Cardiovascular Toxicology最新文献

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.

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.

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.

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.

Mercury exposure is a significant environmental concern due to its toxic effects on the human body, especially on the cardiovascular system. Its accumulation induces oxidative stress, inflammation and endothelial dysfunction in systemic arteries, contributing to the development of cardiovascular diseases. The close relationship between systemic and pulmonary circulation leads us to believe that it must also suffer by the toxic effects of HgCl₂. However, the consequences of HgCl₂ on pulmonary arteries remain unclear. This study aimed to investigate the effects of mercury chloride (HgCl₂) exposure for 60 d on the small intrapulmonary arteries and hemodynamic parameters of male rats. The rats were exposed to HgCl₂ (1st dose, 4.6 μg/kg; subsequent daily doses, 0.07 μg/kg; intramuscular injection). The results revealed that intrapulmonary arteries from exposed rats exhibited reduced contractile responses to potassium chloride and the thromboxane A2 receptor agonist U46619, along with thinning of the arterial wall, which is indicative of vascular remodeling. Impaired pulmonary vasoconstriction in the HgCl₂ group was associated with increased nitric oxide (NO) production and elevated hydrogen peroxide (H₂O₂) levels. In addition, increased production of superoxide anion (O₂^•-) and reduced superoxide dismutase (SOD) expression were observed and indicates an environment of oxidative stress. Furthermore, HgCl₂ increased systemic blood pressure in conscious animals but reduced left ventricular systolic pressure in anesthetized animals. These findings suggest that chronic HgCl₂ exposure induces pulmonary vascular dysfunctions, primarily through enhanced NO and ROS signaling as an adaptive mechanism.

Background: Cadmium exposure has been linked to an increased risk of cardiovascular disease (CVD). Moderate caffeine intake may reduce the risk of CVD. Whether caffeine intake attenuates the association of cadmium exposure with CVD remains unknown.

Methods: The study used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016. Cadmium exposure was estimated by urinary cadmium after adjusting for urinary creatinine (UCd/Cr, μg/g). Caffeine intake was determined using the average of two 24-h dietary recalls. Logistic regression models were used to examine the association of cadmium exposure with CVD and to evaluate the multiplicative interaction between caffeine intake and cadmium exposure.

Results: A total of 7,094 adults aged 20 or older were included in the study, of whom 827 had CVD. The multivariate-adjusted odds ratio (OR) of participants in the highest quartile was 2.10 (95% confidence interval: 1.34-3.28) for CVD compared to participants in the lowest UCd/Cr quartile. The OR of ln-UCd/Cr as a continuous variable was 1.46 (95% confidence interval: 1.23-1.73). Moreover, a significant interaction between caffeine intake and cadmium exposure on CVD was observed (P for interaction = 0.004). The relatively lowest ORs of cadmium exposure with CVD were observed in participants with low or moderate caffeine intake (caffeine intake quartile 2 and quartile 3) in almost all subgroups.

Conclusions: Higher cadmium exposure was associated with increased CVD risk in US adults. Low-to-moderate caffeine intake tends to attenuate this association. Further studies are needed to confirm causality and underlying mechanisms.

Epidemiological studies and in vivo animal models have shown that exposure to PFAS can lead to cardiovascular toxicity and promote atherosclerosis. In this study, we explored the effects of PFOA and PFOS exposure on lipid accumulation in macrophages and analyzed critical markers of foam cell formation, which are early precursors of atherosclerotic lesions. Our results demonstrate that PFOS and PFOA enhance lipid and cholesterol accumulation in human U937-derived macrophages, which is characteristic of foam cells. PFOS and PFOA induced the activity of the peroxisome proliferator-activated receptor gamma (PPARγ) and treatment with a PPARγ antagonist partly reversed the accumulation of lipids after PFAS exposure. Furthermore, the results show that PFOS and PFOA activate (NF)-erythroid-derived 2 (E2)-related factor 2 (Nrf2) and induce markers of oxidative stress. Gene expression analysis revealed that mRNA levels of interleukin-1β (IL-1β) and plasminogen activator inhibitor-2 (PAI-2) were upregulated in a time- and concentration-dependent manner in PFOS- and PFOA-treated macrophages. The expression of other key atherosclerosis-related enzymes, including cytochrome P450 8B1 (CYP8B1) and lanosterol synthase (LSS), was downregulated, whereas the expression of cyclooxygenase 2 (COX-2) and aldo-keto reductase family 1 member C3 (AKR1C3) was induced by PFOS and PFOA. Additionally, elevated levels of matrix metalloproteinases (MMP)-1 and MMP-12 were found in PFOS- and PFOA-treated cells, which were associated with increased cell migration. Furthermore, PFOS and PFOA enhanced the expression of IL-1β when macrophages were activated; however, elevated levels of IL-6 and COX-2 in activated macrophages were repressed by PFOS and PFOA. Together, the findings indicate that PFAS exposure modifies immune responses and promotes lipid accumulation in macrophages, potentially contributing to foam cell and plaque formation in atherosclerosis.