Cardiotoxicity Research Articles

IL-17 signaling pathway: A potential therapeutic target for reducing skeletal muscle inflammation

BackgroundThe interleukin-17 (IL-17) signaling pathway is intricately linked with immunity and inflammation; however, the association between the IL-17 signaling pathway and skeletal muscle inflammation remains poorly understood. The study aims to investigate the role of the IL-17 signaling pathway in skeletal muscle inflammation and to evaluate the therapeutic potential of anti-IL-17 antibodies in reducing muscle inflammation. MethodsA skeletal muscle inflammation model was induced by cardiotoxin (CTX) injection in C57BL6/J mice. Following treatment with an anti-IL-17 antibody, we conducted a comprehensive analysis integrating single-cell RNA sequencing (scRNA-seq), bioinformatics, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and Western blot techniques to elucidate underlying mechanisms. ResultsscRNA-seq analysis revealed a significant increase in neutrophil numbers and activity in inflamed skeletal muscle compared to other cell types, including macrophages, T cells, B cells, endothelial cells, fast muscle cells, fibroblasts, and skeletal muscle satellite cells. The top 30 differentially expressed genes within neutrophils, along with 55 chemokines, were predominantly enriched in the IL-17 signaling pathway. Moreover, the IL-17 signaling pathway exhibited heightened expression in inflamed skeletal muscle, particularly within neutrophils. Treatment with anti-IL-17 antibody resulted in the suppression of IL-17 signaling pathway expression, accompanied by reduced levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as decreased numbers and activity of Ly6g+/Mpo+ neutrophils compared to CTX-induced skeletal muscle inflammation. ConclusionOur findings suggest that the IL-17 signaling pathway plays a crucial role in promoting inflammation within skeletal muscle. Targeting this pathway may hold promise as a therapeutic strategy for ameliorating the inflammatory micro-environment and reducing cytokine production.

Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats

The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.

Cardiovascular toxicity of chemotherapy and thyroid status of patients with gastric and colon cancer: Current state of the problem. A review

Cardiovascular and oncological diseases are the main causes of disability and mortality in Russia, sharing common risk factors and exacerbating each other. The specific toxicological effects of fluoropyrimidines, platinum drugs, and taxanes commonly used in the treatment of gastric and colorectal malignancies have been noted to potentially contribute to the onset of cardiovascular pathologies in some cases. However, the manifestation and prevalence of cardiovascular toxicity due to cancer treatment regimens are influenced by various factors beyond just the chemotherapy protocols employed. Gender, age, overall health status (including cardiac and thyroid functions), and other risk factors play significant roles in the development and progression of heart and vascular diseases in these patients. Thyroid dysfunction, even in the absence of severe clinical symptoms, can significantly impact the course of cardiovascular pathologies, complicating the management of toxic effects associated with polychemotherapy on both the cardiac muscle and vascular system. This paper analyzes modern ideas about pathogenetic relationship between cardiovascular diseases and gastric and colon cancer. The profile and mechanism of cardiovascular toxicity of chemotherapy in patients with gastric and colon cancer, pathogenetic relationship of thyroid status and cardiovascular diseases are presented. Organizational management issues of chemotherapy toxicity are briefly highlighted.

A Phase II Trial of Celecoxib with Neoadjuvant Concurrent Chemoradiation for Patients with Localized Rectal Adenocarcinoma Stage II and III

Abstract Background In recent years, neoadjuvant chemoradiation and subsequent surgical resection with total mesorectal excision has been shown to increase local control with decreased toxicity in comparison to upfront surgical resection followed by adjuvant chemoradiation. Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer. In this study we evaluated the efficacy of adding a selective COX-2 inhibitor to standart neoadjuvant chemoradiation on pathologic response, sphincter preservation and acute toxicity. Materials and Methods Thirty patients with Adenocarcinoma of rectum (up to 15 cm of anal verge) were enrolled in this phase 2 study. Patients undergone full colonoscopy, MRI rectal protocol, abdomino-pelvic and chest CT scan for staging then received neoadjuvant concurrent chemoradiation (capecitabine 825 mg/m2 bid in combination with celecoxib 200 mg bid and radiotherapy (50-50.4Gy/25-28fraction). Surgery was done 5-12 weeks after chemoradiation. Acute complications were scored by common toxicity criteria 5.0 and tumor response was graded according to AJCC and CAP guidelines for rectal adenocarcinoma. Results Of 30 patients, total mesorectal excision was done in 22 patients. Tumor regression grade was reported as: 7 patients (31.8%) had grade 0 or complete response, 7 patients (31.8%) had grade 1 or moderate response, 6 patients (27%) had grade 2 or minimal response and 2 patients (9%) had grade 3 or poor response. Primary tumor down staging was 63% and nodal down staging was 73% with sphincteric preservation rate of 77% among the operated cohort. No patients had hematologic or cardio-vascular toxicity. Conclusion Results indicate celecoxib in combination with neoadjuvant chemoradiation is safe and associated with low toxicity. This combination can promote pathologic complete response, tumor regression grade, sphincteric preservation, T and N down staging in rectal adenocarcinoma.

P-787 Gestational diabetes in mice induces embryonic fibro-adipogenic progenitors memory that impedes the recovery of injured skeletal muscle in adult offspring

Abstract Study question Whether and how intrauterine hyperglycemia induced by Gestational diabetes steadily influences the function and fate of mesenchymal stem cells, specifically fibro-adipogenic progenitors. Summary answer Gestational diabetes in mice caused declines in self-renewal and paracrine in fibro-adipogenic progenitors, prompted adipogenesis and fibrosis, destroyed recovery after muscular injury in adult offspring. What is known already Gestational diabetes contributed to the increased susceptibility to metabolic disorders, cardiovascular diseases and atherosclerosis. Intrauterine hyperglycemia promoted placental inflammation and endowed the hematopoietic stem and progenitor cells. As an important mesenchymal stem cell, fibro-adipogenic progenitors (FAPs) play a key role in the process of “replace, repair, regeneration, restore and regress”. When acute injury happens to skeletal muscle, the fibro-adipogenic progenitors cluster start to renew itself and differentiate into functional cells like fibroblasts or adipocytes, secrete cytokines to nearby myoblasts, inducing myotube formation and muscle regeneration by cell-cell communication. Study design, size, duration Pregnant mice were randomly divided into control (CTR) and gestational diabetes (GDM) groups, GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while CTR group was treated with vehicle buffer. Only when random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. At 8 weeks of offspring, we intramuscular injected cardiotoxin (CTX) to induce acute tibialis anterior muscle injury. Participants/materials, setting, methods 7 days after CTX intramuscular injection (CTX-D7) in offspring, mice were sacrificed and tiabialis anterior muscle was selected. Perilipin immunochemical and immunofluorescent staining, MASSON and Sirius Red staining were used to evaluate the recovery extent between CTR and GDM groups. Then we used fluorescence-activated cell sorting to evaluate the self proliferation of fibro-adipogenic cells at CTX-D3. We also collected FAPs to perform induced differentiation in vitro, co-culture with myoblast and SMART-sequence to explore underlying mechanism. Main results and the role of chance 7 days after cardiotoxin injection (CTX-D7), we used WGA to mark injured myofibers, eMHC to mark regenerated myofibers. Immunofluorescence and hematoxylin-eosin staining showed the muscle fibers in GDM male were still severe damaged and inadequate recovered when compared to CTR group. Perilipin immunochemical staining demonstrated more lipids deposition in GDM male muscle. MASSON and Sirius Red staining also revealed increased accumulation of collagen fibers in GDM group. Fluorescence-activated cell sorting firstly displayed depletion in numbers of Lineage-VCAM-Sca-1+ fibro-adipogeneic progenitors (FAPs) compartment in GDM group at CTX-D3 compared to CTR group. Using α-SMA to mark collagen fibers, perilipin to mark adiposity cells, we also observed activation of the FAPs into fibrosis or adipogenesis by in vitro induced differentiation. Myotubes formation experiment showed that myotubes were thinner and fusion extent was worse in myoblasts co-cultured with GDM FAPs rather than CTR FAPs. Finally, we performed SMART-sequence of FAPs between groups. Regarding p < 0.05 and the absolute of log2 foldchange >1 as significance, we totally found 1572 down-regulated genes, 1527 up-regulated genes in GDM FAPs. And the GO term analysis showed us that WNT signaling pathway, cell surface receptor signaling pathway were most highly affected. Limitations, reasons for caution We haven’t found out the key molecule in WNT signaling pathway, and how intrauterine hyperglycemia steadily affected FAP’s function remains to be explored. Also, whether other mesenchymal stem cells are influenced by short-term intrauterine hyperglycemia needs to be clarified. Wider implications of the findings Fibro-adipogenic progenitors is an important part of mesenchymal stem cells. These results demonstrated GDM in mice might induce mesenchymal memory that affects the long-term health of the offspring, which reminds us the stemness of GDM progenitors or stem cells might be destroyed and its cell-cell function may be also damaged. Trial registration number ZJU20210047

Resveratrol ameliorates cyprodinil-induced zebrafish cardiac developmental defects as an aryl hydrocarbon receptor antagonist.

Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring polyphenolic compound, showcases remarkable defensive properties in nurturing cardiac development. To investigate whether RSV could protect against cyprodinil-induced cardiac defects, we exposed zebrafish embryos to cyprodinil (500μg/L) in the presence or absence of RSV (1μM). Our results showed that RSV significantly mitigated the decrease of survival rate and embryo movement and the hatching delay induced by cyprodinil. In addition, RSV also improved cyprodinil-induced zebrafish cardiac developmental toxicity, including pericardial edema and cardiac function impairment. In mechanism, RSV attenuated the cyprodinil-induced changes in mRNA expression involved in cardiac development, such as myh6, myl7, tbx5, and gata4, and calcium ion channels, such as ncx1h, slc8a4a, and atp2a2b. We further showed that RSV might inhibit the activity of aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In summary, our findings establish that the protective effects of RSV against the cardiac developmental toxicity are induced by cyprodinil due to its remarkable ability to inhibit AhR activity. Our findings not only shed light on a new avenue for regulating and ensuring the safe utilization of cyprodinil but also presents a novel concept to promote its responsible use.

Development of a local controlled release system for therapeutic proteins in the treatment of skeletal muscle injuries and diseases

The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute injury. The therapeutic protein, a membrane-GPI anchored protein called Cripto, was immobilized in an injectable hydrogel delivery vehicle for local administration and sustained release. The hydrogel was made of poly(ethylene glycol)-fibrinogen (PEG-Fibrinogen, PF), in the form of injectable microspheres. The PF microspheres exhibited a spherical morphology with an average diameter of approximately 100 micrometers, and the Cripto protein was uniformly entrapped within them. The release rate of Cripto from the PF microspheres was controlled by tuning the crosslinking density of the hydrogel, which was varied by changing the concentration of poly(ethylene glycol) diacrylate (PEG-DA) crosslinker. In vitro experiments confirmed a sustained-release profile of Cripto from the PF microspheres for up to 27 days. The released Cripto was biologically active and promoted the in vitro proliferation of mouse myoblasts. The therapeutic effect of PF-mediated delivery of Cripto in vivo was tested in a cardiotoxin (CTX)-induced muscle injury model in mice. The Cripto caused an increase in the in vivo expression of the myogenic markers Pax7, the differentiation makers eMHC and Desmin, higher numbers of centro-nucleated myofibers and greater areas of regenerated muscle tissue. Collectively, these results establish the PF microspheres as a potential delivery system for the localized, sustained release of therapeutic proteins toward the accelerated repair of damaged muscle tissue following acute injuries.

Changes in Epicardial Adipose Tissue Assessed by Chest CT in Breast Cancer Patients Receiving Adjuvant Chemotherapy with Anthracyclines and Trastuzumab.

Cardiotoxicity (CTX) induced by adjuvant chemotherapy is a significant factor that impacts the prognosis and quality of life in breast cancer (BC) patients. In this study, we aimed to investigate the changes in epicardial adipose tissue (EAT) before and after treatment in BC patients who received anthracyclines adjuvant chemotherapy protocol (AC-T) and anthracyclines combined with trastuzumabadjuvant chemotherapy protocol (AC-TH). Additionally, we assessed whether there were any differences in the changes in EAT between the two groups of patients. Our objective was to examine the effects of anthracyclines and trastuzumab on EAT and determine the potential role of EAT changes on CTX. We reviewed female BC patients who were treated with adjuvant chemotherapy protocols of AC-T and AC-TH, all of whom underwent baseline (T0) and follow-up (T1) chest computed tomography (CT) and echocardiography. A cohort of healthy women, matched in age, underwent two chest CTs. EAT was quantified on chest CT using semi-automated software. CTX was defined as a 10% reduction in left ventricular ejection fraction (LVEF) from baseline, with an absolute value of 53%. A total of 41 BC patients were included in the study, with 23 patients in the AC-T group and 18 patients in the AC-TH group. Additionally, 22 healthy females were included as the normal group. None of the BC patients developed CTX after chemotherapy. The age did not differ significantly between the normal group and the AC-T group (p = 0.341) or the AC-TH group (p = 0.853). Similarly, the body mass index (BMI) of the normal group was comparable to that of the AC-T group (p = 0.377, 0.346) and the AC-TH group (p = 0.148, 0.119) before and after chemotherapy. The EAT volume index (mL/kg/ ) was significantly higher in both the AC-T group (5.11 1.85 vs. 4.34 1.55, p 0.001) and the AC-TH group (4.53 1.61 vs. 3.48 1.62, p 0.001) at T1 compared with T0. In addition, both the AC-T group (-72.95 5.01 vs. -71.22 3.91, p = 0.005) and the AC-TH group (-72.55 5.27 vs. -68.20 5.98, p 0.001) exhibited a significant decrease in EAT radiodensity (HU) at T1 compared to T0. However, there was no significant difference observed in the normal group. At T0, no difference was seen in EAT volume index (4.34 1.55 vs. 3.48 1.62, p = 0.090) and radiodensity (-71.22 3.91 vs. -68.20 5.98, p = 0.059) between the AC-T and AC-TH groups. Similarly, at T1, there was still no significant difference observed in the EAT volume index (-5.11 1.85 vs. 4.53 1.61, p = 0.308) and radiodensity (-72.95 5.00 vs. -72.54 5.27, p = 0.802) between the two groups. BC patients who underwent AC-T and AC-TH adjuvant chemotherapy protocols demonstrated a significant rise in the volume index of EAT, along with a substantial reduction in its radiodensity post-chemotherapy. These findings indicate that alterations in EAT could potentially aid in identifying cardiac complications caused by chemotherapeutic agents and remind clinicians to focus on changes in EAT after adjuvant chemotherapy in BC patients to prevent the practical occurrence of CTX.

Vascular biomarkers reveal a unique toxicity profile of posttransplant cyclophosphamide: secondary analysis of BMT CTN 0402 and 1202

AbstractPosttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis regimens are associated with very low rates of severe acute and chronic GVHD after hematopoietic cell transplant (HCT). However, concerns about cardiac and other organ toxicities persist. This study aimed to compare the vascular biomarker profile of PTCy with other GVHD regimens, including tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), to generate hypotheses for toxicity mitigation strategies. Plasma samples from day +28 after transplant were analyzed against pretransplant baseline measurements in patients receiving PTCy-based GVHD prophylaxis as part of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 (n = 112) vs Tac/MTX (n = 98) and Tac/Sir (n = 95) regimens from BMT CTN 0402. Compared with Tac/MTX, PTCy was associated with increasing angiopoietin-2 levels and decreasing epidermal growth factor levels at day +28. In contrast, Tac/Sir displayed increasing follistatin and endoglin levels and decreasing vascular endothelial growth factor receptor 2 (VEGFR2) plasma levels after HCT. Across all cohorts, increasing epidermal growth factor was protective from nonrelapse mortality, and decreasing VEGFR2 was associated with subsequent development of extensive chronic GVHD. These distinct biomarker profiles offer insights that could guide strategies to mitigate unique GVHD prophylaxis–associated toxicities.

Mangiferin Enhances the Therapeutic Efficacy of Bone Marrow Mesenchymal Stem Cells on Cyclophosphamide Induced Cardiac Toxicity in Adult Male Albino Rat Models

Mangiferin Enhances the Therapeutic Efficacy of Bone Marrow Mesenchymal Stem Cells on Cyclophosphamide Induced Cardiac Toxicity in Adult Male Albino Rat Models

Iron metabolism in doxorubicin-induced cardiotoxicity: From mechanisms to therapies

Doxorubicin (DOX) is an anti-tumor agent for chemotherapy, but its use is often hindered by the severe and life-threatening side effect of cardiovascular toxicity. In recent years, studies have focused on dysregulated iron metabolism and ferroptosis, a unique type of cell death induced by iron overload, as key players driving the development of DOX-induced cardiotoxicity (DIC). Recent advances have demonstrated that DOX disturbs normal cellular iron metabolism, resulting in excessive iron accumulation and ferroptosis in cardiomyocytes. This review will explore how dysregulated iron homeostasis and ferroptosis drive the progression of DIC. We will also discuss the current approaches to target iron metabolism and ferroptosis to mitigate DIC. Besides, we will discuss the limitations and challenges for clinical translation for these therapeutic regimens.

A clinical study and laboratory evaluation of the cardiac and hepatic toxic effects of paraphenylenediamine

Introduction Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity. Methods This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers. Results Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality. Discussion Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care. Conclusion Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning.

Cardiac Toxicities of Immune Checkpoint Inhibitors: More Awareness is Needed

Immune checkpoints inhibitors (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab) are monoclonal antibodies that target cell membrane receptors (CTLA-4, PD-1, PDL-1) implicated in the immunosuppression. This results in activation of the lymphocytic immune response leading to CD8+ T cells proliferation in many organs including the heart. However, the management consists of stopping the immunotherapy and starting high-dose corticosteroids. The incidence of these toxicities as well as their pathophysiology, risk factors, onset and prognosis are not clearly established yet due to the lack of data and cohort studies. Despite the FDA approval of these drugs in the treatment of many refractory cancers, they should be used with caution due to their devastating repercussions.

The Impact of Regorafenib on Cardiac Function in Metastatic Colorectal Cancer Patients a Retrospective Cohort Study

Introduction: Metastatic colorectal cancer (mCRC) poses significant clinical challenges, necessitating the exploration of novel treatment modalities. Regorafenib, a multi-kinase inhibitor, has emerged as a promising therapeutic option for refractory mCRC. However, concerns regarding its potential cardiotoxic effects warrant comprehensive evaluation of its impact on cardiac function parameters in this patient population. Methods: The purpose of this retrospective cohort research was to find out how regorafenib affected cardiac function measures in patients with metastatic colorectal cancer (mCRC) at the Pakistan Institute of Medical Sciences (PIMS) in Islamabad. 78 adult patients in all, having histologically proven mCRC, who were treated with regorafenib between January 2023 and March 2024 were included in the analysis. Baseline characteristics, treatment details, cardiac function parameters, and incidence of cardiac events were retrospectively analyzed. Statistical analyses were performed to assess changes in cardiac function parameters and identify predictors of cardiac toxicity associated with regorafenib therapy. Results: Following regorafenib therapy, there was a significant decrease in left ventricular ejection fraction (LVEF), alterations in diastolic function indices, and an incidence of clinically significant cardiac events (12%), including heart failure, arrhythmias, and myocardial infarction. Subgroup analyses identified older age, male sex, pre-existing hypertension, longer treatment duration, and higher cumulative doses of regorafenib as potential predictors of cardiac toxicity. Conclusion: This study underscores the potential cardiotoxic effects of regorafenib in mCRC patients and highlights the importance of personalized cardiac monitoring and risk management strategies during treatment. Further research is warranted to validate these findings and inform evidence-based approaches to optimize the cardiovascular safety of regorafenib in clinical practice.

Oxidative damage and cardiotoxicity induced by 2-aminobenzothiazole in zebrafish (Danio rerio)

There is limited information available on cardiovascular toxicity of 2-Aminobenzothiazole (NTH), a derivative of benzothiazole (BTH) commonly used in tire production, in aquatic organisms. In the present study, the zebrafish embryos were exposed to varying concentrations of NTH (0, 0.05, 0.5, and 5 mg/L) until adulthood and the potential cardiovascular toxicity was assessed. NTH exposure resulted in striking aberrations in cardiac development, including heart looping failure and interference with atrioventricular canal differentiation. RNA-sequencing analysis indicated that NTH causes oxidative damage to the heart via ferroptosis, leading to oxygen supply disruption, cardiac malformation, and ultimately, zebrafish death. Quantitative real-time polymerase chain reaction (qPCR) analysis demonstrated the dysregulation of genes associated with early heart development, contraction, and oxidative stress. Additionally, reactive oxygen species accumulation and glutathione/malondialdehyde levels changes suggested a potential link between cardiac developmental toxicity and oxidative stress. In adult zebrafish, NTH exposure led to ventricular enlargement, decreased heart rate, reduced blood flow, and prolonged RR, QRS, and QTc intervals. To the best of our knowledge, this study is the first to provide evidence of cardiac toxicity and the adverse effects of ontogenetic NTH exposure in zebrafish, revealing the underlying toxic mechanisms connected with oxidative stress damage. These findings may provide crucial insights into the environmental risks associated with NTH and other BTHs.

Untargeted metabolic profiling of high-dose methotrexate toxicity shows alteration in betaine metabolism

Cardiotoxicity is a well-established adverse effect of several drugs across multiple therapeutic indications. It is particularly prevalent following anticancer therapy. In order to evaluate the changes in cellular metabolism associated with methotrexate cardiotoxicity, we treated Wistar rats with a single high dose of methotrexate (HDMTX), and after five days, the animals were sacrificed. We then analyzed the cardiotoxicity parameters in serum like Cardiac enzymes(CK-MB, Troponin T, ALP), Inflammatory markers (TNF-α and IL-6), oxidative stress markers (NO, NOX-2), histopathology and cardiac tissue with the goal of identifying a metabolic signature of cardiotoxicity using discovery-based metabolomics. The biochemical parameters for cardiac enzymes, oxidative stress and inflammatory markers showed a significant increase in all three categories in rats treated with HDMTX. These findings were mirrored in the histopathological analysis confirming cardiotoxicity due to HDMTX. The results showed a total of 95 metabolites that were found to be significantly (p < 0.05) modulated: either up- or downregulated in the HDMTX-treated group when compared with the control group. Using integrated pathway analysis we found these metabolites were associated with many important cardiac tissue metabolic pathways, such as the malate aspartate shuttle, taurine and hypotaurine metabolism, betaine metabolism, spermidine biosynthesis, and homocysteine degradation. Among them, L-arginine, homocysteine, and betaine were significantly upregulated, suggesting their possible association with cardiac tissue injury. Overall, we provided evidence for using untargeted metabolomics to identify novel metabolites associated with HDMTX cardiac toxicity.

Beneficial effects of Bacopa monnieri (brahmi) in Doxorubicin-induced cardiotoxicity in rats

Cancer, a leading global cause of death, drives research for safer treatments. Doxorubicin is an effective anticancer drug but is associated with cardiotoxicity as a characteristic adverse effect. Bacopa monnieri, a traditional Ayurvedic herb rich in antioxidants, emerges as a potential adjunct in cancer treatment. The study aims to explore Bacopa monnieri's impact on doxorubicin-induced cardiotoxicity. The study was conducted in 30 rats with 6 rats in each of the 5 groups: Group 1 was administered distilled water; Group 2 received Doxorubicin at 5 mg/kg by IP on days 7, 14, and 21. Groups 3, 4 and 5 were administered Bacopa monnieri at 75mg/kg, 150mg/kg, and 250mg/kg orally daily doses along with Doxorubicin at 5mg/kg by IP on days 7,14 and 21. The Bacopa monnieri-treated groups compared to the Doxorubicin(Dox) group showed a significant reduction in aspartate aminotransferase (AST), troponin I, and malondialdehyde (MDA) levels while the levels of antioxidants Superoxide dismutase (SOD), and Glutathione (GSH) increased. Histopathology showed fibrosis and inflammation in the Doxorubicin group while restoration of normal cardiac tissue in the Bacopa monnieri-treated group. The study illustrates Bacopa monnieri's ability to alleviate Doxorubicin-induced cardiac toxicity by its antioxidant properties.

Elamipretide protects H9c2 Rat Cardiomyoblasts against Doxorubicin-Induced Disruption of Mitochondrial Quality Control by Restoration of Fusion and Fission Balance

Doxorubicin (DOX) has been used to treat malignant diseases for over 40 years. The main constraint to its clinical application is dose-dependent cardiotoxicity which is regarded as a major matter of concern that limits its medical usefulness. Mitochondrial dysfunction is considered the chief contributor to DOX-induced cardiotoxicity and it involves disruption of mitochondrial quality control, mainly impaired fusion, and enhanced fission processes. Compounds that specifically target the mitochondria and restore fusion and fission balance are considered a promising tool to protect or treat cardiomyopathy and heart failure and thus could be investigated as a novel strategy to alleviate DOX-induced cardiac toxicity, one of which is elamipretide (ELAM). In this study, MTT assay revealed that DOX induces a significant reduction in H9c2 cell viability which is both time and dose-dependent whereas ELAM has no significant effect on the viability of the relevant cells at most of the concentrations used. Additionally, western blot analysis showed a significant reduction in the expression of fusion protein MFN2 in the DOX-treated group compared to the control (p***&lt; 0.001) whereas the fission protein DRP1 was significantly upregulated in DOX-treated cells compared to the control (p**&lt; 0.01) and normalization of both proteins was achieved when 10 µM ELAM introduced 48-hour prior to DOX therapy. In conclusion, ELAM could exert an interesting cardioprotective role against DOX-induced cardiotoxicity by restoration of mitochondrial fusion and fission balance.

Application of two-dimensional speckle-tracking echocardiography in radiotherapy-related cardiac systolic dysfunction and analysis of its risk factors: a prospective cohort study

BackgroundThe cardiac toxicity of radiotherapy (RT) can affect cancer survival rates over the long term. This has been confirmed in patients with breast cancer and lymphoma. However, there are few studies utilizing the two-dimensional speckle-tracking echocardiography (2D-STE) to evaluate the risk factors affecting radiation induced heart disease (RIHD), and there is a lack of quantitative data. Therefore, we intend to explore the risk factors for RIHD and quantify them using 2D-STE technology.MethodsWe ultimately enrolled 40 patients who received RT for thoracic tumors. For each patient, 2D-STE was completed before, during, and after RT and in the follow up. We analyzed the sensitivity of 2D-STE in predicting RIHD and the relationship between RT parameters and cardiac systolic function decline.ResultsLeft ventricle global longitudinal strain (LVGLS), LVGLS of the endocardium (LVGLS-Endo), LVGLS of the epicardium (LVGLS-Epi), and right ventricle free-wall longitudinal strain (RVFWLS) decreased mid- and post-treatment compared with pre-treatment, whereas traditional parameters such as left ventricular ejection fraction (LVEF), cardiac Tei index (Tei), and peak systolic velocity of the free wall of the tricuspid annulus (s’) did not show any changes. The decreases in the LVGLS and LVGLS-Endo values between post- and pre-treatment and the ratios of the decreases to the baseline values were linearly correlated with mean heart dose (MHD) (all P values < 0.05). The decreases in the LVGLS-Epi values between post- and pre-treatment and the ratios of the decreases to the baseline values were linearly correlated with the percentage of heart volume exposed to 5 Gy or more (V5) (P values < 0.05). The decrease in RVFWLS and the ratio of the decrease to the baseline value were linearly related to MHD and patient age (all P values < 0.05). Endpoint events occurred more frequently in the right side of the heart than in the left side. Patients over 56.5 years of age had a greater probability of developing right-heart endpoint events. The same was true for patients with MHD over 20.2 Gy in both the left and right sides of the heart.Conclusions2D-STE could detect damages to the heart earlier and more sensitively than conventional echocardiography. MHD is an important prognostic parameter for LV systolic function, and V5 may also be an important prognostic parameter. MHD and age are important prognostic parameters for right ventricle systolic function.

Anti-cancer Therapies in Adults and Their Effects on Cardiovascular System: A Review

The cardio-oncology as a field has been expanded by the rapid development of innovative cancer therapies. While these treatments had significantly improved the overall survival rates for cancer patients, they also carried the risk of cardiovascular and metabolic toxicities. A comprehensive and accurate diagnosis of cancer was paramount to initiate appropriate and effective treatment strategies. It was essential to recognize that each type of cancer presents unique characteristics and complexities, necessitating personalized treatment approaches tailored to individual patients. These treatment regimens often encompassed a combination of modalities such as surgery, radiotherapy, systemic therapy, including chemotherapy, antineoplastic hormonal agents, targeted therapies, and supportive care interventions. By implementing a tailored treatment plan based on the specific nature of the cancer, healthcare professionals might optimize therapeutic outcomes while minimizing adverse effects, ultimately improving the overall prognosis and quality of life for cancer patients. The concise review aims to underscore the effects of cancer and its treatments on cardiovascular health, drawing insights from prior research. By synthesizing findings from existing studies, we aim to elucidate the intricate relationship between cancer therapies and cardiovascular outcomes. Consequently, there is a pressing need for an updated summary to inform contemporary clinical practice, ensuring that healthcare professionals are equipped with the latest knowledge to provide optimal care for cancer patients while safeguarding their cardiovascular well-being.