daily by intraperitoneal injection for 1 week. Cisplatin + Ginger; received ginger (500 mg/kg/day) for 5 days prior to and concomitant with intraperitoneal injection of cisplatin (2 mg/kg/day) for 1 week. Serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were estimated. Cardiac specimens were subjected to light, electron microscopic and immunohistochemical study using anti-P53 and anti-TNF-α antibodies. Morphometric and statistical studies were done. In Cisplatin group, cardiac muscle fibers appeared disorganized, disrupted or degenerated with pyknotic nuclei and showed a significant rise in the number of anti-P53 positive nuclei. Significant increments in the percent area of collagenous fibers and TNF-α immune-expression were observed. Ultrastructurally, the cardiomyocytes displayed disorganized or interrupted myofibrils, swollen disrupted mitochondria, and widening of intercalated discs. Serum levels of CK and LDH were significantly elevated. Cisplatin + Ginger group showed marked improvement in the cardiac histology and ultrastructure, downregulation of P53 and TNF-α immune-expressions and reduction in CK and LDH serum levels. In conclusion, ginger exhibits a protective effect against cisplatin cardiotoxicity mostly through its anti-apoptotic, anti-oxidant and anti-inflammatory properties., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Doxorubicin (DOX) is widely used to treat various cancers affecting adults and children; however, its clinical application is limited by its cardiotoxicity. Previous studies have shown that children are more susceptible to the cardiotoxic effects of DOX than adults, which may be related to different maturity levels of cardiomyocyte, but the underlying mechanisms are not fully understood. Moreover, researchers investigating DOX-induced cardiotoxicity caused by human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown that dexrazoxane, the recognized cardioprotective drug for treating DOX-induced cardiotoxicity, does not alleviate the toxicity of DOX on hiPSC-CMs cultured for 30 days. We have suggested that this may be ascribed to the immaturity of the 30 days hiPSC-CMs. In this study, we investigated the mechanisms of DOX induced cardiotoxicity in cardiomyocytes of different maturity. We selected 30-day-old and 60-day-old hiPSC-CMs (day 30 and day 60 groups), which we term 'immature' and 'relatively mature' hiPSC-CMs, respectively. The day 30 CMs were found to be more susceptible to DOX than the day 60 CMs. DOX leads to more ROS (reactive oxygen species) production in the day 60 CMs than in the relatively immature group due to increased mitochondria number. Moreover, the day 60 CMs mainly expressed topoisomerase IIβ presented less severe DNA damage, whereas the day 30 CMs dominantly expressed topoisomerase IIα exhibited much more severe DNA damage. These results suggest that immature cardiomyocytes are more sensitive to DOX as a result of a higher concentration of topoisomerase IIα, which leads to more DNA damage., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Cancer is the leading cause of deaths around the world, especially in low- and middle- income countries. Pirarubicin (THP) is an effective drug for treatment of cancer, however, there still exists cardiotoxic effects of THP. Rutin is a kind of antioxidative compound extracted from plants, and might be a protective compound for cardiomyocytes. Phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is critical for cellular survival, proliferation and metabolism, and thus we speculated rutin might perform a protective role in cardiomyocytes via PI3K/AKT/mTOR signaling pathway. And in this experiment, we first established a cardiotoxicity model of THP in mice model and cell models, and then found that rutin treatment could increase the proliferation of cells at low concentration. Then we explored the possible mechanism of the protective effect of rutin using Western blotting, quantitative polymerase chain reaction (qPCR) and ELISA methods, and found that the activation of PI3K/AKT/mTOR/nuclear factor-κB (NF-κB) signaling pathway was increased, and expression of downstream molecules involved in antioxidative stress were also increased. We further noticed that concentration of angiogenesis promoting factors were also increased in medium of cultured cells. Thus, we speculated that rutin could increase the activation of PI3K/AKT/mTOR signaling pathway, further decrease the oxidative stress level via increasing the expression of antioxidative stress enzymes with the increasing concentration of angiogenesis promoting factors, resulting in the protective role in cardiomyocytes and cardiac function., (© 2019 The Author(s).)