Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Crosslink between atrial fibrillation and cancer: a therapeutic conundrum.

Atrial fibrillation (AF) is more common in patients with malignancies than in general population. The pathophysiological processes include the pro-inflammatory condition and the exaggerated inflammatory reaction to chemotherapy, radiotherapy, and surgery interventions. Thus, it is pivotal to decrease morbidity and mortality in this group by providing appropriate care and prevention. In this subset, the risk of thromboembolic and bleeding events is high and the common risk score such as CHA2DS2-VASc and HAS-BLED employed in non-oncologic patients have limited evidence in cancer patients. A paucity of evidence in the setting in individuals having both malignancies and atrial fibrillation entangle the clinician when it comes to therapeutic management. Tailored management is recommended of anticoagulation treatment could be difficult, and there is. In this review, we try to explain the mechanism of AF in cancer patients as well as its management in this setting.

Assessment of B-type natriuretic peptide as an early predictor of mortality in acutely poisoned patients with cardiotoxicities.

Background: Cardiotoxicity is a major toxic effect induced by several types of drugs. An electrocardiogram is done routinely in cardiovascular drug exposures. Cardiac troponin I (cTnI) is the usual biomarker for diagnosing myocardial injury. B-type natriuretic peptide (BNP) is a well-established predictor of disease state in suspected heart failure. Aim: The study aimed to assess BNP's role as an early predictor of mortality compared with cTnI and ECG changes in acutely poisoned patients with cardiotoxicities. Methodology: This study enrolled 70 patients with acute cardiotoxicity by drugs and toxins known to cause cardiac injury admitted to Tanta University Poison Control Center (TUPCC). Collected data included socio-demographic data, toxicological history, vital signs, ECG changes, Poison Severity Score (PSS), BNP, and cTnI serum levels. Result: Patients were classified as survivors and non-survivors. Significantly more delay time was recorded in non-survivors. Moreover, vital signs were significantly abnormal in non-survivors. There was no statistical significance regarding the initial ECG abnormalities between survivors and non-survivors. BNP and cTnI levels were significantly higher among non-survivors. For mortality prediction, BNP had good predictive power (AUC = 0.841) with 100% sensitivity and 79.7% specificity while cTnI had an acceptable predictive power (AUC = 0.786), with 83.3% sensitivity and 78.1% specificity with insignificant difference between both biomarkers. Conclusion: BNP and cTnI levels can predict mortality in acute cardiotoxicity compared to ECG which has no statistically significant prediction. BNP has a higher discriminatory power than cTnI for the prediction of mortality.

Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score.

BACKGROUND AND AIMS: Baseline cardiovascular toxicity risk stratification is critical in cardio-oncology. The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) score aims to assess this risk but lacks real-life validation. This study validates the HFA-ICOS score for anthracycline-induced cardiovascular toxicity. METHODS: Anthracycline-treated patients in the CARDIOTOX registry (NCT02039622) were stratified by the HFA-ICOS score. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), with all-cause mortality and cardiovascular mortality as secondary endpoints. RESULTS: The analysis included 1066 patients (mean age 54 ± 14 years; 81.9% women; 24.5% ≥65 years). According to the HFA-ICOS criteria, 571 patients (53.6%) were classified as low risk, 333 (31.2%) as moderate risk, 152 (14.3%) as high risk, and 10 (0.9%) as very high risk. Median follow-up was 54.8 months (interquartile range 24.6-81.8). A total of 197 patients (18.4%) died, and 718 (67.3%) developed CTRCD (symptomatic: n = 45; moderate to severe asymptomatic: n = 24; and mild asymptomatic: n = 649). Incidence rates of symptomatic or moderate to severe symptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio 28.74, 95% confidence interval (CI) 9.33-88.5; P < .001, and hazard ratio 7.43, 95% CI 3.21-17.2; P < .001) for very high-risk patients. The predictive model demonstrated good calibration (Brier score 0.04, 95% CI 0.03-0.05) and discrimination (area under the curve 0.78, 95% CI 0.70-0.82; Uno's C-statistic 0.78, 95% CI 0.71-0.84) for predicting symptomatic or severe/moderate asymptomatic CTRCD at 12 months. CONCLUSIONS: The HFA-ICOS score effectively categorizes patients by cardiovascular toxicity risk and demonstrates strong predictive ability for high-risk anthracycline-related cardiovascular toxicity and all-cause mortality.

Genetic factors in the pathogenesis of cardio-oncology.

In recent years, with advancements in medicine, the survival period of patients with tumours has significantly increased. The adverse effects of tumour treatment on patients, especially cardiac toxicity, have become increasingly prominent. In elderly patients with breast cancer, treatment-related cardiovascular toxicity has surpassed cancer itself as the leading cause of death. Moreover, in recent years, an increasing number of novel antitumour drugs, such as multitargeted agents, antibody‒drug conjugates (ADCs), and immunotherapies, have been applied in clinical practice. The cardiotoxicity induced by these drugs has become more pronounced, leading to a complex and diverse mechanism of cardiac damage. The risks of unintended cardiovascular toxicity are increased by high-dose anthracyclines, immunotherapies, and concurrent radiation, in addition to traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidaemia, and obesity. However, these factors do not fully explain why only a subset of individuals experience treatment-related cardiac toxicity, whereas others with similar clinical features do not. Recent studies indicate that genetics play a significant role in susceptibility to the development of cardiovascular toxicity from cancer therapies. These genes are involved in drug metabolism, oxidative damage, cardiac dysfunction, and other processes. Moreover, emerging evidence suggests that epigenetics also plays a role in drug-induced cardiovascular toxicity. We conducted a review focusing on breast cancer as an example to help oncologists and cardiologists better understand the mechanisms and effects of genetic factors on cardiac toxicity. In this review, we specifically address the relationship between genetic alterations and cardiac toxicity, including chemotherapy-related genetic changes, targeted therapy-related genetic changes, and immune therapy-related genetic changes. We also discuss the role of epigenetic factors in cardiac toxicity. We hope that this review will improve the risk stratification of patients and enable therapeutic interventions that mitigate these unintended adverse consequences of life-saving cancer treatments.

[Cardiotoxicity from anti-HER-2 therapies in patients with HER-2 positive breast cancer]. / Cardiotoxicidad por terapias anti-HER-2 en pacientes con cáncer de mama HER-2 positivo.

Background: HER-2 positive (+) breast cancer (BC) accounts for 20-25% of BC, it is more aggressive, and it has a lower survival rate. Since the approval of trastuzumab in 1998, other HER-2-targeted therapies such as pertuzumab and trastuzumab emtansine (TDM1) have been introduced, improving patient survival. However, cardiotoxicity is an adverse effect of these treatments. Objective: To estimate the incidence of cardiotoxicity with trastuzumab, trastuzumab/pertuzumab, and TDM1 in women with HER-2 + BC treated over a 6-year period at the Hospital de Clínicas and the Hospital Departamental de Soriano. Material and methods: Observational, descriptive, and retrospective study which included patients with HER-2 + BC treated with trastuzumab, trastuzumab/pertuzumab, or TDM1. Results: 81 patients were included, with a cardiotoxicity incidence of 23.4%. Cardiotoxicity was determined by a > 10% decrease in left ventricular ejection fraction (LVEF) (57.9%) and a LVEF < 50% evident during treatment (42.1%). Only 1 patient presented symptomatic heart failure. 63.1% of those who discontinued treatment due to cardiotoxicity managed to resume it. No relationship was evident between cardiovascular history or the administration regimen and the development of cardiotoxicity. Conclusion: The study showed a cardiotoxicity incidence similar to the international one. Most did not present cardiac toxicity, and if they did, it was asymptomatic and reversible.

Introducción: el cáncer de mama (CM) HER-2 positivo (+) representa el 20-25% de los CM, es más agresivo y tiene menor sobrevida. Desde la aprobación del trastuzumab en 1998, se han introducido otras terapias dirigidas al HER-2 como pertuzumab y trastuzumab emtansina (TDM1), con lo cual ha mejorado la supervivencia de las pacientes. Sin embargo, la cardiotoxicidad representa un efecto adverso de estos tratamientos. Objetivo: estimar la incidencia de cardiotoxicidad con trastuzumab, trastuzumab/pertuzumab y TDM1 en mujeres con CM HER-2 +, tratadas en un periodo de 6 años en el Hospital de Clínicas y el Hospital Departamental de Soriano. Material y métodos: estudio observacional, descriptivo y retrospectivo que incluyó pacientes con CM HER-2 +, tratadas con trastuzumab, trastuzumab/pertuzumab o TDM1. Resultados: se incluyeron 81 pacientes. La incidencia de cardiotoxicidad fue del 23.4%. La cardiotoxicidad se determinó por una disminución > 10% de la fracción de ejección del venticulo izquierdo (FEVI) (57.9%) y por una FEVI < 50%, evidenciada durante el tratamiento (42.1%). Únicamente una paciente presentó insuficiencia cardiaca sintomática. El 63.1% de quienes suspendieron el tratamiento por cardiotoxicidad logró reanudarlo. No se evidenció una relación entre los antecedentes cardiovasculares ni con el esquema de administración y el desarrollo de cardiotoxicidad. Conclusión: el estudio mostró una incidencia de cardiotoxicidad similar a la internacional. La mayoría no tuvo toxicidad cardiaca y si la hubo fue asintomática y reversible.

DOXORUBICIN-RELATED CARDIOTOXICITY: REVIEW OF FUNDAMENTAL PATHWAYS OF CARDIOVASCULAR SYSTEM INJURY.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after six decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Assessment of cardiotoxicity induced by PFOS exposure and mechanism research via untarget metabolomics.

Perfluorooctane sulfonate (PFOS), widely used in various industrial and commercial materials, can accumulate in the human body due to its high environmental stability, and thus potentially has cardiotoxicity. We assess cardiotoxicity through rat exposure to PFOS by intraperitoneal injection. Untargeted metabolomic analysis was used to explore the potential cardiotoxicity mechanism of PFOS. In vivo, PFOS exposure increases pro-inflammatory factors TNF-α and IL-1ß and decreases anti-inflammatory factors IL-10 and TGF-ß. PFOS exposure causes pathological changes in cardiac tissue and increases cardiac injury markers brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), C-reactive protein (CRP) in serum and triglyceride (TG), total cholesterol (TC) and ox-LDL in plasma. Increased expression of plasminogen activator inhibitor-1 (PAI-1) and CD36 indicates that PFOS exacerbates cardiac fibrosis. Untargeted metabolites analysis revealed 414 small molecule metabolites and 33 metabolites that differed after PFOS exposure, and identified 3 potential metabolic pathways. In conclusion, our study shows the inflammatory reactions involved in PFOS cardiotoxicity, and identifies potential pathways and differential metabolites involved in PFOS toxicity.

CREG1 attenuates doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis of cardiomyocytes.

OBJECTIVE: Doxorubicin (DOX)-induced cardiotoxicity limits the application of DOX in cancer patients. Currently, there is no effective prevention or treatment for DOX-induced cardiotoxicity. The cellular repressor of E1A-stimulated genes (CREG1) is a cardioprotective factor that plays an important role in the maintenance of cardiomyocytes differentiation and homeostasis. However, the role and mechanism of CREG1 in DOX-induced cardiotoxicity has not yet been elucidated. METHODS: In vivo, C57BL/6J mice, CREG1 transgenic and cardiac-specific CREG1 knockout mice were used to establish a DOX-induced cardiotoxicity model. H&E staining, Masson's trichrome, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis and ferroptosis in the myocardium. In vitro, neonatal mouse cardiomyocytes (NMCMs) were cultured and stimulated with DOX, CREG1-overexpressed adenovirus, and small interfering RNA was used to establish CREG1 overexpression or knockdown cardiomyocytes. Transcriptomics, real-time PCR, western blotting, and immunoprecipitation were used to examine the roles and mechanisms of CREG1 in cardiomyocytes ferroptosis. RESULTS: The mRNA and protein levels of CREG1 were reduced in the hearts and NMCMs after DOX treatment. CREG1 overexpression alleviated myocardial damage and inhibited DOX-induced ferroptosis in the myocardium. CREG1 deficiency in the heart aggravated DOX-induced cardiotoxicity and ferroptosis. In vitro, CREG1 overexpression inhibited cardiomyocytes ferroptosis induced by DOX, and CREG1 knockdown aggravated DOX-induced cardiotoxicity. Mechanistically, CREG1 inhibited the mRNA and protein expression of pyruvate dehydrogenase kinase 4 (PDK4) by regulating the F-box and WD repeat domain containing 7 (FBXW7)-forkhead box O1 (FOXO1) pathway. PDK4 deficiency reversed the effects of CREG1 knockdown on cardiomyocytes ferroptosis following DOX treatment. CONCLUSION: CREG1 alleviated DOX-induced cardiotoxicity by inhibiting ferroptosis in cardiomyocytes. Our findings may help clarify the new roles of CREG1 in the development of DOX-induced cardiotoxicity.

Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

Momordica charantia L.-derived exosome-like nanovesicles stabilize p62 expression to ameliorate doxorubicin cardiotoxicity.

BACKGROUND: Doxorubicin (DOX) is a first-line chemotherapeutic drug for various malignancies that causes cardiotoxicity. Plant-derived exosome-like nanovesicles (P-ELNs) are growing as novel therapeutic agents. Here, we investigated the protective effects in DOX cardiotoxicity of ELNs from Momordica charantia L. (MC-ELNs), a medicinal plant with antioxidant activity. RESULTS: We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs. CONCLUSIONS: Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.

Brugada Phenotype Following a Cocaine Overdose.

Brugada syndrome is a rare cardiac condition characterized by distinctive electrocardiogram patterns, predisposing individuals to fatal arrhythmias. While primarily linked to a loss-of-function mutation in the SCN5A gene, acquired forms of the syndrome have been associated with various factors, including drug use. We present a case of a 31-year-old female who presented to the emergency department unresponsive following cocaine use and developed type 1 Brugada ECG patterns alongside an incomplete right bundle branch block in V1-V3, ST elevations with biphasic waves, and diffuse repolarization abnormalities with J point deviations while in the intensive care unit. This study aimed to discuss the complexity of managing drug-induced Brugada-like findings and highlights the need for further research into the mechanisms underlying cocaine-induced cardiac effects. We aimed to discuss potential mechanisms for the impact of cocaine as its role as a sodium channel blocker and its potential effects on connexin 43 in the context of Brugada syndrome. This study also reinforced the importance of differentiating between true Brugada syndrome and other similar ECG changes for appropriate care management.

Cardioprotective Effects of α-Asarone Against Hexavalent Chromium-Induced Oxidative Damage in Mice.

Introduction: This comprehensive study investigated the therapeutic potential of α-asarone in mitigating myocardial oxidative damage, primarily induced by hexavalent chromium (Cr(VI)) exposure in mice. Methods: In this experiment, 24 mice were divided into four groups to assess the cardioprotective role of α-asarone. The study focused on two treatment groups, receiving 25 mg and 50 mg of α-asarone, respectively. These groups were compared against a control group subjected to Cr(VI) without α-asarone treatment, and a normal control negative group. The key biochemical parameters evaluated included serum levels of Creatine Kinase-MB (CK-MB) and Troponin I, markers indicative of myocardial damage. Additionally, the levels of Malondialdehyde (MDA) were measured to assess lipid peroxidation, alongside the evaluation of key inflammatory biomarkers in cardiac tissue homogenates, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-1ß (IL-1ß). Results Remarkably, α-asarone treatment resulted in a significant reduction in these markers compared to the control group. The treatment also elevated the activity of cardinal antioxidant enzymes like catalase (CAT) and superoxide dismutase (SOD), and reduced the glutathione (GSH). Furthermore, a notable upregulation of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) in cardiac tissue homogenates was observed, highlighting a potential pathway through which α-asarone exerts its protective effects. Histopathological analysis of cardiac tissues revealed that α-asarone ameliorated the structural lesions induced by Cr(VI). The study thus provides substantial evidence that α-asarone ameliorates Cr(VI)-induced cardiotoxicity through a multifaceted approach. It enhances cardiac enzyme function, modulates free radical generation, improves antioxidant status, and mitigates histopathological damage in cardiac tissues. Given these findings, α-asarone emerges as a promising agent against Cr(VI)-induced myocardial injury. Purpose: This study paves the way for further research into the cardioprotective properties of α-asarone and its potential application in clinical settings by specifically exploring the protective efficacy of α-asarone against Cr(VI)-induced cardiotoxicity and delineating the underlying biochemical and molecular mechanisms involved.

The interplay between doxorubicin chemotherapy, antioxidant system, and cardiotoxicity: Unrevealing of the protective potential of tannic acid.

Cardiotoxicity is the leading side effect of anthracycline-based chemotherapy. Therefore, it has gained importance to reveal chemotherapy-supporting strategies and reliable agents with their mechanisms of action. Tannic acid (TA), a naturally occurring plant polyphenol, has diverse physiological effects, including anti-inflammatory, anticarcinogenic, antioxidant, and radical scavenging properties. Therefore, this study was designed to investigate whether TA exerts a protective effect on mechanisms contributing to anthracycline-induced cardiotoxicity in rat heart tissues exposed to doxorubicin (DOX). Rats were randomly divided into control and experimental groups and treated with (18 mg/kg) DOX, TA (50 mg/kg), and DOX + TA during the 2 weeks. Cardiac gene markers and mitochondrial DNA (mtDNA) content were evaluated in the heart tissues of all animals. In addition to major metabolites, mRNA expression changes and biological activity responses of components of antioxidant metabolism were examined in the heart tissues of all animals. The expression of cardiac gene markers increased by DOX exposure was significantly reduced by TA treatment, whereas mtDNA content, which was decreased by DOX exposure, was significantly increased. TA also improved antioxidant metabolism members' gene expression and enzymatic activity, including glutathione peroxidase, glutathione s-transferase, superoxide dismutase, catalase, and thioredoxin reductase. This study provides a detailed overview of the current understanding of DOX-induced cardiotoxicity and preventive or curative measures involving TA.

A fatal case of cabozantinib-induced cardiomyopathy.

Cabozantinib, a multi-kinase receptor inhibitor, is utilized in the treatment of advanced malignancies such as metastatic renal cancers. While rare, cabozantinib-induced cardiotoxicity has emerged as a recognized adverse effect with potentially reversible outcomes. We report the case of a 55-year-old male who developed fatal cardiomyopathy 4 months after initiating cabozantinib therapy. Despite its rarity, cardiomyopathy after initiation of cabozantinib can be lethal if not diagnosed early. This case underscores a significant gap in the surveillance of patients treated with newer agents like cabozantinib. Larger observational studies are needed to assess the prevalence and impact of cardiomyopathy after initiation of cabozantinib therapy, and to determine the cost-effectiveness of early surveillance protocols.

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Gastrointestinal Cancer Therapy and Cardiotoxicity.

OPINION STATEMENT: Gastrointestinal cancers are a heterogenous group of cancers that share common risk factors with cardiovascular disease. Therapy for gastrointestinal cancers have improved cancer-specific outcomes at the cost of cardiotoxicity. The most common cardiotoxic therapies utilized in gastrointestinal cancers include conventional chemotherapy (including fluoropyrimidines and anthracyclines), targeted therapies including anti-vascular endothelial growth factor (VEGF) therapy and tyrosine kinase inhibitors (TKI), and immunotherapy. It is important for clinicians managing patients with gastrointestinal cancers to be aware of potential cardiotoxicity associated with these agents.

Zebrafish as an innovative model for exploring cardiovascular disease induction mechanisms and novel therapeutic interventions: a molecular insight.

Cardiovascular disease (CVD) is a common cardiac disorder that leads to heart attacks, strokes, and heart failure. It is primarily characterized by conditions that impact the heart and blood arteries, including peripheral artery disease, arrhythmias, atherosclerosis, myocardial ischemia, congenital heart abnormalities, heart failure, rheumatic heart disease, hypertension, and cardiomyopathies. These conditions are mainly effect the heart and blood vessels, causing blockages or weakened pumping, due to severe hereditary and environmental factors. The frequency of CVD is rising significantly as life expectancy increases. Despite this, no effective treatment or management for its symptoms has been found. One of the most difficult obstacles to overcome, is finding a suitable animal model for drug screening and drug development. Although rodents, mice, swine, and mammals serve as the basis for most animal models of cardiovascular disease, no model accurately captures the epidemiology of the condition. Zebrafish (Danio rerio) have drawn the interest of the international scientific community due to certain shortcomings of the previously discussed animal models because they are smaller, less costly, and have an incredibly high rate of reproduction. This review article emphasizes the significance of using zebrafish as an animal model to investigate the possible facets of cardiovascular disease. Moreover, the ultimate purpose of this review article is to establish the advantages of employing zebrafish over other animal models and to investigate the boundaries of using zebrafish to study human disease. Furthermore, the mechanisms of cardiovascular diseases induction in zebrafish were covered to improve understanding for readers. Finally, the analysis of cardiotoxicity using Zebra fish model, is also explained. In order to stop the health index from deteriorating, the current study also covers some innovative, effective, and relatively safer treatments for treatment and management of cardiotoxicity.

LncRNA GHET1 from bone mesenchymal stem cell-derived exosomes improves doxorubicin-induced pyroptosis of cardiomyocytes by mediating NLRP3.

Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell-derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes (EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn't. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptor protein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.

Targeting OGF/OGFR Signal to Mitigate Doxorubicin-induced Cardiotoxicity.

Enkephalins are reportedly correlated with heart function. However, their regulation in the heart remains unexplored. This study revealed a substantial increase in circulating levels of opioid growth factor (OGF) (also known as methionine enkephalin) and myocardial expression levels of both OGF and its receptor (OGFR) in subjects treated with doxorubicin (Dox). Silencing OGFR through gene knockout or using adeno-associated virus serotype 9 carrying small hairpin RNA effectively alleviated Dox-induced cardiotoxicity (DIC) in mice. Conversely, OGF supplementation exacerbated DIC manifestations, which could be abolished by administration of the OGFR antagonist naltrexone (NTX). Mechanistically, the previously characterized OGF/OGFR/P21 axis was identified to facilitate DIC-related cardiomyocyte apoptosis. Additionally, OGFR was observed to dissociate STAT1 from the promoters of ferritin genes (FTH and FTL), thereby repressing their transcription and exacerbating DIC-related cardiomyocyte ferroptosis. To circumvent the compromised therapeutic effects of Dox on tumors owing to OGFR blockade, SiO2-based modifiable lipid nanoparticles were developed for heart-targeted delivery of NTX. The pretreatment of tumor-bearing mice with the assembled NTX nanodrug successfully provided cardioprotection against Dox toxicity without affecting Dox therapy in tumors. Taken together, this study provides a novel understanding of Dox cardiotoxicity and sheds light on the development of cardioprotectants for patients with tumors receiving Dox treatment.