Cardiovascular Toxicology最新文献

Statins, widely used for preventing cardiovascular diseases due to their cholesterol-lowering effects, are associated with potential adverse reactions in some individuals, underscoring the need to understand the factors contributing to statin-related complications. The ATP-binding cassette subfamily G member 2 (ABCG2) gene, which encodes a multidrug transporter, has garnered attention due to its involvement in statin metabolism. Specifically, the rs2231142 polymorphism within ABCG2 has been implicated in altered drug metabolism and pharmacokinetics, potentially influencing statin-related toxicity. Despite previous investigations, findings regarding this association remain inconclusive. Thus, this systematic review and meta-analysis aimed to clarify the correlation between the rs2231142 polymorphism and statin-induced toxicity. Through a comprehensive literature search, seven eligible studies were identified and subjected to rigorous data extraction and quality assessment. Meta-analysis revealed a significant association between the rs2231142 polymorphism and an increased risk of overall statin-induced toxicity, including muscular and hepatic toxicity, with odds ratios of 2.6 and 2.7, respectively. These findings suggest a potential role for ABCG2 polymorphisms in statin-related adverse events and emphasize the importance of personalized treatment strategies in managing statin therapy.

Electronic cigarettes are popular tobacco products that heat e-liquid into an aerosol for inhalation. Since their introduction to the market, electronic cigarettes have been considered a safer alternative to combustible tobacco products. However, most of today's users are adolescents and young adults naïve to tobacco products, who are drawn to e-cigarettes by appealing designs and targeted marketing, resulting in exposure to largely unknown short- and long-term health risks. While the cardiovascular effects of electronic cigarettes remain incompletely understood, there has been a growing concern surrounding their potential acute and chronic impact on cardiovascular health and disease risks. In this review, we examine the components of e-cigarettes and evaluate the cardiovascular effects of both acute and regular e-cigarette exposure, summarizing findings from existing preclinical and clinical studies to provide a comprehensive overview about the topic.

Endocrine disrupting chemicals (EDCs) are exogenous compounds that interfere with the normal functioning of the endocrine system. This effect is crucial for maintaining hormonal balance and regulating various physiological processes. Phthalates, parabens, and triclosan are EDCs found in many personal care products (make-up, shampoo, perfume, shaving foam, moisturizing cream, hair dyes, deodorant), plastics, pesticides, pharmaceuticals, and household cleaning products, and can be inhaled or absorbed by the body through inhalation or skin contact. Atherosclerosis is a major cause of cardiovascular diseases, including coronary artery disease, stroke, and peripheral artery disease. While traditional risk factors for atherosclerosis, such as high cholesterol, hypertension, and smoking, have been extensively studied, emerging evidence suggests that EDCs may also play a significant role in the development and progression of atherosclerosis. Several potential mechanisms have been proposed to explain how EDCs contribute to atherosclerosis. One mechanism involves the activation of nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) and estrogen receptors (ERs), by EDCs. Activation of these receptors can lead to dysregulation of lipid metabolism, inflammation, and oxidative stress, all of which are key processes in atherosclerosis development. EDCs have been shown to disrupt endothelial function through various mechanisms. Some of these mechanisms are the formation of reactive oxygen species (ROS) and free oxygen radicals, and impaired nitric oxide (NO) production by EDCs. This literature review aims to explore the current understanding of the role of EDCs in atherosclerosis.

Atypical antipsychotics have experienced a significant increase in use across various disorders, coinciding with a rise in acute intoxication. This retrospective study predicts prolonged QTc interval and the necessity for mechanical ventilation (MV) in patients with acute atypical antipsychotic poisoning using machine learning techniques. This retrospective study included 355 patients with a mean age of 26.1 ± 9.6 years. The overall prevalence of the investigated outcomes was 5.5% for prolonged QTc interval and 7.1% for MV. Eight classifiers were developed, including Logistic Regression, Support Vector Machine, K-Nearest Neighbors, and five tree-based models: Random Forest, XGBoost, LightGBM, CatBoost, and Gradient Boosting Models. Model validation was conducted through external validation using the testing dataset and an internal five-fold cross-validation after optimizing the hyperparameters. As a predictor of prolonged QTc interval, all tree-based models achieved perfect specificity, recall, precision, accuracy, and area under the curve (AUC) of 100% using the training dataset. Similar performance was reported in models predicting the necessity for MV. Upon validation, the tree-based models for predicting prolonged QTc intervals maintained good AUCs, ranging between 0.930 and 0.958 in the training dataset and between 0.927 and 0.949 in the testing dataset. In terms of accuracy, the tree-based models exhibited good values in both external and five-fold cross-validation, with all values above 0.901. The observed declines in recall and precision during the validation of the proposed models underscore the need for future studies to utilize larger validation cohorts, thereby enabling the generalization of the proposed models in relevant clinical settings.

Trastuzumab is a common and effective therapeutic choice for breast cancer treatment. However, the cardiotoxicity induced by this therapy remains a significant challenge, because we lack predictors that help avoid allocating some patients with high risk to this management plan. This study was aimed to evaluate several baseline risk factors such as prolonged QTc interval, age, and lower expression level of estrogen and progesterone receptors that might predict cardiac toxicity after Trastuzumab therapy. This prospective observational study was conducted in Al-Bairouni Hospital at Damascus University. Patients were evaluated with echocardiography and electrocardiography before therapy and three weeks after the last administration of the fourth cycle. A significant Trastuzumab-related cardiotoxicity was determined by a 5% or more reduction in the left ventricular ejection fraction after excluding all other potential causes. A total number of 140 patients with breast cancer, who were indicated Trastuzumab therapy, were recruited for this study. Thirty of them (21.4%) developed Trastuzumab-related cardiotoxicity but all were asymptomatic. Corrected QT interval of more than 450 ms and lower expression level of estrogen and progesterone receptors at baseline were associated with higher susceptibility to develop Trastuzumab-related cardiotoxicity (P = 0.045, P = 0.004, and P = 0.042, respectively). Of note, preexisting cardiac morbidities, age, and chemotherapy accompanying Trastuzumab administration did not reach significant association with cardiotoxicity. Breast cancer patients with prolonged corrected QT interval or lower expression levels of hormone receptors are at a higher risk of developing Trastuzumab-related cardiotoxicity, necessitating careful administration of the therapy.

Ventricular arrhythmias following myocardial infarction (MI) remain a leading cause of sudden cardiac death, yet therapeutic options are limited by incomplete understanding of the molecular mechanisms governing post-infarction arrhythmogenesis. While RNA-binding proteins have emerged as critical regulators of cardiovascular pathophysiology, their role in cardiac electrophysiology remains largely unexplored. Here, we demonstrate that cold- inducible RNA-binding protein (CIRP) functions as a critical regulator of ventricular arrhythmia susceptibility through post-transcriptional control of cardiac ion channels. In a rat MI model, cardiac-specific CIRP overexpression was achieved using AAV9 gene delivery under cTNT promoter control, followed by LAD ligation. Our results show that CIRP gene therapy significantly reduced ventricular arrhythmia inducibility in programmed electrical stimulation studies and improved cardiac function parameters. Electrophysiological analysis revealed that CIRP prolonged action potential duration through selective post-transcriptional downregulation of Kv4.2 and Kv4.3 potassium channel proteins without altering mRNA levels. This post-transcriptional mechanism represents a novel pathway linking temperature-responsive RNA regulation to electrophysiological stability. Western blot and RT-PCR analysis confirmed protein-specific suppression of target ion channels in CIRP-treated hearts. These results establish CIRP as a critical mediator in the post-transcriptional regulatory network governing cardiac rhythm and identify RNA-binding protein modulation as a promising therapeutic strategy for post-MI arrhythmia prevention. This mechanistic insight opens new avenues for understanding how cellular stress responses influence cardiac electrophysiology and may inform the development of next-generation antiarrhythmic therapies.

Congenital heart disease (CHD) is the most common birth defect and involves intricate developmental mechanisms. Uric acid (UA), the final metabolite of purine degradation in humans, has a largely unexplored role in heart development. This study investigated the effects of elevated UA levels-both exogenous and endogenous-on cardiac development in a zebrafish model and explored the involvement of Wnt signaling in this process. UA elevation was achieved through exogenous UA exposure, in vivo overexpression of xdh, and knockdown of uox. Expression levels of Wnt pathway components (wnt1, wnt3a, wnt6b, and β-catenin), cardiac progenitor markers (mesp1 and isl1), neural crest cell markers (sox10 and crestin), and cardiac development genes (nkx2.5, tbx5a, and fgf10a) were assessed at key developmental stages. All UA-elevating strategies significantly increased UA concentrations and led to phenotypes including pericardial edema and reduced heart rate at 72 h post-fertilization (hpf). These phenotypes were accompanied by downregulation of Wnt signaling and cardiac development genes. Treatment with the Wnt activator CHIR99021 partially rescued the cardiac defects induced by UA overload. These findings demonstrate that elevated UA-whether exogenous or endogenous-can disrupt cardiac development in zebrafish, at least in part by suppressing Wnt signaling, thereby impairing downstream gene networks essential for heart morphogenesis.

Due to environmental and medicinal exposures to lithium, as well as its uptake and accumulation in various plant species as human food source, concerns about lithium toxicity and negative impact on different organs especially heart have been raised. The toxicity mechanism of lithium is still unclear, but it has been suggested that some its harmful effects may be related to mitochondrial dysfunction and oxidative stress. Previous studies have demonstrated that plant-derived natural compounds can ameliorate mitochondrial dysfunction induced by various chemicals. In the current study, we examined the effects of vanillic acid as a plant-derived natural compound on lithium-stimulated mitochondrial dysfunction in rat heart-isolated mitochondria and its potential mechanisms of attenuating damages to improve function of mitochondria during 60 min. Mitochondrial injury in rat heart-isolated mitochondria was induced by lithium (125 µM, according to previous studies) and portative effect of vanillic acid (10, 50, and 100 µM) was assessed using mitochondrial toxicity parameters such as the functional state of mitochondria, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and malondialdehyde (MDA) levels. Our results confirmed that vanillic acid (10, 50, and 100 µM) significantly mitigated mitochondrial dysfunction triggered by lithium, evidenced by the decline in formation of ROS and MDA, improvement the mitochondrial membrane potential, inhibition of mitochondrial swelling, and the increase of the functional state of mitochondria. Our findings suggested that vanillic acid mitigated mitochondrial dysfunction via maintenance of mitochondrial function, inhibition of oxidative stress and mitochondrial swelling, it could be developed as mitochondrial protective agents in the prevention of cardiotoxicity induced by lithium.

Cardiac fibrosis is a pathological condition marked by the excessive accumulation of extracellular matrix (ECM) components, which leads to impaired cardiac function and heart failure. Despite its significant contribution to cardiovascular morbidity and mortality, no effective therapeutic drugs specifically target the inhibition of cardiac fibrosis, largely due to the complex etiological heterogeneity and pathogenesis of this disease. Sirtuins (SIRTs), a family of NAD + -dependent deacetylases, play a critical role in cellular processes such as oxidative stress, inflammation, energy metabolism, mitochondrial function, epithelial-to-mesenchymal transition (EMT), and ECM homeostasis, all of which are implicated in cardiac fibrosis. Growing clinical and experimental evidence suggests that SIRTs regulate the cellular and molecular mechanisms of cardiomyocytes through various biological pathways. Emerging evidence indicates that sirtuin activators, including resveratrol and NAD + precursors, hold therapeutic potential in mitigating cardiac fibrosis. However, the complex and context-dependent roles of sirtuins necessitate further research to fully elucidate their mechanisms and translational applications. As the role of SIRTs in relation to cardiac fibrosis and its associated mechanisms is rarely discussed in the literature, this review comprehensively addresses the roles of the seven mammalian sirtuins (SIRT1-SIRT7) in the pathogenesis and progression of cardiac fibrosis. It highlights the key role of SIRTs as molecular targets for innovative anti-fibrotic therapies, offering new avenues for the treatment of cardiac fibrosis and associated cardiovascular diseases.

There have been concerns about potential adverse cardiovascular (CV) events associated with prokinetics that enhance gastrointestinal (GI) motility. To evaluate whether prokinetics use was associated with increased CV risk. We conducted a self-controlled case series (SCCS) study using the National Health Claims Database in South Korea. Age-adjusted incidence rate ratios (IRR) for the development of CV events (composite of myocardial infarction and stroke) were estimated by comparing the incidence during the risk period with prokinetics and the control period without prokinetics. This SCCS study included 15,621 participants who experienced CV events and exposure to prokinetics between 2004 and 2019. The risk period with prokinetics had a significantly increased risk for CV events compared to the control period (IRR 1.56, 95% CI 1.48-1.66). When the risk period was categorized according to the time from initiation of prokinetics, CV risk was highest in the first 7 days (IRR 2.29, 95% CI 2.13-2.47), and declined to non-significance in ≥ 15 days (IRR 1.03, 95% CI 0.94-1.13). In the analysis according to the class of prokinetics, CV risk was highest in the order of central dopamine type 2 (D2) receptor antagonist (IRR 2.14, 95% CI 1.95-2.34), peripheral D2 receptor antagonist (IRR 1.37, 95% CI 1.24-1.51), and selective 5-hydroxytryptamine 4 receptor agonist (IRR 1.29, 95% CI 1.17-1.42). The use of prokinetics was associated with an increased risk of CV adverse events, particularly in the early period following initiation of central D2 receptor antagonists.