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Aims: Cyclophosphamide (CYP) is a potent anticancer agent with well-known cardiotoxicity that limits its clinical applications. Cilostazol is a vosodilating drug, showing a cardioprotective effect in some cardiac disorders; however its effect in CYP-induced cardiotoxicity is still uncertain. We investigated the effect of cilostazol against CYP-induced cardiotoxicity and the contribution of SIRT1 signaling., Materials and Methods: 7 week-old male Wistar albino rats were treated with cilostazol (30 mg/kg/day, orally) in the absence or presence of SIRT1 inhibitor, EX-527 (5 mg/kg/day, IP) for 10 days and injected with CYP (200 mg/kg, IP) on the 7th day of the study. Age-matched rats were used as control group. On the 11th day, hearts were harvested for biochemical, immunoblotting and histological analyses. Markers of cardiac injury were assessed in plasma samples., Key Findings: CYP injection contributed to cardiac injury manifested as significant increases in plasma activities of heart enzymes and cardiac troponin I levels. Cilostazol attenuated cardiac injury and minimized the histological lesions in hearts of CYP-treated rats. Cilostazol induced 3 fold up-regulation of SIRT1 and promoted the antioxidant defense response through FoxO1-related mechanism in hearts of CYP-treated rats. Cilostazol suppressed the CYP-induced up-regulation of PARP1 and p53, and blocked the NF-kB p65-mediated inflammatory response in hearts of CYP-treated rats. All the beneficial effects of cilostazol were almost abolished by EX-527., Significance: These data provided insights into the mechanism underlying the cardioprotective effect of cilostazol in CYP-treated rats through upregulation of SIRT1 signaling, suggesting that cilostazol might be a candidate modality for CYP-induced cardiotoxicity., (Copyright © 2020. Published by Elsevier Inc.)

Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Wen-Bin Zhang et al.)

Anthracycline-induced cardiotoxicity (AIC) persists as a significant cause of morbidity and mortality in cancer survivors. Although many protective strategies have been evaluated, cardiotoxicity remains an ongoing threat. The mechanisms of AIC remain unclear; however, several pathways have been proposed, suggesting a multifactorial origin. When the central role of topoisomerase 2 β in the pathophysiology of AIC was described some years ago, the classical reactive oxygen species (ROS) hypothesis shifted to a secondary position. However, new insights have reemphasized the importance of the role of oxidative stress-mediated signaling as a common pathway and a critical modulator of the different mechanisms involved in AIC. A better understanding of the mechanisms of cardiotoxicity is crucial for the development of treatment strategies. It has been suggested that the available therapeutic interventions for AIC could act on the modulation of oxidative balance, leading to a reduction in oxidative stress injury. These indirect antioxidant effects make them an option for the primary prevention of AIC. In this review, our objective is to provide an update of the accumulated knowledge on the role of oxidative stress in AIC and the modulation of the redox balance by potential preventive strategies., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Rodrigo Carrasco et al.)

Saffron is commonly used in traditional medicines and precious perfumes. It contains pharmacologically active compounds with notably potent antioxidant activity. Saffron has a variety of active components, including crocin, crocetin, and safranal. Oxidative stress plays an important role in many cardiovascular diseases, and its uncontrolled chain reaction is related to myocardial injury. Numerous studies have confirmed that saffron exact exhibits protective effects on the myocardium and might be beneficial in the treatment of cardiovascular disease. In view of the role of oxidative stress in cardiovascular disease, people have shown considerable interest in the potential role of saffron extract as a treatment for a range of cardiovascular diseases. This review analyzed the use of saffron in the treatment of cardiovascular diseases through antioxidant stress from four aspects: antiatherosclerosis, antimyocardial ischemia, anti-ischemia reperfusion injury, and improvement in drug-induced cardiotoxicity, particularly anthracycline-induced. Although data is limited in humans with only two clinically relevant studies, the results of preclinical studies regarding the antioxidant stress effects of saffron are promising and warrant further research in clinical trials. This review summarized the protective effect of saffron in cardiovascular diseases and drug-induced cardiotoxicity. It will facilitate pharmacological research and development and promote utilization of saffron., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Xin Su et al.)

The development of new therapies for cancer has led to dramatic improvements in survivorship. Angiogenesis inhibitors represent one such advancement, revolutionising treatment for a wide range of malignancies. However, these drugs are associated with cardiovascular toxicities which can impact optimal cancer treatment in the short-term and may lead to increased morbidity and mortality in the longer term. Vascular endothelial growth factor inhibitors (VEGFIs) are associated with hypertension, left ventricular systolic dysfunction (LVSD) and heart failure as well as arterial and venous thromboembolism, QTc interval prolongation and arrhythmia. The mechanisms behind the development of VEGFI-associated LVSD and heart failure likely involve the combination of a number of myocardial insults. These include direct myocardial effects, as well as secondary toxicity via coronary or peripheral vascular damage. Cardiac toxicity may result from the 'on-target' effects of VEGF inhibition or 'off-target' effects resulting from inhibition of other tyrosine kinases. Similar mechanisms may be involved in the development of VEGFI-associated right ventricular (RV) dysfunction. Some VEGFIs can be associated with QTc interval prolongation and an increased risk of ventricular and atrial arrhythmia. Further pre-clinical and clinical studies and trials are needed to better understand the impact of VEGFI on the cardiovascular system. Once mechanisms are elucidated, therapies can be investigated in clinical trials and surveillance strategies for identifying VEGFI-associated cardiovascular complications can be developed., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

This study was undertaken to evaluate the therapeutic potential effect of pentoxifylline (PTX) against arsenic trioxide (ATO)-induced cardiac oxidative damage in mice. Thirty-six male albino mice were divided into six groups and treated intraperitoneally with normal saline (group 1), ATO (5 mg/kg; group 2), PTX (100 mg/kg; group 3), and different doses of PTX (25, 50, and 100 mg/kg; groups 4, 5, and 6, respectively) with ATO. After four weeks, the blood sample was collected for biochemical experiments. In addition, cardiac tissue was removed for assessment of oxidative stress markers and histopathological changes (such as hemorrhage, necrosis, infiltration of inflammatory cells, and myocardial degeneration). The findings showed that ATO caused a significant raise in serum biochemical markers such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and troponin-I (cTnI), glucose, total cholesterol (TC), and triglyceride (TG) levels. In addition to histopathological changes in cardiac tissue, ATO led to the significant increase in cardiac lipid peroxidation (LPO) and nitric oxide (NO); remarkable decrease in the activity of cardiac antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx); and the depletion of the total antioxidant capacity (TAC) and total thiol groups (TTGs). PTX was able to reduce the increased levels of serum cardiac markers (LDH, CPK, cTnI, TC, and TG), cardiac LPO, and improve antioxidant markers (TAC, TTGs, CAT, SOD, and GPx) alongside histopathologic changes. However, no significant changes were observed in elevated serum glucose and cardiac NO levels. In conclusion, the current study showed the potential therapeutic effect of PTX in the prevention of ATO-induced cardiotoxicity via reversing the oxidative stress., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Atefeh Gholami et al.)

Contrary to the fact that doxorubicin is a powerful chemotherapeutic agent for the treatment of neoplastic diseases, cardiotoxicity is too important to be ignored. Thymoquinone serves as a powerful free radical scavenger. In the study, the effects of thymoquinone against doxorubicin-cardiotoxicity will be evaluated. Forty rats were divided into five groups. Group I: control group (n = 8); group II: olive oil group (n = 8); group III: thymoquinone group (n = 8); given 10 mg/kg thymoquinone intraperitoneally per day throughout the experiment; group IV: doxorubicin group (n = 8); injected with a single dose of 15 mg/kg ip doxorubicin on the 7th day of the experiment; group V: doxorubicin + thymoquinone group (n = 8); administered with 10 mg/kg thymoquinone per day during the experiment and 15 mg/kg doxorubicin ip on the 7th day. The experiment was planned for 14 days. Immunohistochemically, heat shock protein (HSP) 70 and HSP90, glucose-regulated protein 78 (GRP78), caspase-3 were stained. We made terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptotic evaluation. Total oxidant status (TOS) levels and total antioxidant status (TAS) were measured in the heart tissue. Atrial natriuretic peptide (ANP) and pro-B type natriuretic peptide (proBNP) were evaluated. In the study, HSP70, HSP90, GRP78, and caspase-3 levels increased in group IV. TOS and TAS levels were significant compared to group I. Doxorubicin significantly increased ANP and NT-proBNP levels. Thymoquinone revealed significant differences in these values. Thymoquinone can be an important cardioprotective agent against doxorubicin-cardiotoxicity., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Breast cancer is the most common cancer in women in the world and in Morocco. Anthracyclines and anti-HER2 therapy are major drugs in the therapeutic management of localized breast cancer. The most serious toxicity of these drugs is cardiotoxicity. Our work aims to assess the prevalence of this toxicity in the Moroccan population., Patients and Methods: We conducted a prospective longitudinal observational study between January 2017 and June 2018. All our patients were followed in The Cardio-Oncology Unit, 1st unit of its kind in Morocco, created thanks to the collaboration between the Mohammed VI Cancer Treatment Center and The Cardiology Departement of Ibn Rochd University Hospital in Casablanca. Eligible patients (n=549) had Stage I-III localized breast cancer, verified histologically, and a pre-treatment adequate cardiac function with a LVEF = 50%, measured with echocardiography, and received systemic cardiotoxic treatment (anthracycines, anti-her2 drugs). All patients received regular monitoring of cardiac function mainly by echocardiography. Cardiotoxicity was defined as a decrease in LVEF of 10 points and / or <50%., Results: A decrease in LVEF was observed in 8.4% of our patients, with 4% symptomatic heart failure. The baseline average LVEF in the cardiotoxicity group was 63.5% (50-77) versus 60.5% (60-74) in the group without cardiotoxicity. 97.1% of these patients received anthracyclines, 98% received trastuzumab against 97% and 65% in the group without cardiotoxicity respectively. Cardiotoxicity was reversible in 6.4% of patients, permanent discontinuation of cardiotoxic treatment was observed in 2.2%. A statistically significant relationship was found between cardiotoxicity and arterial hypertension (HTA) (p = 0.002), trastuzumab (p = 0.0001) and radiotherapy for left breast cancer (p = 0.023)., Conclusion: This is one of the first observational studies in Morocco with a large number of patients, which gives us an idea of the cardiotoxicity of systemic treatments in Moroccan localized breast cancer patients. Our results join those of the literature, but are still worrying and invite us, oncologists and cardiologists, to be more vigilant with this toxicity, which influences the oncological and cardiac prognosis of our patients, especially cancer survivors.

Cyclophosphamide (CP) is an extensively used anticancer drug, but its cardiotoxic manifestation is a major concern for its widespread clinical use. The observed cardiotoxic attributes have been reported at the therapeutic dose and often result into a high mortality rate and poor clinical outcome. Fall in the level of antioxidant enzymes catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) generation of reactive oxygen species (ROS), inflammatory cytokines nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL- 1β), apoptotic proteins (caspases) and direct damage to myocardial tissue (histological and ultrastructural damage) are some of the reported manifestations of cardiotoxicity. The observed clinical attributes of CP-induced cardiotoxicity are myocarditis, hemorrhage, thrombosis, myocardial infarction (MI), reduced ejection fraction, altered electrocardiogram (ECG) reading and heart failure. However, unlike Daxarazasone (an adjuvant to reduce doxorubicin-induced cardiotoxicity), no approved adjuvant is available to mitigate CPinduced cardiotoxicity. Thus, various natural bioactives have been explored for the possible cardioprotective effect against CP-induced cardiotoxicity. In the current manuscript, we have discussed the clinical and preclinical aspects of CP-induced cardiotoxicity, its clinically used combination with other anticancer drugs, and the available therapeutic regimen to mitigate this cardiotoxicity. Further, we discussed the limitations of available synthetic drugs used as an adjuvant and discussed various natural bioactive and their experimental details. This manuscript's overall goal is to throw light on CP-induced cardiotoxicity and summarize all the experimental data so that researchers working in this field may scientifically get up-to-date information in one place., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Doxorubicin (DOX)-induced cardiomyopathy has a poor prognosis. No early detection or effective treatment methods are available in clinical. The mechanisms of cardiotoxicity were considered as oxidative stress and apoptosis in cardiomyocytes. However, the effect of DOX on cardiac fibroblasts remains to be developed. We investigated the direct effect of DOX on the function of human cardiac fibroblasts (HCFs) independently of cell death pathway. Animal study showed that lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulate dose, induced perivascular fibrosis without cell death in hear of mice. DOX increased the protein expression of α-SMA (a marker of trans-differentiation) in HCFs culture cells, indicating that DOX promoted the trans-differentiation of HCFs into myofibroblast. DOX also increased the mRNA and protein expression of matrix metalloproteinase (MMP)-1 in less than 0.1 μM which did not induce cell apoptosis of HCFs cells via PI3K/Akt pathway in HCFs. DOX increased Interleukin-6 (IL-6) via transforming growth factor (TGF)-β/Smad pathway. In addition, DOX induced the mitochondrial damage and increased the expression of Interleukin-1 (IL-1) via stress-activated protein kinases (SAPK)/ c-Jun NH-2termial kinase (JNK). A peroxisome proliferator-activated receptor gamma (PPARγ) agonist, pioglitazone hydrochloride attenuated the expression of fibrotic marker such as α-SMA and galectin-3 and collagen1 via SAPK/JNK signaling. Pioglitazone also suppressed DOX-induced early fibrotic response in vivo. In conclusion, these findings suggested that low dose DOX induced reactive fibrotic change of cardiac fibroblasts via cell death-independent pathway. There may be potentially new mechanisms of DOX induced cardiotoxicity in clinical usage.

The review is devoted to the current issues of radiation-induced cardiovascular complications, their diagnostics andincidence depending on the radiation doses and exposure regimens, potential efficiency of the screening strategiesfor cardiotoxicity monitoring after radiotherapy in cancer patients by analyzing the data from literature and clinical trials, based on recommendations of European Society of Cardiology and European Society of Medical Oncology., (S. M. Kozhukhov, О. Ye. Bazyka, N. V. Dovganych, О. A. Yarynkina, N. V. Tkhor.)

Diabetes mellitus has developed into one of the debilitating diseases disturbing the health of many people living with cardiovascular diseases in modern times. The root of Ageratum conyzoides was investigated for its effects on alloxan-induced diabetic Wistar rats' cardiac tissues. Thirty-two (32) Wistar rats weighing between 180 and 190 g were randomly divided into four groups. The animals in groups B-D were induced with a single dose of 150 mg/kg body weight of alloxan (ALX) intraperitoneally. They were confirmed hyperglycemic after 72 hours of induction and then sustained in hyperglycemic condition for 2 weeks. Animals in groups C and D received AC intervention, as stated above, for four weeks. The body weight of the experimental animals and blood collection for glucose estimation were taken weekly for six weeks using appropriate instruments. Biochemical assays for lipid profile, antioxidant enzymatic, and nonenzymatic markers were carried out. Histopathological changes in the cardiac tissues were also studied. Administration of 150 mg/kg of ALX to experimental rats induced diabetes and significantly reduced the body weights, significantly ( p < 0.05) increased the glucose level, triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, and decreased the levels of high-density lipoprotein (HDL) and antioxidant enzymatic markers such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) while the antioxidant nonenzymatic marker such as malondialdehyde (MDA) level was significantly increased. By contrast, rats given the ethanolic extract root of A. conyzoides had significantly ( p < 0.05) increased the body weight gain, whereas the glucose levels significantly ( p < 0.05) improved in treated diabetic rats. This extract also improved the cardiovascular system of the diabetic rats by significantly decreasing TG and LDL levels, significantly ( p < 0.05) increasing the HDL level, significantly reducing the cardiac contents of CAT, SOD, and GPx, and significantly ( p < 0.05) decreasing MDA. Ethanolic extract root of A. conyzoides exhibited antihyperglycemic and antihyperlipidemic activities and mitigates damage to the heart from the ALX-induced myocardial toxicity associated with type-1 diabetes., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 Abdulfatai Ojewale et al.)

Propofol, a commonly used anesthetic, is convenient to use, induces quick effect, enables rapid recovery, and is widely accessible given its stable supply. However, its adverse effects are a concern. Reportedly, propofol exhibits a significant inhibitory effect on the respiratory and circulatory systems. Furthermore, intravenous administration of this drug results in hypotension, rapid heart rate, and respiratory failure. Because many pregnant women are administered propofol during childbirth, it may have a significant negative effect on the development of infants. Propofol can cause considerable developmental neurotoxicity and has known activity on the heart. However, the underling mechanisms of these toxicities remain unclear. In the present study, zebrafish embryos were exposed to propofol at different concentrations (0.05, 0.1, 0.5, 1, 5, 10, and 20 μg/ml) to determine its developmental and cardiac toxicities. Propofol exposure decreased the survival rate and hatchability of zebrafish embryos. Additionally, the embryo malformation rate increased in a concentration-dependent manner. Different types of malformations were observed following propofol administration. The proportion of pericardial cysts increased, whereas the heart rate and size decreased with an increase in propofol concentration. The quantitative reverse-transcription polymerase chain reaction revealed that propofol significantly altered the expression of genes related to cardiac development and functions in zebrafish. Collectively, our findings indicate that propofol exposure induces significant developmental and cardiac toxicities in zebrafish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Chemotherapy-associated cardiotoxicity may delay or impair the ability to administer fully myeloablative chemotherapy for stem cell transplant in those with reduced left ventricular ejection fraction. Studies in adults have been inconsistent regarding the value of ejection fraction in predicting cardiotoxicity in the posttransplant period. Recent publications, however, have demonstrated successful stem cell transplantation in adults despite low ejection fractions. This case series highlights 2 pediatric patients who were successfully treated with stem cell transplantation without posttransplant cardiac complications, despite pretransplant ejection fractions of 38% and 29%.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

Chemotherapy related cardiotoxicity is now becoming one of the biggest hurdles for the prognosis of cancer patients. Therapeutically delivering protective small RNAs holds promise for the cardiotoxicity prevention and therapy. However, heart is intrinsically refractory to the nanoparticle-mediated drug delivery. In this study, we found that the exosome-mediated miRNA delivery into the heart could be significantly augmented with the aid of ultrasound targeted microbubble destruction (UTMD). Moreover, we found that UTMD assisted exosomal miR-21 delivery into the heart significantly decreased the cell death, and restored the cardiac function in a doxorubicin induced cardiotoxicity mouse model. Our study here not only provides a promising strategy to protect the heart from the chemotherapy related cardiotoxicity, but also sheds light on gene therapy of other heart diseases., Competing Interests: Declaration of competing interest All the authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An individual's inherited genetic makeup and acquired genomic variants may account for a significant portion of observable variability in therapy efficacy and toxicity. Pharmacogenomics (PGx) is the concept that treatments can be modified to account for these differences to increase chances of therapeutic efficacy while minimizing risk of adverse effects. This is particularly applicable to oncology in which treatment may be multimodal. Each tumor type has a unique genomic signature that lends to inclusion of targeted therapy but may be associated with cumulative toxicity, such as cardiotoxicity, and can impact quality of life. A greater understanding of therapeutic agents impacted by PGx and subsequent implementation has the potential to improve outcomes and reduce risk of drug-induced adverse effects., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Immune checkpoint blockade (ICB) has become a standard of care in a subset of solid tumors. Although cancer survivorship has extended, rates of durable response of ICB remain poor; furthermore, cardiac adverse effects are emerging, which impact several mechanical aspects of the heart. Cardio-oncology programs implement a clinical assessment to curtail cardiovascular disease progression but are limited to the current clinical parameters used in cardiology. Pharmacogenomics provides the potential to unveil heritable and somatic genetic variations for guiding precision immunotherapy treatment to reduce the risk of immune-related cardiotoxicity. A better understanding of pharmacogenomics will optimize the current treatment selection and dosing of immunotherapy. Here, we summarize the recent pharmacogenomics studies in immunotherapy responsiveness and its related cardiotoxicity and highlight how patient genetics and epigenetics can facilitate researchers and clinicians in designing new approaches for precision immunotherapy. We highlight and discuss how single-cell technologies, human-induced pluripotent stem cells and systems pharmacogenomics accelerate future studies of precision cardio-oncology., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The phosphoinositide 3-kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3'-hydroxyl group of inositol membrane lipids, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. This results in downstream effects, including cell growth, proliferation, and migration. The heart expresses three PI3K class I enzyme isoforms (α, β, and γ), and these enzymes play a role in cardiac cellular survival, myocardial hypertrophy, myocardial contractility, excitation, and mechanotransduction. The PI3K pathway is associated with various disease processes but is particularly important to human cancers since many gain-of-function mutations in this pathway occur in various cancers. Despite the development, testing, and regulatory approval of PI3K inhibitors in recent years, there are still significant challenges when creating and utilizing these drugs, including concerns of adverse effects on the heart. There is a growing body of evidence from preclinical studies revealing that PI3Ks play a crucial cardioprotective role, and thus inhibition of this pathway could lead to cardiac dysfunction, electrical remodeling, vascular damage, and ultimately, cardiovascular disease. This review will focus on PI3Kα, including the mechanisms underlying the adverse cardiovascular effects resulting from PI3Kα inhibition and the potential clinical implications of treating patients with these drugs, such as increased arrhythmia burden, biventricular cardiac dysfunction, and impaired recovery from cardiotoxicity. Recommendations for future directions for preclinical and clinical work are made, highlighting the possible role of PI3Kα inhibition in the progression of cancer-related cachexia and female sex and pre-existing comorbidities as independent risk factors for cardiac abnormalities after cancer treatment., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Trastuzumab ( TZM ) is a humanized monoclonal antibody that has been approved for the clinical management of HER2-positive metastatic breast and gastric cancers but its use is limited by its cumulative dose and off-target cardiotoxicity. Unfortunately, till date, there is no approved antidote to this off-target toxicity. Therefore, an acute study was designed at investigating the protective potential and mechanism(s) of CVE and IGE in TZM -induced cardiotoxicity utilizing cardiac enzyme and oxidative stress markers and histopathological endpoints. 400 mg/kg/day CVE and IGE dissolved in 5% DMSO in sterile water were investigated in Wistar rats injected with 2.25 mg/kg/day/ i.p. route of TZM for 7 days, using serum cTnI and LDH, complete lipid profile, cardiac tissue oxidative stress markers assays, and histopathological examination of TZM -intoxicated heart tissue. Results showed that 400 mg/kg/day CVE and IGE profoundly attenuated increases in the serum cTnI and LDH levels but caused no significant alterations in the serum lipids and weight gain pattern in the treated rats. CVE and IGE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving TZM -associated cardiac histological lesions. These results suggest that CVE and IGE could be mediating its cardioprotection via antioxidant, free radical scavenging, and antithrombotic mechanisms, thus, highlighting the therapeutic potentials of CVE and IGE in the management of TZM -mediated cardiotoxicity., Competing Interests: The authors have none to declare., (Copyright © 2020 Olufunke Olorundare et al.)

Doxorubicin is a commonly used anthracycline chemotherapeutic agent; however, its application is limited owing to its cardiotoxicity. Current clinical treatments cannot efficiently or fully prevent doxorubicin-induced toxicity, primarily because its pathogenesis and mechanisms of action remain unknown. In this study, we established a rat model of chronic doxorubicin-induced cardiotoxicity, in which the severity of cardiac fibrosis and hydroxyproline levels increased in a time-dependent manner. Doxorubicin damaged the mitochondria and blood vessels and induced autophagy. Cells undergoing endothelial-to-mesenchymal transition (EndoMT)and those expressing endothelial cell and myofibroblast markers were simultaneously observed in vitro and in rats treated with doxorubicin. The NF-κB pathway was activated during EndoMT, andp65 and p-p65 were strongly expressed in the nucleus of endothelial cells in vitro. Taken together, these results suggest that vascular injury and cardiac fibrosis are characteristic symptoms of doxorubicin-induced cardiotoxicity. The NF-κB pathway-associated EndoMT may influence the pathogenesis of doxorubicin-induced cardiotoxicity, and the constituents of this pathway may be potential therapeutic targets to prevent the development of this condition., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Cantharidin (CTD) is a compound which have the potential to be exploited as an antitumor drug, and it has been demonstrated antitumor effects in a variety of cancers. However, the use is limited due to its severe toxicity. It has reported that it can induce fatal cardiac arrhythmias. Fortunately, we found that L-glutamine can alleviate cardiac toxicity caused by cantharidin in mice., Methods: To investigate the protective effect of L-glutamine, we used a high dose of cantharidin in mice to create a model of cardiotoxicity. In the experimental mice, glutamine was given orally half an hour before they were administrated with cantharidin. The mice of control group were intraperitoneally injected with DMSO solution. The general state of all mice, cardiac mass index, electrocardiogram change and biological markers were determined. Hematoxylin-eosin staining (HE staining) of heart tissue was carried out in each group to reflect the protective effect of glutamine. To investigate the mechanisms underlying the injury and cardio-protection, multiple oxidative stress indexes were determined and succinate dehydrogenase activity was evaluated., Result: The results showed that L-glutamine (Gln) pretreatment reduced weight loss and mortality. It also decreased the biological markers (p < 0.05), improved electrocardiogram and histological changes that CTD induced cardiotoxicity in mice. Subsequently, the group pretreated with L-glutamine before CTD treatment increases in MDA but decreases in SOD and GSH, in comparison to the group treated with CTD alone. Besides, succinate dehydrogenase activity also was improved when L-glutamine was administrated before cantharidin compared to cantharidin., Conclusions: This study provided evidence that L-glutamine could protect cardiac cells against the acute cantharidin-induced cardiotoxicity and the protective mechanism of glutamine may be related to the myocardial cell membrane or the tricarboxylic acid cycle in the mitochondria.

Lung cancer is a major cause of cancer-related mortality worldwide, both in men and women. The vast majority of patients are diagnosed with non-small-cell lung cancer (NSCLC, 80-85% of lung cancer cases). Therapeutics named immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in the last decade. They are monoclonal antibodies, and those directed against PD-1 (programmed cell death protein 1) or PD-L1 (programmed cell death-ligand 1) have been used in the treatment of lung cancer and significantly improved the prognosis of NSCLC patients. However, during treatment with ICIs, immune-related adverse events (irAEs) can occur in any organ and any tissue. At the same time, although cardiac irAEs are relatively rare compared to irAEs in other organs, they have a high mortality rate. The two most common clinical manifestations of immunotherapy-related cardiotoxicity are myocarditis and pericarditis. Various types of arrhythmias have been reported in patients treated with ICIs, including the occurrence of life-threatening complete atrioventricular block or ventricular tachyarrhythmias. Here, we aim to summarize the incidence, clinical manifestations, underlying mechanisms, diagnosis, and treatment strategies for ICI-associated cardiotoxicity as these issues become very important in view of the increasing use of ICI in the treatment of lung cancer.

Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte's death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by 1 H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and cis- epoxysuccinate ( cis -ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and cis -ES either alone or in combination with DOX in H9C2 cells. A 1 H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and cis -ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of cis -ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.

Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors., Competing Interests: NO authors have competing interest.

5-Fluorouracil (5-FU) is used in the treatment of different solid tumors; however, its use is associated with rare, but serious cardiotoxicity. Nevertheless, the involvement of ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 trajectories in the cardiotoxic effect and in the potential cardioprotective upshot of simvastatin has been elusive. Male Wistar rats were allocated into 5-FU (50 mg/kg/week; i.p, 6 weeks), simvastatin (15 mg/kg/day; p.o, 8 weeks) treated groups and simvastatin + 5-FU, besides the normal control group. 5-FU-induced cardiotoxicity boosted the serum level of N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP), aortic contents of endothelin (ET)-1 and thromboxane (TX) A2, as well as cardiac contents of NADPH oxidases (Nox), cyclooxygenase (COX)-2, malondialdehyde (MDA), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated kinase (p-ERK)1/2 and the protein expressions of rho-kinase (ROCK) and caspase-3. On the other hand, it suppressed cardiac reduced glutathione (GSH) and phosphorylated endothelial nitric oxide synthase (p-eNOS). Contrariwise, co-administration with simvastatin overcame these disturbed events and modulated the ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 signaling pathways. This study highlights other mechanisms than coronary artery spasm in the 5-FU cardiotoxicity and reveals that NT-proBNP is a potential early marker in this case. Moreover, the cross-talk between ROCK/ NF-κB, ROS/COX-2/TXA2, Akt/eNOS and ET-1/ERK1/2 pathways contributes via different means to upsetting the vasoconstriction/vasodilatation equilibrium as well as endothelial cell function and finally leads to cardiomyocyte stress and death-the modulation of these trajectories offers simvastatin its potential cardio-protection against 5-FU.

Sorafenib, a tyrosine kinase inhibitor that is used in the treatment of hepatocellular and renal cell carcinoma, was reported to induce cardiotoxicity. This study aimed to investigate the potential cardioprotective effect of losartan against sorafenib-induced cardiotoxicity in rat. Sorafenib significantly reduced the left ventricular pressure, heart rate dp/dt max & dp/dt min (indexes of myocardial contractility and relaxation; respectively), and prolonged both the systolic and diastolic periods. Coadminstration of losartan significantly reversed the effects of sorafenib on heart rate, dp/dt max and dp/dt min. In addition, there was a tendency for losartan to reverse sorafenib reduction in left ventricular pressure and perfusion pressure but it did not reach statistical significance. A GC-MS non-targeted based metabolites profiling of rat plasma revealed elevated metaboites, including urea and fatty acids levels, associated with sorafenib induced cardiotoxicity. However, only glycine and lactic acid were statistically significant. Interestingly, losartan co-administration with sorafenib restored these changes, and resulted in a significantly reduced glycine, urea and some fatty acids levels namely; Cis-vaccenic acid, oleic acid, stearic acid and undecanoic acid. In addition, based on histology results, losartan coadminitration almost obviated sorafenib-induced changes in cardiac tissues. The study suggests that losartan has the potential to exert a protective effect against sorafenib-induced cardiotoxicity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Clinical application of doxorubicin (DOX) is limited by its toxic cardiovascular side effects. Our previous study found that toll-like receptor (TLR) 5 deficiency attenuated cardiac fibrosis in mice. However, the role of TLR5 in DOX-induced cardiotoxicity remains unclear. Methods: To further investigate this, TLR5-deficient mice were subjected to a single intraperitoneal injection of DOX to mimic an acute model. Results: Here, we reported that TLR5 expression was markedly increased in response to DOX injection. Moreover, TLR5 deficiency exerted potent protective effects against DOX-related cardiac injury, whereas activation of TLR5 by flagellin exacerbated DOX injection-induced cardiotoxicity. Mechanistically, the effects of TLR5 were largely attributed to direct interaction with spleen tyrosine kinase to activate NADPH oxidase (NOX) 2, increasing the production of superoxide and subsequent activation of p38. The toxic effects of TLR5 activation in DOX-related acute cardiac injury were abolished by NOX2 deficiency in mice. Our further study showed that neutralizing antibody-mediated TLR5 depletion also attenuated DOX-induced acute cardiotoxicity. Conclusion: These findings suggest that TLR5 deficiency attenuates DOX-induced cardiotoxicity in mice, and targeting TLR5 may provide feasible therapies for DOX-induced acute cardiotoxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Doxorubicin (DOX) administration decreases cardiac soluble guanylate cyclase (sGC) activity. We hypothesized that bypassing impaired NO-sGC-cGMP pathway resulting from the activation of oxidized and heme-free soluble guanylate cyclase (sGC) could be a therapeutic target for DOX-mediated cardiomyopathy (DOX-CM). The present study investigated the therapeutic roles and mechanism of BAY60-2770, an activator of oxidized sGC, in alleviating DOX-CM., Methods: H9c2 cardiomyocytes were pretreated with BAY60-2770 followed by DOX. Cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. To determine the role BAY60-2770 in mitochondrial ROS generation and mitochondrial membrane potential, we examined mitoSOX RED and TMRE fluorescence under DOX exposure. As animal experiments, rats were orally administered with 5 mg/kg of BAY60-2770 at 1 h prior to every DOX treatment and then assessed by echocardiography and apoptotic marker and autophagy., Results: BAY60-2770 ameliorated cell viability and DOX-induced oxidative stress in H9c2 cells, which was mediated by PKG activation. Mitochondrial ROS and TMRE fluorescence were attenuated by BAY60-2770 in DOX-treated H9c2 cells. DOX-induced caspase-3 activation decreased after pretreatment with BAY60-2770 in vivo and in vitro. Echocardiography showed that BAY60-2770 significantly improved DOX-induced myocardial dysfunction. Autophagosome was increased by BAY60-2770 in vivo., Conclusions: BAY60-2770 appears to mitigate DOX-induced mitochondrial ROS, membrane potential loss, autophagy, and subsequent apoptosis, leading to protection of myocardial injury and dysfunction. These novel results highlighted the therapeutic potential of BAY60-2770 in preventing DOX-CM., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) acts as the cornerstone in multiple tumour chemotherapy regimens, however, its clinical application is often impeded due to the induction of a severe cardiotoxicity that eventually provokes left ventricular dysfunction and congestive heart failure. Coumestrol (CMT) is a common dietary phytoestrogen with pleiotropic pharmacological effects. The present study aims to investigate the role and mechanism of CMT on DOX-induced cardiotoxicity. Mice were intragastrically administrated with CMT (5 mg/kg/day) for consecutive 2 weeks and then received a single intraperitoneal injection of DOX (15 mg/kg) to mimic the clinical toxic effects after 8-day additional feeding. To verify the role of 5' AMP-activated protein kinase alpha (AMPKα), AMPKα2 global knockout mice were used. H9C2 cells were cultured to further validate the beneficial role of CMT in vitro . CMT administration notably ameliorated oxidative damage, cell apoptosis and cardiac dysfunction in DOX-treated mice. Besides, we observed that DOX-induced reactive oxygen species overproduction and cardiomyocyte apoptosis were also reduced by CMT incubation in H9C2 cells. Mechanistically, CMT activated AMPKα and Ampkα deficiency abolished the beneficial effects of CMT in vivo and in vitro . Finally, we proved that protein kinase A (PKA) was required for CMT-mediated AMPKα activation and cardioprotective effects. CMT activated PKA/AMPKα pathway to alleviate DOX-induced oxidative damage, cell apoptosis and cardiac dysfunction. Our findings provide a promising therapeutic agent for cancer patients receiving anthracycline chemotherapy.

Purpose: Aloin, an anthraquinone present in the aloe species, possesses antiangiogenic, chemopreventive and antioxidant properties. It exerts cytotoxicity against breast cancer and ovarian cancer cell lines. These properties of aloin project it as a chemopreventive adjuvant to anticancer chemotherapy., Methods: We evaluated the effect of concurrent oral administration of aloin against doxorubicin (DOX)-induced cardiotoxicity in rats. The protective effects of aloin against DOX-induced toxicity were evident as a statistically significant inhibition of a rise in the biochemical markers of myocardial damage including lactate dehydrogenase (LDH), creatinine kinase-myocardial band (CK-MB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)., Results: Aloin dose dependently inhibited the DOX-induced changes in ECG like increased ST-height and prolonged QT interval. It protected heart against the lipid peroxidation and restored the levels of antioxidative defenses: reduced glutathione, catalase and superoxide dismutase. Aloin prominently reduced the levels of proinflammatory cytokines- TNF-α, IL-1β and IL-6. Notably, the significant protective effects of aloin were evident even at the strikingly lower doses of 1 and 5 mg/kg per day., Conclusion: Our results highlight the necessity to further investigate the chemopreventive effects of aloin against other chemotherapeutic agents.

Oxidative stress is widely accepted as a key factor of doxorubicin (Doxo)‑induced cardiotoxicity. There is evidence to indicate that nitrosative stress is involved in this process, and that Doxo interacts by amplifying cell damage. Mitochondrial connexin 43 (mitoCx43) can confer cardioprotective effects through the reduction of mitochondrial reactive oxygen species production during Doxo‑induced cardiotoxicity. The present study aimed to evaluate the involvement of mitoCx43 in Doxo‑induced nitrosative stress. Rat H9c2 cardiomyoblasts were treated with Doxo in the absence or presence of radicicol, an inhibitor of Hsp90, the molecular chaperone involved in Cx43 translocation to the mitochondria that underlies its role in cardioprotection. FACS analysis and RT‑qPCR revealed that Doxo increased superoxide dismutase, and catalase gene and protein expression. As shown by hypodiploid nuclei and confirmed by western blot analysis, Doxo increased caspase 9 expression and reduced procaspase 3 levels, which induced cell death. Moreover, a significant increase in the activation of the NF‑κB signaling pathway was observed. It is well known that the increased expression of inducible nitric oxide synthase results in nitric oxide overproduction, which then rapidly reacts with hydrogen peroxide or superoxide generated by the mitochondria, to form highly reactive and harmful peroxynitrite, which ultimately induces nitrotyrosine formation. Herein, these interactions were confirmed and increased effects were observed in the presence of radicicol. On the whole, the data of the present study indicate that an interplay between oxidative and nitrosative stress is involved in Doxo‑induced cardiotoxicity, and that both aspects are responsible for the induction of apoptosis. Furthermore, it is demonstrated that the mechanisms that further increase mitochondrial superoxide generation (e.g., the inhibition of Cx43 translocation into the mitochondria) significantly accelerate the occurrence of cell death.

Background: Radiotherapy for breast cancer (BC) and its resulting cardiac exposure are associated with subclinical left ventricular dysfunction characterized by early decrease of global longitudinal strain (LS) measurement based on 2D speckle-tracking echocardiography. Recent software allows multi-layer and segmental analysis of strain, which may be of interest to quantify and locate the impact of cardiac exposure on myocardial function and potentially increase the early detection of radiation-induced cardiotoxicity. The aim of the study was to evaluate whether decrease in LS 6 months after radiotherapy is layer-specific and if it varies according to the left ventricular regional level and the coronary arterial territories., Methods: LS was measured at baseline before radiotherapy and 6 months post-radiotherapy. The LS was obtained for each myocardial layer (endocardial, mid-myocardial, epicardial), left ventricular regional level (basal, mid, apical) and coronary artery territory (left anterior descending artery (LAD), circumflex artery, right coronary artery)., Results: The study included 64 left-sided BC patients. Mean age was 58 years, mean doses to the heart, the left ventricle and the LAD were respectively 3.0, 6.7 and 16.4 Gy. The absolute decrease of LS was significant for the three layers (endocardial: - 20.0 ± 3.2% to - 18.8 ± 3.8%; mid-myocardial: - 16.0 ± 2.7% to - 15.0 ± 3.1%; epicardial: - 12.3 ± 2.5% to - 11.4 ± 2.8%, all p = 0.02), but only the relative decrease of LS in the endocardial layer was close to be significant (- 4.7%, p = 0.05). More precisely, the LS of the endocardial layer was significantly decreased for the most exposed parts of the left ventricle corresponding to the apical level (- 26.3 ± 6.0% vs. -24.2 ± 7.1%, p = 0.03) and LAD territory (- 22.8 ± 4.0% vs. -21.4 ± 4.8%, p = 0.03)., Conclusion: Six months post-radiotherapy, LS decreased predominantly in the endocardial layer of the most exposed part of the left ventricle. For precise evaluation of radiotherapy-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter., Trial Registration: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin -induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na + , K + , and Cl - ), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin., Competing Interests: All authors declare no conflict of interests., (Copyright © 2020 Maya P. Radeva-Ilieva et al.)

Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. Resveratrol is commercially available polyphenol that exerts beneficial effects in wide array of cardiovascular diseases including cardiac hypertrophy, myocardial infarction and heart failure. Nevertheless, the underlying mechanisms responsible for these effects are not fully elucidated. Since resveratrol is a well-known CYP1B1 inhibitor, the purpose of this study is to test whether resveratrol attenuates angiotensin II (Ang II)-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. RL-14 and H9c2 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 2, 10 or 50 μM resveratrol for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography-mass spectrometry (LC/MS). Hypertrophic markers and CYP1B1 gene expression and protein levels were measured using real-time PCR and Western blot analysis, respectively. Our results demonstrated that resveratrol, at concentrations of 10 and 50 μM, was able to attenuate Ang-II-induced cellular hypertrophy as evidenced by substantial inhibition of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide. Ang II significantly induced the protein expression of CYP1B1 and increased the metabolite formation rate of its associated mid-chain HETEs. Interestingly, the protective effect of resveratrol was associated with a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Our results provided the first evidence that resveratrol protects against Ang II-induced cellular hypertrophy, at least in part, through CYP1B1/mid-chain HETEs-dependent mechanism.

The chemotherapy drug doxorubicin (DOX) is effective in treating many types of cancers. However, due to its pro-inflammatory and cardiotoxic side effects, other remedies have also been explored as alternative treatments. The plant Alangium longiflorum was reported to contain cytotoxic activity against cancer cells, but it is unclear whether this plant would also yield side effects similar to doxorubicin. Hence,  this study investigated cytotoxic activity of A. longiflorum leaf extract against lung cancer cells and compared its pro-inflammatory and cardiotoxic side effects with those of DOX., Methods: Cytotoxic activity of A. longiflorum in human lung (A549) and breast (MCF-7) cancer cells was initially assessed by MTT assay and then was compared with doxorubicin. Presence of secondary metabolites in the leaf extract was examined by phytochemical screening. The ability of the plant extract to induce apoptosis was determined by measuring caspase-3/7 activity and apoptosis-related gene expression. Pro-inflammatory response was assessed by quantifying NFκB transcriptional activity and nuclear translocation with dual luciferase reporter and immunofluorescence assays, respectively. Cardiotoxicity was measured using zebrafish as a model organism., Results: A. longiflorum leaf extract displayed high cytotoxic activity against A549 versus MCF-7, which led this study to focus further on A549. Phytochemical screening showed that the extract contained terpenoids, alkaloids, phenols, cardiac glycosides, and tannins. The extract induced apoptosis through activation of caspase-3/7 and upregulation of pro-apoptotic genes without causing NFκB transcriptional activation and nuclear localization. The extract also did not significantly reduce heart function in zebrafish., Conclusion: Overall, our data suggested that extract from leaves of A. longiflorum can have the potential to serve as apoptotic agent towards lung cancer without inducing significant cardiotoxicity.

Cardiotoxicity is a highly relevant, because often life-threatening, adverse effect of doxorubicin (Doxo)-based anticancer therapy. Here, we investigated the Doxo-response of cardiovascular stem/progenitor cells employing a mouse embryonic stem cell (mESC)-based in vitro differentiation model. Endothelial progenitor cells revealed a pronounced Doxo sensitivity as compared to mESC, differentiated endothelial-like (EC) and cardiomyocyte-like cells (CM) and CM progenitors, which rests on the activation of senescence. Doxo treatment of EC progenitors altered protein expression of individual endothelial markers, actin cytoskeleton morphology, mRNA expression of genes related to mitochondrial functions, autophagy, apoptosis, and DNA repair as well as mitochondrial DNA content, respiration and ATP production in the surviving differentiated EC progeny. By contrast, LDL uptake, ATP-stimulated Ca 2+ release, and cytokine-stimulated ICAM-1 expression remained unaffected by the anthracycline treatment. Thus, exposure of EC progenitors to Doxo elicits isolated and persistent dysfunctions in the surviving EC progeny. In conclusion, we suggest that Doxo-induced injury of EC progenitors adds to anthracycline-induced cardiotoxicity, making this cell-type a preferential target for pharmacoprotective and regenerative strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: To evaluate the incidence and risk of cardiac toxicities associated with panitumumab in advanced cancer of Caucasian patients. Materials & methods: The incidence of cardiac toxicity was assessed by simple incidence rates and rates per 100 person-years. Univariate and multivariate Cox regression was conducted. Results: Panitumumab-containing therapy significantly increased the risk of developing cardiac arrhythmias (p = 0.036), but not for any cardiac event (p = 0.24) or ischemic event (p = 0.087). The absolute rate of developing cardiac arrhythmia was 10.0 events versus 7.5 events per 100 person-years. Pre-existing hypertension (p = 0.033), history of cardiac disease (p = 0.055) or panitumumab usage (p = 0.046) were risk factors for cardiac arrhythmias. Conclusion: The addition of panitumumab to chemotherapy increases the risk of developing cardiac arrhythmia, but not for any cardiac toxicity or ischemic events.

Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.

Anthracyclines is an effective chemotherapeutic treatment used for many types of cancer. However, high cumulative dosage of anthracyclines leads to cardiac toxicity and heart failure. Dysregulation of mitochondrial dynamics and function are major pathways driving this toxicity. Several pharmacological and non-pharmacological interventions aiming to attenuate cardiac toxicity by targeting mitochondrial dynamics and function have shown beneficial effects in cell and animal models. However, in clinical practice, there is currently no standard therapy for the prevention of anthracycline-induced cardiotoxicity. This review summarizes current reports on the impact of anthracyclines on cardiac mitochondrial dynamics and mitochondrial function and potential interventions targeting these pathways. The roles of mitochondrial dynamics and mitochondrial function in the development of anthracycline-induced cardiotoxicity should provide insights in devising novel strategies to attenuate the cardiac toxicity induced by anthracyclines., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism., Methods: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway., Results: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB., Conclusions: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.

Significance: The cardiac side effects of hematological treatments are a major issue of the growing population of cancer survivors, often affecting patient survival even more than the tumor for which the treatment was initially prescribed. Among the most cardiotoxic drugs are anthracyclines (ANTs), highly potent antitumor agents, which still represent a mainstay in the treatment of hematological and solid tumors. Unfortunately, diagnosis, prevention, and treatment of cardiotoxicity are still unmet clinical needs, which call for a better understanding of the molecular mechanism behind the pathology. Recent Advances: This review article will discuss recent findings on the pathomechanisms underlying the cardiotoxicity of ANTs, spanning from DNA and mitochondrial damage to calcium homeostasis, autophagy, and apoptosis. Special emphasis will be given to the role of reactive oxygen species and their interplay with major signaling pathways. Critical Issues: Although new promising therapeutic targets and new drugs have started to be identified, their efficacy has been mainly proven in preclinical studies and requires clinical validation. Future Directions: Future studies are awaited to confirm the relevance of recently uncovered targets, as well as to identify new druggable pathways, in more clinically relevant models, including, for example, human induced pluripotent stem cell-derived cardiomyocytes.

Significance: Despite their serious side effects, anthracyclines (ANTs) are the most prescribed chemotherapeutic drugs because of their strong efficacy in both solid and hematological tumors. A major limitation to ANTs clinical application is the severe cardiotoxicity observed both acutely and chronically. The mechanism underlying cardiac dysfunction under chemotherapy is mainly dependent on the generation of oxidative stress and systemic inflammation, both of which lead to progressive cardiomyopathy and heart failure. Recent Advances: Over the years, the iatrogenic ANTs-induced cardiotoxicity was believed to be simply given by iron metabolism and reactive oxygen species production; however, several experimental data indicate that ANTs may use alternative damaging mechanisms, such as topoisomerase 2β inhibition, inflammation, pyroptosis, immunometabolism, and autophagy. Critical Issues: In this review, we aimed at discussing ANTs-induced cardiac injury from different points of view, updating and focusing on oxidative stress and inflammation, since these pathways are not exclusive or independent from each other but they together importantly contribute to the complexity of ANTs-induced multifactorial cardiotoxicity. Future Directions: A deeper understanding of the mechanistic signaling leading to ANTs side effects could reveal crucial targeting molecules, thus representing strategic knowledge to promote better therapeutic efficacy and lower cardiotoxicity during clinical application.

Background: Cardiotoxicity, characterized by severe cardiac dysfunction, is a major problem in patients treated with different classes of anticancer drugs. Development of predictable human-based models and assays for drug screening are crucial for preventing potential drug-induced adverse effects. Current animal in vivo models and cell lines are not always adequate to represent human biology. Alternatively, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show great potential for disease modelling and drug-induced toxicity screenings. Fully automated high-throughput screening of drug toxicity on hiPSC-CMs by fluorescence image analysis is, however, very challenging, due to clustered cell growth patterns and strong intracellular and intercellular variation in the expression of fluorescent markers., Results: In this paper, we report on the development of a fully automated image analysis system for quantification of cardiotoxic phenotypes from hiPSC-CMs that are treated with various concentrations of anticancer drugs doxorubicin or crizotinib. This high-throughput system relies on single-cell segmentation by nuclear signal extraction, fuzzy C-mean clustering of cardiac α-actinin signal, and finally nuclear signal propagation. When compared to manual segmentation, it generates precision and recall scores of 0.81 and 0.93, respectively., Conclusions: Our results show that our fully automated image analysis system can reliably segment cardiomyocytes even with heterogeneous α-actinin signals.

The chemotherapeutic and immunosuppressive agent cyclophosphamide has previously been shown to induce complications within the setting of bone marrow transplantation. More recently, cardiotoxicity has been shown to be a dose-limiting factor during cyclophosphamide therapy, and cardiooncology is getting wider attention. Though mechanism of cyclophosphamide-induced cardiotoxicity is not completely understood, it is thought to encompass oxidative and nitrative stress. As such, this review focuses on antioxidants and their role in preventing or ameliorating cyclophosphamide-induced cardiotoxicity. It will give special emphasis to the cardioprotective effects of natural, plant-derived antioxidants that have garnered significant interest in recent times., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Muluken Altaye Ayza et al.)

Background: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting., Methods: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm., Results: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m 2 (vs < 25 mg/kg 2 , OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m 2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m 2 (OR 2.33 [95% CI 1.55-3.51])., Conclusions: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial., Trial Registration Number: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

Introduction: This case report signifies the need to systemically assess antimalarial toxicity in those undergoing long-term treatment., Case Report: A 59-year-old man with a history of ischemic-labeled heart disease revealed by conduction disorders and cutaneous lupus treated initially with hydroxychloroquine followed by chloroquine consulted for asthenia and weight loss. Clinically, he had a muscular atrophy, a motor deficit, and an abolition of the osteo-tendinous reflexes in the lower limbs. Adverse drug effects of the antimalarial therapy were suspected-specifically, muscular and cardiac toxicity. The diagnosis was confirmed with a muscle biopsy, which showed typical and florid vacuolar myopathy. Cessation of the drug resulted in a slow regression of symptoms., Conclusion: Cardiac and muscular toxicity related to antimalarials are rare and sometimes fatal; thus, they must be systematically assessed in a patient with several years of exposure. A muscle biopsy could be sufficient to allow for the diagnosis., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

The present study designed to investigate the protective effect of curcumin nanoparticles (CUR-NPs) on the cardiotoxicity induced by doxorubicin. Rats were divided into four groups; control, rats treated daily with CUR-NPs (50 mg/kg) for 14 days, rats treated with an acute dose of doxorubicin (20 mg/kg) and rats treated daily with CUR-NPs for 14 days injected with doxorubicin on the 10th day. After electrocardiogram (ECG) recording from rats at different groups, rat decapitation was carried out and the heart of each rat was excised out to measure the oxidative stress parameters; lipid peroxidation (MDA), nitric oxide (NO) and reduced glutathione (GSH) and the activities of Na,K,ATPase and acetylcholinesterase (AchE). In addition, the levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were determined in the cardiac tissues. Lactate dehydrogenase (LDH) activity was measured in the serum. The ECG recordings indicated that daily pretreatment with CUR- NPs has prevented the tachycardia (i.e. increase in heart rate) and ameliorated the changes in ST wave and QRS complex induced by doxorubicin. In addition, CUR-NPs prevented doxorubicin induced significant increase in MDA, NO, DA, AchE and LDH and doxorubicin induced significant decrease in GSH, NE, 5-HT and Na,K,ATPase. According to the present findings, it could be concluded that CUR-NPs have a protective effect against cardiotoxicity induced by doxorubicin. This may shed more light on the importance of CUR-NPs pretreatment before the application of doxorubicin therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)