Cardiotoxic Effects Research Articles

Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.

Nutrition Modulation of Cardiotoxicity in Breast Cancer: A Scoping Review

Background/Objectives: Advancements in breast cancer therapeutics, such as anthracyclines, are improving cancer survival rates but can have side effects that limit their use. Cardiotoxicity, defined as damage to the heart caused by cancer therapeutics, is characterised by a significant reduction in left ventricular ejection fraction (LVEF) and symptoms of cardiac dysfunction. Multiple oral supplements exist with antioxidant and anti-inflammatory properties that have the potential to lower cardiotoxicity risk and ameliorate the complications associated with left ventricular dysfunction. In this review, we evaluate the current status of using nutritional interventions to modulate cardiotoxicity. Methods: We used specific keywords to search for articles that met our predetermined inclusion and exclusion criteria to review the evidence and provide insights for future research. Results: Seven studies were identified as eligible for this review: six focused on oral supplementation strategies in breast cancer patients undergoing chemotherapy, and one focused on nutritional counselling and adherence to the Mediterranean diet in breast cancer survivors’ post-treatment. There was a significantly attenuated reduction in LVEF in five studies that monitored cardiometabolic health, and there were significant improvements in blood serum levels of cardiac biomarkers across all studies. Conclusions: Current evidence suggests that appropriate nutritional interventions, alongside chemotherapy, can modulate the risk of cardiotoxic side effects. This highlights the potential of oral antioxidant supplementation and Mediterranean diet counselling to decrease tertiary cancer therapy costs associated with cardiovascular complications.

Unveiling the Heart's Hidden Enemy: Dynamic Insights into Polystyrene Nanoplastic-Induced Cardiotoxicity Based on Cardiac Organoid-on-a-Chip.

Exposure to micro- and nanoplastics (MNPs) has been implicated in potential cardiotoxicity. However, in vitro models based on cardiomyocyte cell lines lack crucial cardiac characteristics, while interspecies differences in animal models compromise the reliability of the conclusions. In addition, current research has predominantly focused on single-time point exposures to MNPs, neglecting comparative analyses of cardiac injury across early and late stages. Moreover, there remains a large gap in understanding the susceptibility to MNPs under pathological conditions. To address these limitations, this study integrated cardiac organoids (COs) and organ-on-a-chip (OoC) technology to develop the cardiac organoid-on-a-chip (COoC), which was validated for cardiotoxicity evaluation through multiple dimensions. Based on COoC, we conducted a dynamic observation of the cardiac damage caused by short- and long-term exposure to polystyrene nanoplastics (PS-NPs). Oxidative stress, inflammation, disruption of calcium ion homeostasis, and mitochondrial dysfunction were confirmed as the potential mechanisms of PS-NP-induced cardiotoxicity and the crucial events in the early stages, while cardiac fibrosis emerged as a prominent feature in late stages. Notably, low-dose exposure exacerbated myocardial infarction symptoms under pathological states, despite no significant cardiotoxicity shown in healthy models. In conclusion, these findings further deepened our understanding of PS-NP-induced cardiotoxic effects and introduced a promising in vitro platform for assessing cardiotoxicity.

Molecular mechanisms involved in therapeutic effects of natural compounds against cisplatin-induced cardiotoxicity: a review.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various cancers. However, the clinical use of cisplatin is limited by its cardiotoxic side effects. The primary mechanisms implicated in this cardiotoxicity include mitochondrial dysfunction, oxidative stress, inflammation, and apoptotic. Numerous natural compounds (NCs) have been introduced as promising protective factors against cisplatin-mediated cardiac damage. The current review summarized the potential of various NCs as cardioprotective agents at the molecular levels. These compounds exhibited potent antioxidant and anti-inflammatory effects by interaction with the PI3K/AKT, AMPK, Nrf2, NF-κB, and NLRP3/caspase-1/GSDMD pathways. Generally, the modulation of these signaling pathways by NCs represents a promising strategy for improving the therapeutic index of cisplatin by reducing its cardiac side effects.

Improved Therapeutic Efficacy of Doxorubicin Chemotherapy With Cannabidiol in 4T1 Mice Breast Cancer Model.

High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects. Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor. Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX. This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone.

Heart Transplant Rejection in the Setting of Glyphosate Herbicide Exposure; A Case Report

Glyphosate is a common herbicide utilized worldwide with known exposure related toxicities. Numerous adverse effects related to glyphosate exposure have been documented, specifically in non-human models, however literature is lacking on cardiotoxic effects specific to heart transplant patients. Rejection is the most common post-transplant complication and the diagnosis of such is vital in order to guide immediate and appropriate treatment. In addition to the endomyocardial biopsy, noninvasive genetic testing can aid in rejection diagnosis and distinguish between cell-mediated and antibody-mediated rejection. We describe a case of glyphosate exposure in a post orthotopic heart transplant and the subsequent heart transplant rejection, patient’s clinical course, treatment, and follow up.

Nephro- and Cardiotoxic Effects of Etoricoxib: Insights into Arachidonic Acid Metabolism and Beta-Adrenergic Receptor Expression in Experimental Mice

Background: Etoricoxib is a widely used anti-inflammatory drug, but its safety profile concerning cardiovascular and renal health remains inadequately explored. This study aimed to assess the nephro- and cardiotoxic effects of etoricoxib in a murine model, with a focus on its impact on arachidonic acid-metabolizing enzymes and beta-adrenergic receptors associated with drug-induced toxicity. Methods: Thirty-five BALB/C mice were randomly assigned to five groups: control, low-dose etoricoxib, high-dose etoricoxib, low-dose celecoxib, and high-dose celecoxib (a well-known nephro- and cardiotoxic NSAID). The treatments were administered for 28 days, after which hearts and kidneys were excised for physical and histopathological analysis, and the expression of arachidonic acid-metabolizing enzymes (cytochrome P450s, lipoxygenases, cyclooxygenases) and beta-1 adrenergic receptor (adrb1) and angiotensin-converting enzyme (ace2) genes were quantified using quantitative reverse transcription PCR (qRT-PCR). Results: Etoricoxib administration resulted in dose-dependent nephro- and cardiotoxic effects. Renal histology revealed glomerular atrophy or hypertrophy and significant damage to the proximal and distal convoluted tubules, including epithelial flattening, cytoplasmic vacuolation, and luminal widening. Cardiac analysis showed disorganized muscle fibers and hyaline degeneration. These changes were associated with altered gene expression: the downregulation of cox2, cyp1a1, and cyp2c29 in the kidneys and the upregulation of cyp4a12, cox2, and adrb1, along with the downregulation of cyp2c29 and ace2 in the heart. Conclusions: Etoricoxib induces nephro- and cardiotoxicity, marked by alterations in arachidonic acid metabolism and beta-adrenergic signaling pathways. The drug affects the expression of arachidonic acid-metabolizing enzymes and adrb1 in the heart while downregulating cox2 and other related enzymes in the kidneys. These findings underscore the need for caution when prescribing etoricoxib, particularly in patients with pre-existing renal or cardiac conditions.

Arrhythmogenic effects of DEHP exposure: insights into cardiac electrophysiology and myocardial cells

Abstract Introduction Hemodialysis patients, who are exposed to plasticizers through the hemodialysis circuit, face a high risk of cardiovascular disease (CVD). Plasticizers, such as the endocrine-disrupting compound Di(2-ethylhexyl) phthalate (DEHP), have emerged as potential contributors to CVD. This study explores the impact of DEHP on cardiac electrophysiology and myocardial cells, providing insights into its cardiotoxic effects. Methods We employed optical mapping techniques to assess cardiac electrophysiology in Langendorff-perfused rat hearts exposed to DEHP, comparing them to a control group. Additionally, we evaluated the effect of DEHP on cardiac muscle cells using H9C2 rat cardiomyoblasts. Results Prolonged DEHP exposure resulted in elevated heart rate, increased electrocardiographic variability, and higher low-frequency values, indicative of sympathetic nervous system overactivity. Action potential duration at APD80 increased, leading to greater action potential triangulation. Electrical alternans observed in the DEHP-treated group heightened the risk of arrhythmias. Single-cell analysis revealed severe mitochondrial damage, myocardial cell apoptosis, and disrupted calcium ion balance. Conclusion This study highlights DEHP's cardiotoxicity, suggesting its potential role in arrhythmogenesis and cardiac dysfunction. Environmental pollutants like DEHP warrant consideration as contributors to cardiovascular diseases, emphasizing the need for further research on preventive strategies.

Incidence of acute cardiovascular hospitalizations and association with hemodynamic biomarkers in cancer patients treated with Immune Checkpoint Inhibitor therapy

Abstract Background/Introduction Immune checkpoint inhibitors (ICI) have significantly improved outcomes for several malignancies. Despite these benefits, patients with cancer face an increased risk for the development of cardiovascular disease due to mutual risk factors, similar biological mechanisms, as well as cardiotoxic side effects of therapy. Therefore, there is a pressing need for effective risk stratification strategies. Purpose This study aimed to explore the association between NT-proBNP levels and the risk of acute cardiovascular hospitalizations and death in patients who receive ICI. Methods We used electronic health records of patients treated with ICI who had available baseline NT-proBNP levels at our hospital, a tertiary academic center, between January 2017 and July 2022. The primary outcome of interest was the composite of acute cardiovascular hospitalization or death. The associations between NT-proBNP and outcomes were analyzed using cox regression models adjusted for age, sex, serum creatinine, diabetes, HF, CAD, hypertension, AF, LDL-C, and CRP. Results In total, 550 patients (35% female, median age 65 yrs) were included in the study. The median NT-proBNP levels were 272 pg/mL (IQR 102-742 pg/mL) and 388 (71%) patients had NT-proBNP levels ≥125 pg/mL. During a median FU of 67 weeks, 190 patients (35%) died, and 103 CV hospitalizations occurred in 76 patients (14%). Compared with patients with NT-proBNP concentrations <125, those with NT-proBNP concentrations ≥125 pg/ml had significantly higher event rates of the combined endpoint (12-Month KM event rates: 38% vs 21%, P<0.001). After multivariable adjustment, NT-proBNP remained independently associated with an increased risk of cardiovascular hospitalization and death (Adjusted HR for 1-SD increase in log-transformed biomarker 1.64, 95% CI 1.24 to 2.14; Figure). Conclusion These data highlight NT-proBNP levels as a valuable marker for identifying patients at increased risk of cardiovascular complications during ICI therapy.

Assessment of right ventricular dysfunction in breast cancer patients undergoing anthracycline and trastuzumab treatment

Abstract Background Anthracyclines and trastuzumab continue to be within the most popular systemic agents used in breast cancer treatment. Nonetheless, their cardiotoxic effects contribute to significant morbidity and mortality, which have been extensively studied and acknowledged. Left ventricular impairment and remodeling due to chemo- and target-therapy induced cardiotoxicity has been well described. However, effects on right ventricular function have not been fully elucidated and are incompletely understood. Purpose We aim to comprehensively assess right ventricular function in breast cancer patients before and during treatment with anthracyclines and trastuzumab. Methods We prospectively evaluated echocardiographic right ventricle (RV) parameters in 160 women (median age 48, IQR 43.00 - 57.00) diagnosed with breast cancer undergoing treatment with doxorubicin, trastuzumab or its combination. These patients were referred to a national cardiac reference centre to assess cancer therapy related cardiovascular dysfunction (CTRCD) risk. Two-dimensional echocardiography with speckle tracking imaging of left ventricle (LV) and RV was performed at baseline, 3 and 6 months. Right ventricular function was assessed with tricuspid annular plane systolic excursion (TAPSE), S’wave of the tricuspid annulus (S'), fractional area change (FAC), and free wall strain (RV-FWS). We designed a composite variable of right ventricular dysfunction constituted by any decrease in systolic function as evidenced by standard cutoff values of TAPSE, FAC, S’wave and RV-FWS. Descriptive statistics were calculated. Categorical values were compared using either the Fisher’s exact test or Chi-squared test and differences between means were assessed with the Kruskal-Wallis test or the Wilcoxon test as appropriate. Results TAPSE and S’ were significantly reduced from baseline, at 3 and 6 months, respectively (TAPSE: 21.62 ± 2.22, 21.00 ± 1.83, 20.72 ± 1.99, P=<0.001; S’:12.16 ± 1.91, 11.70 ± 1.76, 11.51 ± 1.53, P = 0.012) (Table 1). There were no significant changes in right ventricular echocardiographic parameters comparing patients with and without CTRCD, nevertheless, a notable proportion in both groups was observed (see Table 2). Conclusions There is a progressive decline in right ventricular systolic function over treatment with anthracyclines and trastuzumab. Even though RV dysfunction does not significantly differ between patients with or without cardiotoxicity, the high proportion observed highlights the need for comprehensive echocardiographic assessments.

Clinical evaluation and outcome in patients with heart failure receiving chemotherapy with different anti-cancer agents

Abstract Background Over the last few decades, advances in cancer therapy have prolonged the life expectancies of patients diagnosed with malignancies. Although traditional cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy have improved survival rates, off-target adverse effects such as complications of the cardiovascular system require attention. The optimal strategy for modern chemotherapy should be based on a comprehensive approach for patients with cancer and cardiovascular diseases. Therefore, cardio-oncology has received increasing attention owing to the cardiotoxic effects of anti-cancer therapies. Purpose To assess the clinical characteristics and outcomes of patients with heart failure (HF) who received chemotherapy compared with those of a matched cohort with HF who did not receive chemotherapy, using real-world HF data. Methods This study used the Diagnosis Procedure Combination database of the Japanese Registry of All Cardiac and Vascular Disease. We identified 1,328,113 patients hospitalized for HF between April 2012 and March 2021. We excluded 14,043 patients with unknown outcomes, non-emergency admissions, and unknown chemotherapy data. The primary endpoint was readmission. Thus, our study included 5,774 patients who received chemotherapy and 39,412 patients who did not. The propensity score (PS) was estimated using a logistic regression model, with chemotherapy as the dependent variable, and clinically score-matched analysis of 11,532 patients with HF with or without chemotherapy. Results Colon, lung, breast, and prostate cancers accounted for > 60% of all cancer types. After PS matching, 62.5% and 19.5% of patients with HF had prostate and breast cancer, respectively. After PS matching, readmission was more frequently observed in patients undergoing chemotherapy than those not undergoing chemotherapy (odds ratio [OR], 1.26; 95% confidence interval [CI] 1.17–1.36, p<0.0001). Treatment with genomic epidermal growth factor receptor tyrosine kinase inhibitors (OR, 1.69; 95% CI 1.39–2.07), taxane (OR, 2.95; 95% CI 2.11–4.12), anthracyclines (OR, 1.86; 95% CI 1.19–2.90), and fluorouracil agents (OR, 1.65; 95% CI 1.18–2.30) resulted in a significant risk of readmission. Moreover, patients treated with endocrine therapy before hospitalization had significantly higher readmission rates than the matched patients who did not receive chemotherapy (aromatase inhibitors: OR, 1.40; 95% CI 1.19–1.65: anti-androgens: OR, 1.39; 95% CI 1.27–1.52: luteinizing hormone-releasing hormone agonists: OR, 1.18; 95% CI 1.08–1.30 and gonadotropin-releasing hormone antagonists: OR, 2.17; 95% CI 1.68–2.79). Conclusions Medical providers need to monitor and follow-up patients with HF, depending on the characteristics of the anticancer agents and types of cancer. Furthermore, close collaboration among oncologists, cardiologists, and healthcare professionals will ensure the delivery of optimal care for patients with HF undergoing chemotherapy.

Phytochemical profiling and biological evaluation of the residues from industrial hemp (Cannabis sativa L.) inflorescences trimming: Focus on water extract

The study focused on investigating the phytochemical composition and bio-pharmacological properties of a water extract obtained from industrial hemp by-products, after trimming female inflorescences of Cannabis sativa L., cultivar Kompolti. The extract was found to be rich in phenolic compounds, particularly gallic acid, catechin, coumaric acid, ferulic acid, and benzoic acid. It also contained significant amounts of cannabidiolic acid and cannabigerolic acid as the main terpenophenols. To assess the biological potential of the extract, various ecotoxicological assays were conducted. The extract did not show significant phytotoxic effects on seedling germination in the allelopathic assay. In the brine shrimp (Artemia salina) lethality test, the LC50 value was 1.726 mg/mL, and in the Daphnia magna test, the extract showed no cardiotoxicity effects at the same concentration; thus, confirming its biocompatibility with these eukaryotic organisms. Additionally, the extract did not induce cytotoxicity in the murine C2C12 cell line till to the concentration of 1000 μg/mL. In isolated mouse prostate specimens, the extract (10–1000 μg/mL) also prevented LPS-induced gene expression of pro-inflammatory cytokines, namely tumor necrosis factor (TNF)α, interleukin (IL)-6, and IL-1β. Furthermore, the extract exhibited inhibitory effects on the growth of pathogenic bacterial, fungal, and dermatophyte species commonly associated with prostatitis. These results suggest that the residual powder from female inflorescence trimming can be considered an innovative plant material from the industrial hemp supply chain that deserves to be valorised in terms of recycling and upcycling; thus, reducing the environmental impact of the by-products and also opening the way for innovative health-promoting agents.

Long term risk of heart failure in adult cancer survivors: a systematic review and meta-analysis

Abstract Background Evaluation of the cardiotoxic effects from cancer is most commonly evaluated at the time of chemotherapy. Although cancer survivorship populations are rapidly expanding, there is a paucity of evidence regarding the frequency and causes of heart failure (HF) >5 years after cardiotoxic therapy. Objectives This systematic review sought to investigate the relationship between cardiotoxic cancer therapies and late-onset HF. Methods We searched the EMBASE and MEDLINE databases for studies reporting HF in adult survivors (≥50 years old), who were ≥5 years post-breast/lymphoma cancer therapy. A random effects model was used to examine the associations of HF. A meta-regression analysis was implemented to determine causes of heterogeneity. Results Thirteen papers were included in the review and meta-analysis (Figure 1), comprising 190,259 participants (mean age 53.5 years, 93% female). The risk of HF was increased (overall log risk-ratio 0.39 (95%CI (0.16-0.62)), (Figure 2). Cardiotoxic treatment, compared with cancer alone, provided a similar risk (log risk ratio of 0.38 [95% CI 0.02-0.77]). In the breast cancer population ratio (11 studies) the overall heart failure log risk was 0.41 [95% CI 0.13-0.69]). Although heterogeneity was significant (I²=77.17), this was explained by differences in patient characteristics; once multivariable analysis accounted for follow up (0.99, 95%CI (0.97-0.99), p=0.047), age (1.14, 95%CI (1.04-1.25), p=0.003) and hypertension (0.95, 95%CI (0.92-0.98), p<0.001), residual heterogeneity was low (I²=28.73). Conclusions HF is increased in adult cancer survivors, associated with cardiotoxic cancer therapy and standard risk factors. Consideration should be given for selective screening for HF in this at-risk population.Fig 1:Literature Search Flow DiagramFig 2:Incident HF in Cancer Survivors

The potential protective effect of dapagliflozin on the development of cardiotoxicity in cancer patients after one year of observation

Abstract Introduction Despite the widespread use of anthracyclines (ANT) and anti-HER2 agents as trastuzumab (TZB) in chemotherapy schemes, it is known the potential cardiotoxic effects that can limit the intensity and duration of treatments. The clinical trial "DECLARE-TIMI 58" (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a Sodium glucose cotransporter 2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. Purpose We aimed to study if dapagliflozin could exerts cardioprotective effects in anthracycline, carfilzomib and trastuzumab-induced cardiotoxicity through the analysis of ejection fraction (LVEF), global longitudinal strain (GLS) of both left and right ventricle, E/A ratio, E/e’ ratio, left atrium diameter, BNP/NT-pro-BNP and troponin I. Methods 32 diabetic patients were randomized (16 dapagliflozin;16 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function as well as chemotherapeutic agents ). Our patients who were diagnosed with cancer at our medical center, receiving potentially cardiotoxic treatment: 52% were treated with only trastuzumab, 34% were treated with only anthracycline and 14% carfilzomib. The primary endpoint was the development of cardiotoxicity after treatment with chemotherapy. Cardiotoxicity was defined as a decrease of LVEF by 5% or more to less than 55% in the presence of symptoms of heart failure or an asymptomatic decrease in LVEF by 10% or more to less than 55%. Results In the first year of observation patients treated with dapagliflozin didn’t show any deterioration of LV GLS (¬19.8±2.8 vs ¬19.3±4.1%, p=0.403) There was no change in LVEF (57.8±4.9% vs 59±6.8%) and GLS of right ventricle (20.3±2.8% vs 20.0±3.6%). Conversely, patients treated with placebo, presented a significant impairment of LV GLS (¬20.8±2.1% vs ¬18.5±2.2%, p=0,001) while a borderline deterioration of EF was noticed after treatment with placebo(60±5.4 vs 56.7±6.7%, p=0,045). Conclusions At the best of our knowledge, our study is the first to investigate the prophylactic use of dapagiflozin in the development of non-ischemic cardiomyopathy in diabetic patients receiving anthracycline or trastuzumab,carflilzomib therapies. Treatment with dapagliflozin prevented deterioration of myocardial function and preserved ejection fraction

A causal network model to estimate the cardiotoxic effect of oncological treatments in young breast cancer survivors

A causal network model to estimate the cardiotoxic effect of oncological treatments in young breast cancer survivors

Potential ameliorative effect of Dapagliflozin on systemic inflammation-induced cardiovascular injury via endoplasmic reticulum stress and autophagy pathway.

Dapagliflozin (DPG) is a sodium-glucose cotransporter-2 inhibitor and is used in the treatment of diabetes. In this study, we aimed to investigate the effect of DPG on cardiotoxicity caused by systemic inflammation via endoplasmic reticulum (ER) stress and autophagy. Four groups of thirty-two Wistar Albino rats were created: Control (1ml oral physiological saline for five days and intraperitoneal saline on the 5th day), LPS (1ml oral physiological saline for five days and intraperitoneal 5mg/kg of LPS on the 5th day), LPS + DPG (10mg/kg of DPG orally for five days and 5mg/kg of LPS intraperitoneally on the 5th day), and DPG (10mg/kg of DPG orally for five days and 5mg/kg of SF intraperitoneally on the 5th day). Histopathological and immunohistochemical analyses were performed on heart and aorta tissues. ER stress and autophagy gene markers in heart tissues were evaluated by RT-qPCR. Oxidative stress in heart tissues and serum cardiac enzymes were analyzed by spectrophotometric method. The heart and aortic tissues of the LPS group showed increased expressions of Tumor Necrosis Factor-α (TNF-α) and Caspase-3 (Cas-3), along with mild hyperemia, slight inflammatory cell infiltrations, and myocardial cell damage. The heart tissues also showed genetically increased expressions of include binding immunoglobulin protein (BiP/ GRP78), protein kinase RNA-like ER Kinase (PERK), inositol-requiring enzyme 1 (IRE-1), activating transcription factors 4 (ATF-4), activating transcription factors 4 (ATF6), C/EBP homologous protein (CHOP), and BECLIN 1. Furthermore, Creatine kinase-MB (CK-MB) and Lactate dehydrogenase (LDH) levels in blood tissue significantly increased, according to biochemical analysis. With DPG therapy, all of these findings were reversed. In conclusion, DPG protects against the cardiotoxic effect of systemic inflammation with its antioxidant and anti-inflammatory properties by regulating ER stress and autophagy pathways.

A novel approach to assessing cardiotoxic effects of nanoparticles in a toxicological experiment

Introduction. The study of nanoparticles for potential cardiotoxic effects is a comprehensive multi-stage process based on an integrated approach. Along with generally accepted research methods, molecular biology techniques using modern highly sensitive equipment are being actively introduced into toxicology testing. The aim of the study was to describe a novel approach to assessing cardiotoxic effects of nanoparticles, from the molecular level to the functional response of the whole organism. Materials and methods. Our new approach to assessing cardiotoxic effects of nanoparticles in rats included the examination of changes at the molecular (e.g., the ratio of myosin heavy chains), subcellular (by electron microscopy), cellular and tissue (by histological testing), system and organ (by non-invasive recording of electrocardiogram and blood pressure parameters and biochemical testing of blood serum) levels. We have tested the proposed approach by evaluating lead (PBO) and cadmium oxide (CdO) nanoparticles in rats. Results. Hypotension observed after PbO and/or CdO nanoparticle exposure indicates to the damage to the vascular bed due to penetration and accumulation of the nanoparticles in vascular cells, as well as direct damage to the endothelium, increased oxidative stress, and inflammation. In accordance with the system for assessing nanoparticle-induced cardiotoxicity developed on the basis of toxicology test results, lead and cadmium oxides, both separately and combined, have a pronounced cardiotoxic effect. Limitations. Our work was limited to examining the main indicators of the cardiotoxic effects of nanoparticles in a toxicological experiment on one animal species (rats). Conclusion. The data analysis revealed varying degrees of manifestation of nanoparticle cardiotoxicity, both at the molecular level and at the intracellular, cellular, tissue, organ, and body levels. The use of this approach will allow a better in-depth assessing effects of nano-sized particles on the heart and blood vessels for identification of risks for cardiovascular disease.

Doxorubicin Incorporation into Gold Nanoparticles: An In Vivo Study of Its Effects on Cardiac Tissue in Rats.

Gold nanoparticles (Au-NPs) have been explored as potential vectors for enhancing the antitumor efficacy of doxorubicin (DOX) while minimizing its cardiotoxic effects. However, the impacts of DOX Au-NPs on cardiac function and oxidative stress remain inadequately understood. This study aimed to explore the effects of DOX Au-NPs in comparison to free DOX, focusing on oxidative stress markers, inflammation, ultrastructural changes, and cardiac function. Male rats were divided into the following four groups: control, citrate Au-NPs, DOX, and DOX Au-NPs. Cardiac function was assessed using echocardiography, and oxidative stress was evaluated through Nrf2, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, and the GSH/GSSG ratio. The ultrastructure of cardiac tissue was assessed by transmission electron microscopy (TEM). Rats treated with DOX Au-NPs exhibited significant cardiac dysfunction, as indicated by a reduction in fractional shortening and ejection fraction. Oxidative stress markers, including elevated MDA levels and a reduced GSH/GSSG ratio, were significantly worse in the DOX Au-NP group. SOD levels decreased, indicating compromised antioxidant defenses. Citrate Au-NPs also caused some alterations in cardiac function and ultrastructure but without other molecular alterations. DOX Au-NPs failed to mitigate cardiotoxicity, instead exacerbating oxidative stress and cardiac dysfunction. DOX Au-NPs possess cardiotoxic effects, necessitating further investigation into alternative nanoparticle formulations or therapeutic combinations to ensure both efficacy and safety in cancer treatment.

Hypersensitivity myocarditis induced by isoniazid overdose in a 15-year-old girl: a case report.

Myocarditis represents a diverse group of inflammatory diseases affecting the heart muscle, with both infectious and non-infectious etiologies. Among the non-infectious causes, drug-induced hypersensitivity reactions are rare but serious. Isoniazid, a cornerstone in tuberculosis treatment, is known for its hepatotoxicity but has rarely been documented to cause hypersensitivity myocarditis. We present a case of a 15-year-old girl from Eastern Turkmenistan who was admitted to our emergency department with altered consciousness and seizure activity. She was diagnosed with status epilepticus and treated accordingly. The patient, with no prior medical history, was found to have hypotensive shock and myocarditis upon further examination. A detailed history revealed she had ingested 45 tablets of expired isoniazid in a suicide attempt. She was treated with pyridoxine and supportive therapies, resulting in a gradual recovery. This case underscores the critical need to consider drug-induced hypersensitivity myocarditis in the differential diagnosis of myocarditis, especially in patients with recent medication use. Prompt recognition and appropriate treatment with pyridoxine, steroid, and supportive cardiac care can be lifesaving. This case also highlights the importance of awareness regarding the potential cardiotoxic effects of isoniazid overdose.

The mechanisms of effects of oil-derived polyaromatic hydrocarbons on cardiac electrical activity in navaga cod (Eleginus nawaga)

The intensive development of oil and gas industries in the Arctic threatens Arctic aquatic ecosystems. The toxic and primarily lethal cardiotoxic effects of oil in living organisms are believed to be associated with polyaromatic hydrocarbons (PAHs), and previous works revealed the electrophysiological mechanisms of action of individual oil-derived PAHs. However, the physiological effects of a complex PAHs mixture in oil water-soluble fraction (WSF) have not been previously studied. This study is focused on the effects of oil WSF on electrical activity and major ionic currents in the working myocardium of navaga (Eleginus nawaga), which is one of the most important commercial fish species in the Arctic. We found that 1% and 10% solutions of oil WSF cause a marked increase in the duration of action potentials (APs) in navaga cardiomyocytes. This effect appears to be due to the suppression of rapid delayed rectifying current IKr (IC50 about 3% in ventricular and atrial myocardium). At higher concentrations, oil WSF also suppressed calcium current ICaL (IC50 = 10.6%), which led to a decrease in the contractile activity in isolated myocardial preparations. Unlike individual tricyclic PAHs, oil WSF did not affect fast sodium current INa and AP upstroke velocity. An assessment of the content of tricyclic PAHs in 10% solution of oil WSF showed that their total concentration is relatively low and does not exceed 100 nM. Thus, oil WSF also has a powerful cardiotoxic effect in fish myocardium, but its effects differ from the previously studied effects of tricyclic PAHs and suggest the presence of yet unexplored oil compounds that have a more powerful toxic potential against ERG channels.