Cardiotoxicity Research Articles

Phytochemicals Targeting Mitophagy to Treat Heart Diseases: Retrospective Insights and Prospective Directions.

Mitophagy is a process by which cells selectively eliminate damaged or dysfunctional mitochondria through the autophagy-lysosome pathway, thereby maintaining mitochondrial quality and cellular homeostasis. This process is closely linked to the onset and progression of various heart diseases. Modern pharmacological research has demonstrated that phytochemicals can regulate mitochondrial homeostasis in cardiomyocytes through multiple mechanisms, influencing mitophagy and protecting cardiomyocytes, which in turn exerts anti-cardiovascular effects. However, the underlying mechanisms of these effects are not yet fully understood. This study summarizes the pharmacological effects and molecular mechanisms of mitophagy in heart diseases, aiming to provide reference for the research and treatment of phytochemicals targeting mitophagy against heart diseases. The results indicated that phytochemicals (such as Berberine, Ginsenoside Rg1, Quercetin, Resveratrol, Baicalein, and so on) can exert preventive and therapeutic effects on heart diseases (such as cardiac toxicity or damage, myocardial ischemia/reperfusion injury, heart failure, heart aging, cardiac hypertrophy, cardiomyopathy, and so on.) via regulating the PINK1/Parkin and FUNDC1-dependent mitophagy pathway. These compounds mainly exert their effects by regulating mitochondrial homeostasis, mitochondrial dynamics, mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial energy metabolism. This study provides a reference that phytochemicals have effect on anti-cardiovascular effects by regulating mitophagy. However, further in-depth mechanistic and clinical research are needed in the future.

Acute and Chronic Cardiovascular Adverse Events in Patients with Acute Myeloid Leukemia: A Systematic Review

Background/Objectives: Patients with acute myeloid leukemia (AML) have a higher propensity for adverse cardiovascular outcomes, primarily due to the toxic effects of chemotherapeutic agents. The purpose of this systematic review is to explore the association of acute myeloid leukemia treatment with adverse cardiovascular events. Methods: We systematically screened the literature for studies providing comparative data on cardiovascular toxicities in patients treated for acute myeloid leukemia. After the initial search, 3649 papers were screened and a final total number of 46 were included for the review process. Results: Common chemotherapeutic agents used in AML may cause cardiovascular (CV) toxicities. A plethora of pathophysiological mechanisms are incriminated for these effects. Drug combinations may increase the risk in a synergistic way. In addition, common mutations of AML, personal history of previous cardiovascular disease and impaired heart function carry an increased complication risk. Biomarkers, as well as multimodality imaging, may be used for the early detection of cardiovascular toxicities. Conclusions: Increased risks of CV toxicity and comorbidities are observed among AML patients. With all the available diagnostic modalities, early detection and CV prevention strategies can improve the patient’s prognosis and quality of life.

Effects of oral γ-aminobutyric acid intake on muscle regeneration in diabetic mice.

Though γ-aminobutyric acid (GABA) serves as the primary inhibitory neurotransmitter in the brain, its numerous biological activities in the periphery, including anti-inflammatory and anti-diabetic functions, have been documented. Additionally, GABA may be a mediator underlying effects of ketone bodies/ketogenic diets on muscle regeneration. Here, we investigated effects of GABA on muscle regeneration in Type 1 Diabetes mouse models. Akita and wild-type (WT) mice were treated with GABA in drinking water for 6 weeks, followed by cardiotoxin (CTX)-induced muscle injury. At 5 days post-injury, GABA treatment exhibited no effects on regenerating myofiber size in both WT and Akita mice. Unexpectedly, regenerating GABA-treated Akita muscles exhibited significantly increased embryonic myosin heavy chain (eMHC) expression and higher intramuscular-macrophage content, suggesting delays in muscle regeneration and in elevated macrophage infiltration in diabetic muscles. Next, we determined if GABA treatment delayed the inflammatory process during muscle regeneration. Providing GABA in the drinking water during the peak inflammatory period (days 0 to 5 post-injury) resulted in a significantly greater amount of small regenerating myofibers and higher expressions of TNFα and eMHC in regenerating streptozotocin (STZ)-diabetic muscles, indicating delays in inflammation process and muscle regeneration in diabetes. Plasma GABA levels were found higher in GABA-treated STZ mice than WT mice and negatively correlated with regenerating myofiber size. This delay in muscle regeneration in STZ-diabetic mice was abolished by a lower dose of GABA water that did not raise plasma GABA levels. Together, high doses of GABA intake during the early phases of muscle repair may delay regeneration.

Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling

Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents.

Mercury-Mediated Cardiovascular Toxicity: Mechanisms and Remedies.

Mercury is a significant environmental pollutant and public health threat, primarily recognized for its neurotoxic effects. Increasing evidence also highlights its harmful impact on the cardiovascular system, particularly in adults. Exposure to mercury through contaminated soil, air, or water initiates a cascade of pathological events that lead to organ damage, including platelet activation, oxidative stress, enhanced inflammation, and direct injury to critical cells such as cardiomyocytes and endothelial cells. Endothelial activation triggers the upregulation of adhesion molecules, promoting the recruitment of leukocytes and platelets to vascular sites. These interactions activate both platelets and immune cells, creating a pro-inflammatory, prothrombotic environment. A key outcome is the formation of platelet-leukocyte aggregates (PLAs), which exacerbate thromboinflammation and endothelial dysfunction. These processes significantly elevate cardiovascular risks, including thrombosis and vascular inflammation. This study offers a comprehensive analysis of the mechanisms underlying mercury-induced cardiotoxicity, focusing on oxidative stress, inflammation, and cellular dysfunction.

Automated contouring for breast cancer radiotherapy in the isocentric lateral decubitus position: aneural network-based solution for enhanced precision and efficiency.

Adjuvant radiotherapy is essential for reducing local recurrence and improving survival in breast cancer patients, but it carries arisk of ischemic cardiac toxicity, which increases with heart exposure. The isocentric lateral decubitus position, where the breast rests flat on asupport, reduces heart exposure and leads to delivery of amore uniform dose. This position is particularly beneficial for patients with unique anatomies, such as those with pectus excavatum or larger breast sizes. While artificial intelligence (AI) algorithms for autocontouring have shown promise, they have not been tailored to this specific position. This study aimed to develop and evaluate aneural network-based autocontouring algorithm for patients treated in the isocentric lateral decubitus position. In this single-center study, 1189 breast cancer patients treated after breast-conserving surgery were included. Their simulation CT scans (1209 scans) were used to train and validate aneural network-based autocontouring algorithm (nnU-Net). Of these, 1087 scans were used for training, and 122 scans were reserved for validation. The algorithm's performance was assessed using the Dice similarity coefficient (DSC) to compare the automatically delineated volumes with manual contours. Aclinical evaluation of the algorithm was performed on 30additional patients, with contours rated by two expert radiation oncologists. The neural network-based algorithm achieved asegmentation time of approximately 4 min, compared to 20 min for manual segmentation. The DSC values for the validation cohort were 0.88 for the treated breast, 0.90 for the heart, 0.98 for the right lung, and 0.97 for the left lung. In the clinical evaluation, 90% of the automatically contoured breast volumes were rated as acceptable without corrections, while the remaining 10% required minor adjustments. All lung contours were accepted without corrections, and heart contours were rated as acceptable in 93.3% of cases, with minor corrections needed in 6.6% of cases. This neural network-based autocontouring algorithm offers apractical, time-saving solution for breast cancer radiotherapy planning in the isocentric lateral decubitus position. Its strong geometric performance, clinical acceptability, and significant time efficiency make it avaluable tool for modern radiotherapy practices, particularly in high-volume centers.

Survivorship concerns among posttreatment cancer survivors in South Korea: A secondary analysis of a cross-sectional survey.

Cancer survivors may have a variety of survivorship concerns despite their cancer treatment having ended, with some negatively affecting their health-related quality of life. An in-depth understanding of survivorship concerns is essential for the development of survivorship care programs. However, previous findings have been limited to Western countries, and evidence from Asian countries is lacking. This study aimed to examine the prevalence of survivorship concerns among posttreatment cancer survivors in South Korea, identify factors associated with survivorship concerns, and explore their relationship with health-related quality of life. Secondary analysis of a cross-sectional survey. Data were collected through an online survey of five online communities of cancer survivors in South Korea. Overall, 1019 cancer survivors diagnosed with breast, colorectal, lung, stomach, and thyroid cancer (top five cancers in South Korea) who completed their cancer treatment. The survey collected data on demographic, disease- and treatment-related characteristics, survivorship concerns, and health-related quality of life. Survivorship concerns were measured using the checklist for survivorship concerns from the National Comprehensive Cancer Network Guidelines for Cancer Survivorship, which includes 12 survivorship concerns (e.g. cardiac toxicity, distress, cognitive dysfunction, fatigue, lymphoedema). Health-related quality of life was assessed using the Korean version of the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire. Data were analysed using descriptive statistics, the Chi-square test, and multiple regression. The prevalence of survivorship concerns ranged from 34.7% to 78.4%. Fatigue (78.4%), unhealthy lifestyle (74.8%), cognitive dysfunction (60.5%), insomnia (58.9%), and distress (52.9%) were the five most frequent concerns. Survivors aged in their 50s, those diagnosed with stomach cancer, those with an elapsed time of ≥2years but <5years since diagnosis, and those who had received chemotherapy and/or radiotherapy were significantly more likely to report survivorship concerns. Regression analyses revealed that all survivorship concerns were significant predictors of one or more subscales of health-related quality of life. Distress was found to be a significant predictor of all six subscales of the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire. This study revealed that posttreatment cancer survivors in South Korea had various survivorship concerns that decreased their health-related quality of life. To improve their health-related quality of life, systematic screening of survivorship concerns and timely appropriate interventions are critical. Our findings can thus contribute to the development of targeted survivorship care programs in Asia. Not registered.

Incidence and Risk of Thromboembolic and Cardiovascular Adverse Events with PARP Inhibitor Treatment in Patients with Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Safety Meta-analysis.

PARP inhibitor (PARPi) treatment is an effective option for patients with metastatic castration-resistant prostate cancer (mCRPC). There are few data on the cardiovascular and thromboembolic safety of these agents in mCRPC, as cardiovascular and thromboembolic adverse events (AEs) are uncommon. Our aim was to analyze the incidence and risk of major adverse cardiovascular events (MACEs), thromboembolic events, and hypertension with PARPi therapy in mCRPC. We conducted a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases and the American Society of Clinical Oncology and European Society of Medical Oncology meeting abstracts for clinical trials on PARPi use in mCRPC up to March 31, 2024. We analyzed the pooled incidence of all-grade and high-grade MACEs, thromboembolic events, and hypertension, and calculated risk ratios (RRs) for PARPi versus non-PARPi treatment. We included 11 phase 2 or 3 trials in our meta-analysis. Hypertension was the most common AE for both any-grade (17.2%) and high-grade (9.3%) events. In comparison to other treatments, PARPi was associated with significantly higher risk of high-grade MACEs (RR 2.03; p=0.03) and thromboembolic events (RR 2.15; p=0.002), especially venous thromboembolism (VTE; RR 2.13; p=0.004) and pulmonary embolism (RR 3.60; p=0.001). The risk of hypertension, any-grade MACEs, and thromboembolic AEs was not significantly higher, apart from VTE (RR 2.17; p=0.01). There is higher risk of high-grade cardiovascular and thromboembolic toxicity with PARPi use in comparison to other treatments in mCRPC, although these toxicities are rare. Clinicians should be aware of this risk, especially in a population that often has comorbidities and concomitant treatments, for correct monitoring and management of these AEs. Drugs called PARP inhibitors are very effective in the treatment of metastatic prostate cancer that does not respond to hormone treatment. However, their use is associated with some cardiovascular adverse events, although these are rare. Our study shows that these events seem to be more frequent with PARP inhibitors than with other treatments, especially for severe grades. Doctors and patients should be aware of this risk to help in preventing, recognizing, and managing the occurrence of these rare complications.

Cardiotoxicity associated with immune checkpoint inhibitors: Systematic review and meta-analysis.

The aim of this systematic review was to assess the risk of cardiac toxicity in patients undergoing approved PD-1 (nivolumab, pembrolizumab, cemiplimab, dostarlimab), PD-L1 (atezolizumab, avelumab, durvalumab), and CTLA-4 (ipilimumab) inhibitors. Among a total of 2272 articles, 11 phase II and III clinical trials included: 5463 patients and 175 cardiac adverse events. The most common cardiac disorder was atrial fibrillation (12 %), while cardiac arrest and cardiac failure (6 %) led to death in three cases. Overall, ICI treatment increased the risk of cardiotoxicity compared with control groups (RR=1.62, 95 %-CI= 1.18-2.24, p-value=0.0033; OR=1.71, 95 %-CI= 1.20-2.42, p-value=0.0027). This study proved that the recognition of frequency and severity of all grade cardiotoxicity associated with ICIs is still underestimated. Thus, a systematic cardiological screening becomes necessary, in order to intercept the potential cardiological complications beforehand and optimize the outcomes of the respective treatment with PD-1, PD-L1 and CTLA-4 inhibitors.

A multicenter retrospective study of early cardiac toxicity in operable breast cancer patients receiving concurrent dual or mono anti-HER2 therapy with postoperative radiation therapy.

This study aims to assess whether dual anti-HER2 therapy with trastuzumab and pertuzumab increases early cardiac toxicity compared to trastuzumab alone in breast cancer (BC) patients receiving postoperative radiation therapy (RT). Consecutive operable BC patients receiving postoperative RT and trastuzumab with or without pertuzumab between January 2017 and September 2020at seven tertiary hospitals in China were retrospectively reviewed. Cardiac examinations included echocardiography, electrocardiogram (ECG), NT-proBNP, and cTnI at baseline before RT and during the follow-up. The cardiac event is any new-onset symptomatic heart disease or abnormality in the cardiac examination after RT. In total, 681 patients were enrolled in the analysis, of whom 567 were treated with trastuzumab-alone and 124 patients received dual anti-HER2 therapy. The median follow-up was 11 months. Multivariate analysis showed that left-sided breast cancer (HR 2.38; 95%CI 1.65-3.44, p<0.001) and IMN RT (HR 1.47; 95% CI 1.01-2.15, P-value=0.047) are independent risk factors for ECG abnormalities. Age >50 years is an independent risk factor for developing LVDD (HR 5.16; 95%CI 1.17-22.73, P-value=0.030). Dosimetric analysis showed that patients who developed subclinical cardiac events had increased mean heart dose (412.0±249.6 vs. 347.2±242.6cGy, P-value=0.010). Among right-sided patients or patients receiving anthracycline-based chemotherapy, the dual-targeted cohort had a higher risk of developing ECG abnormalities compared to the trastuzumab-only cohort. Compared with trastuzumab-only, dual anti-HER2 therapy does not increase early cardiac toxicity in combination with postoperative RT in BC patients. Cardiac radiation exposure remains the primary risk factor for early toxicity.

Fluconazole induces cardiovascular toxicity in zebrafish by promoting oxidative stress, apoptosis, and disruption of key developmental genes.

This study systematically evaluated the toxic effects of fluconazole on the cardiovascular development of zebrafish. Zebrafish embryos were treated with different concentrations of fluconazole (200, 400, and 800μg/ml) to observe its impact on heart development, reactive oxygen species (ROS) generation, apoptosis, and hemoglobin production. The results showed that as the concentration of fluconazole increased, significant changes in zebrafish heart structure were observed, along with a notable reduction in heart rate. Pericardial edema and cardiac morphological abnormalities were particularly prominent in the high-dose group. In addition, fluconazole treatment significantly increased ROS levels and induced apoptosis in cardiac cells. Enzyme-linked immunosorbent assay (ELISA) results showed that fluconazole treatment significantly increased the malondialdehyde (MDA) content and reduced superoxide dismutase (SOD) and catalase (CAT) activity, suggesting that oxidative stress and cell death may play a key role in its cardiotoxicity. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that fluconazole treatment significantly affected the expression of several key genes related to heart development and function, particularly cardiac myosin light chain 2 (cmlc2), ventricular myosin heavy chain (vmhc), and myosin heavy chain 6 (myh6), whose expression changes were closely associated with alterations in heart morphology and function. Transcriptomic analysis showed that several signaling pathways related to cardiac development, apoptosis, and metabolism were affected. In summary, this study reveals the multifaceted cardiotoxic mechanisms of fluconazole in zebrafish and provides new insights into drug safety assessment.

Effects of engineered nanomaterials on the cardiovascular system.

With the explosive development of nanotechnology, engineered nanomaterials are currently being used in various industries, including food and medicine. Concern about the health effects of nanomaterials has been raised, and available research indicates that the relative surface area of nanomaterials seems to correlate with the severity of their toxicity. With regard to engineered nanomaterials, the scope of their acute and chronic toxicities and their mechanisms are not fully understood. Studies suggest that exposure to certain nanomaterials can generate reactive oxidant species and enhance permeability of the phagolysosomal membrane, which leads to inflammasome activation, causing oxidative stress and inflammation. Since the latter two are implicated in the development of cardiovascular diseases, such as hypertension and atherosclerosis, it can be presumed that exposure to engineered nanomaterials could significantly impact cardiovascular function. In this review, I raise issues that should be considered in the assessment of the effects of engineered nanomaterials on cardiovascular function and evaluate their cardiovascular toxicity as described in various in vitro and/or in vivo toxicological studies and industrial investigations.

Creatine Supplementation Mitigates Doxorubicin-Induced Skeletal Muscle Dysfunction but Not Cardiotoxicity

Creatine has demosntrated protective effects against muscle dysfunction, but its potential protection against doxorubicin-induced cardio and skeletal muscle toxicity remains poorly understood. We aimed to investigate the protective effects of creatine supplementation against doxorubicin-induced cardio and skeletal muscle myotoxicity. This study analyzed twenty male C57BL/6J mice, divided into three groups: Control (C; n = 6), Dox (n = 7) which received weekly doxorubicin injections (16 mg/kg i.p. in 20 days) and DoxCr (n = 7) with both doxorubicin and creatine supplementation (4%). Doxorubicin administration induced skeletal muscle atrophy in extensor digitorum longus (EDL) (-28%) and soleus muscles (-17%), accompanied by a decline in muscle strength. This atrophic response was concomitant with increased oxidative stress and elevated levels of IL-6. Cardiotoxic effects of doxorubicin were marked by a 15% reduction in cardiac mass and a significant 21% decrease in cardiomyocyte diameter, alongside a substantial 58% rise in IL-6 levels. On the opposite creatine supplementation mitigated doxorubicin-induced oxidative stress (elevated MDA and IL-6, and reduced GSH/GSSG ratio) and prevented skeletal muscle atrophy in both the EDL and soleus muscles, while also enhancing muscle strength. However, protective effects were not observed in cardiac muscle. Creatine protects skeletal, but not cardiac muscle against doxorubicin-induced toxicity, atrophy and strength loss.

Association of echocardiographic radiomics-based features with cardiotoxicity effect in breast cancer patients from the CARDIOCARE project

Abstract Introduction Improvements in breast cancer (BC) treatment including chemotherapy have increased significantly the BC survivors. However, higher BC survival rates have been compromised by life-threatening collateral toxic effects. Effects such as cardiomyopathy and heart failure, described as cardiotoxicity, have become main causes of comorbidity and mortality, having a great impact on patients’ quality of life. Purpose Leverage radiomics-based analysis to explore innovative, non-invasive echocardiography biomarkers that can associate with cardiotoxicity. Method A cohort of 28 prospective patients (above 60 years old, 10 cardiotoxic) of the EU-funded CARDIOCARE project [1] undergoing cardiotoxic antineoplasmatic therapy was utilized to investigate potential association between imaging features calculated from the end diastolic (ED) and end systolic (ES) apical 4- and 2-chamber views and patients’ cardiotoxicity status as defined by the project's cardiologists using imaging data (Left Ventricle Ejection Fraction , Global Longitudinal Strain) and blood test markers (high sensitive Troponin I and Nt-pro-Bnp). Imaging data were collected at baseline visit (start of the treatment) and 3 months after. A pre-trained deep neural network [2] was initially utilized to automatically segment the myocardium (MY) and the left ventricle (LV) from the ED and ES 4- and 2-chamber static views both at baseline (T0) and 3-month follow-up (T1). More than 1500 imaging features were calculated from all images of the MY and LV using radiomics, a state-of-the-art technique to elicit hidden image patterns using histogram, shape and textural features. Apart from radiomics at T0 and T1, time-dependent features (delta-radiomics) were also provided as the relative change in radiomics values between T0 and T1, aiming to reveal potential changes at the MY and LV areas through treatment. Cardiotoxicity status was defined at T1. Results A univariate analysis using the Wilcoxon rank-sum test identified a subset of 40 radiomics features (20 delta-radiomics and 20 from T1) to be considered statistically significant (p-value&amp;lt;0.05) in differentiating cardiotoxic from non-cardiotoxic patients. Histogram and shape-based characteristics showed no association with cardiotoxicity status. Additionally, radiomics-based features at T0 were not statistically significant. All significant features corresponded to textural properties of the MY, indicating that the heterogeneity of the MY can be a significant factor for cardiotoxicity. 17 out of 20 T1 features were calculated from the 4-chamber view of the MY (19/20 from the ED). 15 delta-radiomics textural features were extracted from the 2-chamber view of the MY region at the ES. Conclusion Heterogeneity of the myocardium quantified by radiomics has potential diagnostic impact in assessing cardiotoxicity response, paving the way for the development of image-based risk stratification models for the early detection of cardiac toxicity.

Evaluation of the Effect of Virgin Rice Bran Oil (VRBO) on DoxorubicinInduced Cardiotoxicity in Wistar Rats.

The usage of doxorubicin (DOX), an antineoplastic drug that is frequently used for the cure of cancer, is restricted to maximal doses due to its cardiac toxicity. Reactive oxygen species produced by DOX result in lipid peroxidation and organ failure, ultimately resulting in cardiomyopathy. Due to its high polyphenol content, virgin rice bran oil (VRBO) is a diet nutritional supplement with a strong antioxidant. This study aimed to assess the potential defense of VRBO against DOX-induced cardiotoxicity. VRBO and DOX injections were administered to thirty male Wistar rats for 42 days after being randomly assigned to five groups. The study demonstrated the cardioprotective effects of VRBO against doxorubicin (DOX)-induced cardiotoxicity. VRBO (0.71 and 1.42 ml/kg) significantly improved the heart-tobody weight ratio, reduced elevated serum CK-MB and LDH levels by 18.4% and 52.7%, respectively, and increased HDL by 43.1%. ECG parameters also improved, with reductions in QT interval (19%), ST interval (28%), and QRS complex (15%). VRBO enhanced systolic blood pressure (up to 21%) and heart rate (7.1%). Antioxidant markers showed notable recovery, with MDA levels reduced by 66.1%, while GSH, SOD, and catalase levels increased by 129.4%, 158.2%, and 84.8%, respectively. A cardioprotective benefit was found at middle and higher VRBO dosages. In order to demonstrate the effectiveness of VRBO as a cardioprotective medication, further research on dosage response and bioavailability is required.

Mitigating PM2.5 Induced Myocardial Metal Deposition Through Sodium Thiosulfate Resulted in Reduction of Cardiotoxicity and Physiological Recovery From Ischemia-Reperfusion via Mitochondrial Preservation.

The cardiovascular risks linked to PM2.5 include calcification in both vasculature and myocardial tissues, leading to structural changes and functional decline. Through the selection of a clinically proven endogenous agent, sodium thiosulfate (STS), capable of addressing PM2.5 related cardiac abnormalities, we not only address the absence of effective solutions to mitigate PM2.5 toxicity, but also provide evidence for the repurposing potential of STS in ameliorating PM2.5 induced cardiac damage. Female Wistar rats were exposed to PM2.5 (250 μg/m3) for 3 h daily for 21 days. STS was administered thrice weekly for 3 weeks during exposure after which the hearts were excised and mounted on a Langendorff apparatus for induction of ischemia-reperfusion injury (IR). STS administration improved cardiac function in PM2.5 exposed rat hearts, accompanied by increased expression of the master regulator gene PGC1-α and increased mitochondrial mass. Moreover, STS restored bioenergetic function and balanced mitochondrial fission-fusion dynamics. The beneficial effects of STS were further evidenced by its ability to scavenge metals, thereby reducing heavy metal deposition in mitochondria and alleviating oxidative stress and inflammation. Furthermore, STS facilitated the clearance of damaged mitochondria through mitophagy. Additionally, STS activated the PI3K/AKT/GSK3ß signaling pathway, providing cardio protection against IR injury in PM2.5-exposed hearts by preserving mitochondrial function. These results underscore the potential therapeutic benefits of STS in mitigating the adverse cardiac effects induced by PM2.5 exposure. The translation of these findings to clinical practice holds promise for the development of targeted interventions aimed at reducing the cardiovascular toxicity associated with PM2.5 exposure.

Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation

Doxorubicin (DOX) is a prevalent chemotherapeutic drug for treating several malignancies. However, the mechanisms of DOX induced cardiac toxicity is not fully understood. Previous studies have demonstrated that autophagy activation is essential in DOX-induced cardiac toxicity. Nevertheless, studies on the role of autophagy protein 5 (ATG5) in DOX-induced cardiac toxicity remain limited. Therefore, this study aimed to investigate the role of ATG5 in DOX-induced cardiac toxicity. Mice were intravenously administered DOX (5 mg/kg) for 4 weeks to establish a cardiac toxicity model. Heart function was determined using echocardiography, and cardiac tissue was assessed for protein expression, mRNA levels, fibrosis, and immunofluorescent staining. DOX treatment upregulated autophagy-related gene expression but inhibited autophagic flux in vitro and in vivo. DOX–treated mice exhibited decreased heart function and cardiomyocyte size and increased cardiac fibrosis, oxidative stress, and apoptosis. These effects of DOX were partially alleviated by rAAV9 expressing shRNA-ATG5 and deteriorated by rAAV9-ATG5. We demonstrated that genetic ATG5 knockdown or autophagy inhibition by chemical inhibitors increased GATA4 protein expression, which was reduced by ATG5 overexpression or autophagy activator in vitro and in vivo, suggesting that ATG5-mediated autophagy promoted GATA4 degradation. Moreover, enforced GATA4 re-expression significantly counteracted the toxic effects of ATG5 on DOX-treated hearts. In conclusion, our study demonstrated that manipulating ATG5 expression to regulate GATA4 degradation in the heart may be a promising approach for DOX-induced cardiac toxicity.

Central arterial stiffness in young adults with perinatal HIV exposure & infection.

To compare arterial stiffness between young adults with perinatally acquired HIV (YAPHIV) and young adults perinatally HIV exposed but uninfected (YAPHEU). Cross-sectional analysis of pulse wave velocity (PWV) measures among participants with echocardiography in the PHACS Cardiac Toxicity Substudy. A total of 150 participants (95 YAPHIV, 55 YAPHEU, mean 23.4 years, 60% female, 72% Black, 24% Hispanic) had echocardiography and PWV measured. We compared PWV between groups. Among YAPHIV, we fit linear regression models to evaluate the association of measures of HIV disease severity and antiretroviral treatment (ART) with PWV. We computed correlations between PWV and measures of left ventricular structure and function. Mean PWV did not differ by group (YAPHIV 5.63 vs YAPHEU 5.39 m/s; P = 0.50). HIV control was good (82% with viral load <400 copies/ml); 91% used combination ART. Mean PWV was normal, but 3 of 95 YAPHIV (3%) had values above 11.8 m/s (level associated with cardiovascular events in adults). Weak correlations (<0.20) were observed between PWV and echocardiographic measures. Among YAPHIV, current and historical HIV severity measures were not associated with PWV. YAPHIV on protease inhibitor (PI)-based ART had higher mean PWV than those on integrase strand inhibitors (1.68 m/s higher, 95% CI -0.36, 3.72) or nonnucleoside transcriptase inhibitors (1.58 m/s higher, 95% CI -0.94, 4.11). Our data shows no difference in PWV between those perinatally exposed to and perinatally infected with HIV. Therefore, CV risk reduction guidelines should be followed to prevent CV disease in all young adults.

Prediction of Radiation Therapy Induced Cardiovascular Toxicity from Pretreatment CT Images in Patients with Thoracic Malignancy via an Optimal Biomarker Approach.

Cardiovascular toxicity is a well-known complication of thoracic radiation therapy (RT), leading to increased morbidity and mortality, but existing techniques to predict cardiovascular toxicity have limitations. Predictive biomarkers of cardiovascular toxicity may help to maximize patient outcomes. The machine learning optimal biomarker (OBM) method was employed to predict development of cardiotoxicity (based on serial echocardiographic measurements of left ventricular ejection fraction and longitudinal strain) from computed tomography (CT) images in patients with thoracic malignancy undergoing RT. Manual segmentations of 10 cardiovascular objects of interest were performed on pre-treatment non-contrast-enhanced CT simulation images in 125 patients with thoracic malignancy (41 who developed cardiotoxicity and 84 who did not after RT). 1078 features describing morphology, image intensity, and texture for each of these objects were extracted and the top 5 features among them that were most uncorrelated and showed the best ability to discriminate between cardiotoxicity/ no cardiotoxicity were determined. The best combination among all possible combinations among these 5 features that yielded the highest accuracy of prediction on a training data set was selected, an SVM classifier was then trained on this combination, and tested for prediction accuracy on an independent data set. Prediction accuracy was quantified for the optimal features derived from each object. The best feature combination based on 5 CT-based features derived from the left ventricle had the highest testing prediction accuracy of 0.88 among all objects. Prediction accuracies over all objects ranged from 0.76-0.88. Heart, Left Atrium, Aortic Arch, Thoracic Aorta, and Descending Thoracic Aorta showed the next best accuracy of 0.84. Most optimal features were texture properties based on the co-occurrence matrix. It is feasible to predict future cardiotoxicity following RT with high accuracy in individual patients with thoracic malignancy from available pre-treatment CT images via machine learning techniques.

Protective Effect of Fisetin on Subacute and Chronic Arsenic and Fluoride Co‐Exposure Induced Hepatic, Renal and Cardiac Toxicities in Mice

ABSTRACTArsenic and fluoride are potent toxicants frequently present in drinking water and food, posing severe health risks through toxic impacts on key organs, primarily by inducing oxidative stress. Combined exposure to these elements exacerbates oxidative damage, yet effective strategies for preventing and managing their toxicities remain elusive. Fisetin, a bioflavonoid known for its antioxidant and anti‐inflammatory properties, has demonstrated protective effects in multiple toxicity studies. However, its effect on arsenic‐ and fluoride‐induced toxicity in vital organs (particularly the liver, kidneys, and heart) remains unexplored. This study investigates the protective potential of fisetin against subacute and chronic co‐exposure to arsenic and fluoride‐induced organ toxicity in a murine model. Male mice were administered arsenic and fluoride through drinking water, while fisetin (5, 10, and 20 mg/kg/day, orally) was co‐administered simultaneously. Animals were sacrificed at 4 weeks (subacute) and 24 weeks (chronic) for liver, kidney, and heart tissue analysis, assessing biochemical markers and arsenic accumulation. Spectrophotometry study revealed some degree of arsenic chelation with fisetin. The results of In Vivo studies showed that both subacute and chronic exposure led to significant increases in pro‐oxidant levels (ROS, TBARS, and nitrite) and arsenic accumulation, along with reduced GSH content in these organs compared to control. Fisetin treatment dose‐dependently reduced oxidative stress and arsenic content in vital organs of exposed animals. The findings highlight fisetin's antioxidant activity and its capacity to reduce arsenic burden as potential protective mechanisms. These results support fisetin or fisetin‐rich fruit consumption as a therapeutic strategy to mitigate organ toxicity from arsenic and fluoride co‐exposure.