Study on the underlying mechanism of Huachansu Capsule induced cardiotoxicity of normal rat by integrating transcriptomics, metabolomics and network toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown. AIM OF THE STUDY: The aim of this study was to elucidate the possible cardiotoxic symptoms caused by high-doses of HCSc and to further reveal the complex mechanisms by which it causes cardiotoxicity. MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and sub-acute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot. RESULTS: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage, while low-dose of HCSc had no such changes. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1ß, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway. CONCLUSIONS: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of possible cardiotoxicity induced by high-dose HCSc. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.

Comparative Study of the Protective Effects of Citral, Thymoquinone, and Silymarin on Methotrexate-induced Cardiotoxicity in Rats.

Objectives: Methotrexate (MTX), an immunosuppressant and anti-cancer medication, can harm the heart. The goal of the current investigation was to assess the cardiotoxicity caused by MTX and the potential cardioprotective properties of silymarin, citral, and thymoquinone as antioxidants. Methods: Forty-eight rats were divided into six groups, which included control, MTX, cosolvent, citral, thymoquinone, and silymarin groups. At the end of the study, the rats were anesthetized (ketamine and xylazine) and killed using CO2. Their blood samples were collected to measure the enzymatic activities of creatine kinase-myoglobin binding (CK-MB), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH). Also, the heart tissue was sampled to determine the antioxidant capacity and examine the histopathology. Results: The findings revealed that the activity of CPK, CK-MB, and LDH enzymes significantly reduced in the thymoquinone treatment group compared to the MTX group (p < 0.05). On the other hand, total antioxidant capacity was significantly increased in the thymoquinone group compared to the MTX group (p < 0.05). The pathological modifications (i.e. severe congestion, edema fluid, the presence of inflammatory cells around the blood vessels, mild to moderate hemorrhaging between cardiac muscle fibers) were seen in the MTX group. The treatment groups, particularly thymoquinone, did not experience any appreciable pathological changes. Conclusion: The thymoquinone was found to have the strongest protective effect against the heart damage caused by MTX.

Investigation of 5-fluorouracil cardiotoxicity in combinational therapy: Influence of risk factors and demographics in a Pakistani population.

INTRODUCTION: 5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat various types of cancers. Although widely used, it has consistently been attributed to cardiotoxicities after administration. The purpose of this study was to assess the parameters and predictors of cardiotoxicities associated with various 5-FU-based chemotherapeutic protocols in patients with GI/colorectal cancer, as well as the correlation of these cardiotoxic events with age, sex, cumulative dose, and risk factors such as obesity, hypertension, and family history of cardiac diseases. METHODS: A prospective study consisting of 396 patients of both sexes was conducted in the oncology ward of Nishtar Hospital in Multan, Pakistan. Patients were grouped according to the therapeutic protocol they received (5-FU monotherapy or in combination, with different dosing regimens). Electrocardiography and serum troponin levels were used to assess 5-FU-induced cardiotoxicity. In cases where cardiotoxicity was detected, 5-FU treatment was interrupted; nitroglycerin, nitrates, and calcium channel blockers were administered; and cardiac monitoring was initiated. 5-FU was discontinued in all cases of acute myocardial infarction. RESULTS: Of the 396 patients, 28.5% reported different cardiotoxic symptoms after receiving various 5-FU-containing protocols. 35% had anginal pain, 13% suffered a myocardial infarction, 11% developed hypertension, and 10% presented heart failure. Patients receiving 5-FU combination therapy showed cardiotoxic events that were significantly different from those on 5-FU monotherapy. Based on the ECG results, only the QTc-d interval increased significantly (p < 0.001) after therapy. 68% of the patients had troponin levels > 2 ng/mL at the end of treatment. CONCLUSIONS: Pre-existing cardiac diseases, treatment duration, smoking, and obesity were found to be influential components in the development of cardiotoxicity, and patients with cancer should be closely monitored during 5-FU chemotherapy.

Fasting: A Complex, Double-Edged Blade in the Battle Against Doxorubicin-Induced Cardiotoxicity.

In recent years, there has been a surge in the popularity of fasting as a method to enhance one's health and overall well-being. Fasting is a customary practice characterized by voluntary refraining from consuming food and beverages for a specified duration, ranging from a few hours to several days. The potential advantages of fasting, including enhanced insulin sensitivity, decreased inflammation, and better cellular repair mechanisms, have been well documented. However, the effects of fasting on cancer therapy have been the focus of recent scholarly investigations. Doxorubicin (Dox) is one of the most widely used chemotherapy medications for cancer treatment. Unfortunately, cardiotoxicity, which may lead to heart failure and other cardiovascular issues, has been linked to Dox usage. This study aims to comprehensively examine the possible advantages and disadvantages of fasting concerning Dox-induced cardiotoxicity. Researchers have investigated the potential benefits of fasting in lowering the risk of Dox-induced cardiac damage to solve this problem. Nevertheless, new studies indicate that prolonged alternate-day fasting may adversely affect the heart's capacity to manage the cardiotoxic properties of Dox. Though fasting may benefit overall health, it is essential to proceed cautiously and consider the potential risks in certain circumstances.

Protein overexpression by adeno-associated virus-based gene therapy products in cardiomyocytes induces endoplasmic reticulum stress and myocardial degeneration in mice.

Gene therapy (GT) products created using adeno-associated virus (AAV) vectors tend to exhibit toxicity via immune reactions, but other mechanisms of toxicity remain incompletely understood. We examined the cardiotoxicity of an overexpressed transgenic protein. Male C57BL/6J mice were treated with a single intravenous dose of product X, an AAV-based GT product, at 2.6 × 1013 vg/kg. Necropsies were performed at 24 h, 7 days, and 14 days after dosing. Pathological examination and gene expression analysis were performed on the heart. Histopathologically, hypertrophy and vacuolar degeneration of cardiomyocytes and fibrosis were observed 14 days after dosing. Immunohistochemistry for endoplasmic reticulum (ER) stress-related proteins revealed increased positive reactions for glucose-regulated protein 78 and C/EBPR homologous protein in cardiomyocytes 7 days after dosing, without histopathological abnormalities. Fourteen days after dosing, some cardiomyocytes showed positivity for PKR-like endoplasmic reticulum kinase and activating transcription factor 4 expression. Ultrastructurally, increases in the ER and cytosol were observed in cardiomyocytes 7 days after dosing, along with an increase in the number of Golgi apparatus compartments 14 days after dosing. The tissue concentration of the transgene product protein increased 7 days after dosing. Gene expression analysis showed upregulation of ER stress-related genes 7 days after dosing, suggesting activation of the PKR-like ER kinase pathway of the unfolded protein reaction (UPR). Thus, the cardiotoxicity induced by product X was considered to involve cell damage caused by the overexpression of the product protein accompanied by UPR. Marked UPR activation may also cause toxicity of AAV-based GT products.

Cardiorespiratory Fitness in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis.

AIMS: Cardiovascular disease (CVD) is a leading cause of mortality in childhood cancer survivors (CCS) that may be related to the cardiotoxic effects of radiation or chemotherapy and concomitant reductions in cardiorespiratory fitness. Therefore, we sought to compare cardiorespiratory fitness (peak oxygen uptake, V̇O2peak) between CCS and age-matched non-cancer controls (CON). Secondary outcomes included hemodynamics and resting cardiac function. METHODS: Embase, Scopus, MEDLINE, CINAHL and SPORTDiscus databases were searched from inception to June 2023 for eligible studies. Cross-sectional studies with V̇O2peak measured in CCS and CON were included. Differences in outcomes and pooled estimates for each outcome were estimated from a fixed effects meta-analysis and between group differences were reported as a weighted mean difference (WMD). RESULTS: Of 2026 studies identified, 18 reported V̇O2peak (CCS: n=786, 44% female, mean age: 16-years, time post-therapy: 5.8 years; CON: n=1379, 50% female, mean age: 16-years). V̇O2peak was lower in CCS (WMD: -7.08mL/kg/min, 95% CI: -7.75 to -6.42, I2: 79%, n=2,165) with no difference for peak exercise heart rate (WMD: -1.4bpm, 95% CI: -3.0 to 0.2, I2: 63%, n=741). Resting left-ventricular ejection fraction (WMD: -1.61%, 95% CI: -2.60 to -0.62, I2.: 49%, n=222) and systolic blood pressure were lower (WMD: -3.8mmHg, 95% CI: -5.7 to -1.9, I2: 25%, n=184) while resting heart rate was higher in CCS (WMD: 4.9bpm; 95% CI: 1.8 to 7.9, I2: 55%, n=262). CONCLUSIONS: CCS have a marked reduction in cardiorespiratory fitness (7.1ml/kg/min lower than CON) that may have important prognostic implications for their future risk of CVD and mortality.

Childhood cancer survivors are at increased risk of developing cardiovascular disease, in particular, heart failure. This increased cardiovascular risk is partly due to cardiovascular damage from cancer treatment, but may also be due to reductions in cardiorespiratory fitness that accompany increased sedentary behavior prior to, during, or after cancer treatment. In this review, we assessed the degree of cardiorespiratory fitness impairment and cardiovascular function in childhood cancer survivors relative to their cancer-free peers. Key Findings:  Whilst traditional markers of cardiovascular function appear normal, childhood cancer survivors have a marked reduction in cardiorespiratory fitness that may increase their risk of heart failure and cardiovascular mortality.Measuring cardiorespiratory fitness alongside traditional cardiovascular risk markers may help to identify cancer survivors at increased risk of cardiovascular disease.

Two-dimensional Speckle Tracking Imaging in Cardiotoxicity Caused by Treatment of Breast Carcinoma with Anthracyclines.

Objective: This research was conducted to investigate the monitoring values of routine echocardiography (ECG) and two-dimensional speckle tracking imaging (2D-STI) in cardiotoxicity caused by the treatment of breast carcinoma with anthracyclines (ANTH). Methods: 100 patients with breast carcinoma were selected and enrolled into normal group (n=53 cases) and abnormal group (47 cases) according to whether ECG was abnormal. Routine ECG and 2D-STI were employed for the detection, ECG- and 2D-STI-related parameters were compared, receiver operating characteristic (ROC) curves were drawn, and the clinical application values of monitoring methods for two groups were assessed. Results: Before chemotherapy, no remarkable statistical difference was detected in routine ECG and 2D-STI parameters between normal and abnormal groups (P>0.05). After 6 cycles, E/V value of abnormal group was inferior to that of normal group ((0.93±0.16) vs (1.33±0.23). Besides, longitudinal peak strain (SRI) values of rear wall, front spacer, and rear spacer in abnormal group were inferior to those in normal group (P<0.05). Routine ECG combined with 2D-STI had the best predictive effect followed by 2D-STI and routine ECG. Conclusion: To sum up, 2D-STI was a new method for assessing myocardial lesions and possessed significant early clinical monitoring values in cardiotoxicity caused by chemotherapy after the treatment of breast carcinoma with ANTH. It had higher clinical application values than routine ECG.

Breast cancer and cardiovascular health.

Modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities. Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a sub-speciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer.

An integrated multi-omics analysis of the effects of the food processing-induced contaminant 2-monochloropropane-1,3-diol (2-MCPD) in rat heart.

Many foods including edible oils contain 2-monochloropropane-1,3-diol (2-MCPD), a processing-induced chemical contaminant. Cardiotoxic effects have been shown to result from oral 2-MCPD exposure in rodents, but the underlying mechanisms of action remain poorly understood. We undertook a comprehensive multi-omics approach to assess changes at the transcriptomic, proteomic, and oxylipin levels in heart tissues from male F344 rats that were exposed to 0 or 40 mg/kg BW/day of 2-MCPD in the diet for 90 days, in a regulatory compliant rodent bioassay. Heart tissues were collected for RNA sequencing, quantitative PCR analysis, proteomic analysis via two-dimensional gel electrophoresis and mass spectrometry, and targeted lipidomic profiling by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Transcriptomic and proteomic data analyses revealed upregulation of immune/inflammatory response processes and downregulation of energy metabolism and cardiac structure and functions. Among differentially expressed gene-protein pairs, coronin-1A, a key leukocyte-regulating protein, emerged as markedly up-regulated. Oxylipin profiling highlighted a selective suppression of docosahexaenoic acid-derived metabolites, suggesting a disruption in cardioprotective lipid pathways. These findings suggest that 2-MCPD disrupts homeostasis through inflammatory activation and suppression of metabolic and cardiac function. This research provides insights into 2-MCPD's cardiotoxicity, emphasizing the need for further studies to support hazard characterization.

Precision Treatment of Colon Cancer Using Doxorubicin-Loaded Metal-Organic-Framework-Coated Magnetic Nanoparticles.

Due to the limited efficacy and evident side effects of traditional chemotherapy drugs attributed to their lack of specificity and selectivity, novel strategies are essential for improving cancer treatment outcomes. Here, we successfully engineered Fe3O4 magnetic nanoparticles coated with zeolitic imidazolate framework-8 (ZIF-8). The resulting nanocomposite (Fe3O4@ZIF-8) demonstrates efficient adsorption of a substantial amount of doxorubicin (DOX) due to the porous nature of ZIF-8. The drug-loaded nanoparticles, Fe3O4@ZIF-8/DOX, exhibit significant accumulation at the tumor site in SW620 colon-cancer-bearing mice when guided by an external magnetic field. Within the acidic microenvironment of the tumor, the ZIF-8 framework collapses, releasing DOX and effectively inducing tumor cell death, thereby inhibiting cancer progression while not causing undesired side effects, as confirmed by a variety of in vitro and in vivo characterizations. In comparison to free DOX, Fe3O4@ZIF-8/DOX nanoparticles show superior efficacy in colon cancer treatment. Our findings suggest that Fe3O4@ZIF-8 holds promise as a carrier for small-molecule drug adsorption and its ferromagnetic properties provide drug targeting capabilities, thereby enhancing therapeutic effects on tumors at the same drug dosage. With excellent biocompatibility, Fe3O4@ZIF-8 demonstrates potential as a drug carrier in targeted cancer chemotherapy. Our work suggests that a combination of magnetic targeting and acid-responsiveness holds great promise for advancing targeted cancer therapy in precision nanomedicine.

Management of Cancer Therapy-Related Cardiac Dysfunction: A Case-Based Review.

With an ever-expanding repertoire of cancer therapies, cardiologists increasingly encounter patients with cancer therapy-related cardiac dysfunction. This can range from asymptomatic mild left ventricular dysfunction to severe symptomatic congestive heart failure. A multidisciplinary approach involving oncologists and cardiologists is needed in the management of these patients. This case-based review provides a practical guide for clinicians regarding the diagnosis and management of cancer therapy-related cardiac dysfunction associated with commonly used cancer treatments: anthracyclines, human epidermal receptor 2-targeted therapies, and immune checkpoint inhibitors.

In vitro endocrine and cardiometabolic toxicity associated with artificial turf materials.

Artificial turf, a consumer product growing in usage in the United States, contains diverse chemicals, some of which are endocrine disruptive. Endocrine effects from turf material extracts have been primarily limited to one component, crumb rubber, of these multi-material products. We present in vitro bioactivities from non-weathered and weathered turf sample extracts, including multiple turf components. All weathered samples were collected from real-world turf fields. Non-weathered versus weathered differentially affected the androgen (AR), estrogen (ER), glucocorticoid (GR), and thyroid receptors (TR) in reporter bioassays. While weathered extracts more efficaciously activated peroxisome proliferator activated receptor γ (PPARγ), this did not translate to greater in vitro adipogenic potential. All turf extracts activated the aryl hydrocarbon receptor (AhR). High AhR-efficacy extracts induced modest rat cardiomyoblast toxicity in an AhR-dependent manner. Our data demonstrate potential endocrine and cardiometabolic effects from artificial turf material extracts, warranting further investigation into potential exposures and human health effects.

Elucidating the interplay of PPAR gamma inhibition and energy demand in adriamycin-induced cardiomyopathy: In Vitro and In Vivo perspective.

Adriamycin is an anticancer anthracycline drug that inhibits the progression of topoisomerase II activity and causes apoptosis. The effective clinical application of the drug is very much limited by its adverse drug reactions on various tissues. Most importantly, Adriamycin causes cardiomyopathy, one of the life-threatening complications of the drug. Altered expression of PPARγ in adipocytes inhibited the glucose and fatty acids uptake by down regulating GLUT4 and CD36 expression and causes cardiotoxicity. Therefore, the influence of Adriamycin in cardiac ailments was investigated in vivo and in vitro. Adriamycin treated rats showed altered ECG profile, arrhythmic heartbeat with the elevated levels of CRP and LDH. Dysregulated lipid profiles with elevated levels of cholesterol and triglycerides were also observed. Possibilities of cardiac problems due to cardiomyopathy were analyzed through histopathology. Adriamycin treated rats showed no signs for atheromatous plaque formation in aorta but disorganized cardiomyocytes with myofibrillar loss and inflammation in heart tissue, indicative of cardiomyopathy. Reduced levels of antioxidant enzymes confirmed the incidence of oxidative stress. Adriamycin treatment significantly reduced glucose and insulin levels, creating energy demand due to decreased glucose and insulin levels with increased fatty acid accumulation, ultimately resulting in oxidative stress mediated cardiomyopathy. Since PPARs play a vital role in regulating oxidative stress, the effect of Adriamycin on PPARγ was analyzed by western blot. Adriamycin downregulated PPARγ in a dose-dependent manner in H9C2 cells in vitro. Overall, our study suggests that Adriamycin alters glucose and lipid metabolism via PPARγ inhibition that leads to oxidative stress and cardiomyopathy that necessitates a different therapeutic approach.

Early detection of chemotherapy-induced cardiotoxicity in breast cancer patients: a comprehensive analysis using speckle tracking echocardiography.

Introduction: Chemotherapy-induced cardiotoxicity poses a significant challenge in the treatment of breast cancer, potentially compromising both the efficacy of cancer therapy and cardiac health of patients. This study aimed to enhance the early detection of cardiotoxic effects by integrating advanced imaging modalities and biomarker analysis, thereby facilitating timely interventions to mitigate cardiac risk. Methods: A prospective cohort design was employed, enrolling breast cancer patients scheduled for potentially cardiotoxic chemotherapy regimens. The study utilized a comprehensive diagnostic toolkit, including echocardiography with strain imaging, cardiac MRI, and serial measurements of cardiac biomarkers such as high-sensitivity troponins and natriuretic peptides. Results: The analysis revealed that subtle changes in myocardial strain parameters and early biomarker elevations were predictive of subsequent declines in left ventricular function, preceding conventional echocardiographic evidence of cardiotoxicity. Logistic regression analysis highlighted the additive predictive value of integrating biomarker data with advanced imaging findings to identify patients with the highest risk of significant cardiotoxicity. Discussion: The study concluded that an integrated diagnostic approach, combining detailed imaging assessments with sensitive biomarker analysis, offers a superior strategy for the early detection of chemotherapy-induced cardiotoxicity in breast cancer patients. This proactive diagnostic strategy empowers clinicians to tailor cancer therapy more precisely, balancing oncologic efficacy with cardiovascular safety and underscores the importance of a multidisciplinary approach in the management of patients undergoing potentially cardiotoxic chemotherapy.

Schisandrin C prevents Regorafenib-Induced cardiotoxicity by recovering EPHA2 expression in cardiomyocytes.

Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 days by gavage or treated cardiomyocyte lines with 8, 16 or 32 µM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic.

The Sirt1/Nrf2 pathway is a key factor for drug therapy in chemotherapy-induced cardiotoxicity: a Mini-Review.

The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.

Unveiling the Cardiotoxicity Conundrum: Navigating the Seas of Tyrosine Kinase Inhibitor Therapies.

Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of various solid and hematologic malignancies by targeting dysregulated signaling pathways critical for malignant cell growth. However, these therapeutic benefits are often accompanied by cardiotoxicities, such as hypertension, left ventricular dysfunction, QT prolongation, and tachyarrhythmias, among others. These cardiotoxicities post a significant challenge in clinical management, often limiting the use of otherwise effective therapies. The underlying mechanism of TKI-induced cardiotoxicity appears to be multifaceted, involving several pathways including: direct cardiomyocyte damage, mitochondrial dysfunction, endothelial damage, and disruption of signaling pathways critical for cardiac function. The range and severity of cardiotoxicities vary significantly across different TKIs, necessitating a comprehensive understanding of each agent's specific cardiovascular risk profile. Preventing and managing TKI-induced cardiotoxicity requires a comprehensive, multidisciplinary approach. Early identification of at-risk patients through baseline cardiovascular risk assessments and appropriate monitoring during therapy is crucial. Strategies to mitigate cardiotoxic effects include dose modification, the use of cardioprotective agents, and temporary discontinuation of therapy. Additionally, decision making via multidisciplinary teams ensures minimization of cardiovascular complications while also continuing effective cancer treatment. Historically, data have been limited regarding cardiotoxicity and most cancer therapies, which certainly includes TKIs. This review aims to synthesize the current body of knowledge on TKI-associated cardiotoxicities, while highlighting the importance of vigilance and proactive management to minimize cardiovascular complications.

Many Tyrosine Kinase Inhibitors have cardiac side effects. This article provides an up-to-date review of these toxicities.

Drug-induced torsadogenicity prediction model: An explainable machine learning-driven quantitative structure-toxicity relationship approach.

Drug-induced Torsade de Pointes (TdP), a life-threatening polymorphic ventricular tachyarrhythmia, emerges due to the cardiotoxic effects of pharmaceuticals. The need for precise mechanisms and clinical biomarkers to detect this adverse effect presents substantial challenges in drug safety assessment. In this study, we propose that analyzing the physicochemical properties of pharmaceuticals can provide valuable insights into their potential for torsadogenic cardiotoxicity. Our research centers on estimating TdP risk based on the molecular structure of drugs. We introduce a novel quantitative structure-toxicity relationship (QSTR) prediction model that leverages an in silico approach developed by adopting the 4R rule in laboratory animals. This approach eliminates the need for animal testing, saves time, and reduces cost. Our algorithm has successfully predicted the torsadogenic risks of various pharmaceutical compounds. To develop this model, we employed Support Vector Machine (SVM) and ensemble techniques, including Random Forest (RF), Extreme Gradient Boosting (XGBoost), and Categorical Boosting (CatBoost). We enhanced the model's predictive accuracy through a rigorous two-step feature selection process. Furthermore, we utilized the SHapley Additive exPlanations (SHAP) technique to explain the prediction of torsadogenic risk, particularly within the RF model. This study represents a significant step towards creating a robust QSTR model, which can serve as an early screening tool for assessing the torsadogenic potential of pharmaceutical candidates or existing drugs. By incorporating molecular structure-based insights, we aim to enhance drug safety evaluation and minimize the risks of drug-induced TdP, ultimately benefiting both patients and the pharmaceutical industry.