Cardiovascular Toxicology最新文献

Radiation-induced cardiac remodeling (RICR) is one of the complications of exposure to radiotherapy. These disorders may occur for a subset of cancer patients, when the heart remains in part or in full in the radiation field. Despite advancements in radiotherapy techniques, cardiotoxicity has remained a concern after radiotherapy. RICR includes complex pathophysiological processes, which can be initiated by oxidative stress and cardiomyocyte cell death and continue with inflammation, arrhythmia, vascular and valvular abnormalities, and fibrosis, collectively contributing to structural and functional changes in the heart. Some studies have suggested strategies for RICR encompass pharmacological interventions, including angiotensin-converting enzyme (ACE) inhibitors, natural products, antioxidants, and others, which aim to mitigate cardiac damage and improve outcomes. Advanced therapies, including stem cell and gene therapy, as well as some adjuvants and novel drugs targeting specific molecular pathways, represent future directions for treatment. This review aims to elucidate the mechanisms underlying RICR, highlight early detection strategies, and discuss current and emerging therapeutic approaches.

Trihalomethanes (THMs), the major byproducts of water chlorination which are associated with various adverse health outcomes. However, the relationship of THMs with cardiovascular disease (CVD) in aging populations remains underexplored. We analyzed data from 5,400 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2012. Associations between blood THM concentrations and CVD were evaluated using weighted multivariable logistic regression. Weighted quantile sum (WQS) regression was applied to identify the most relevant THM components. We also performed mediation analysis to evaluate the role of inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), white blood cell count (WBC), and systemic inflammation response index (SIRI). Network toxicology analysis was used to explore the biological pathways linking THM exposure, CVD, and aging. Elevated blood concentrations of THMs, particularly chloroform (TCM) and total THMs (TTHMs), were significantly associated with increased odds of CVD. Stratified analyses revealed stronger associations among older adults, males, individuals with higher BMI, and those with hypertension. WQS regression identified TCM as the predominant contributor to the THM-CVD association, accounting for 58.0% of the mixture's effect. Mediation analysis showed that NLR partially mediated the association between TTHMs and CVD, explaining 7.12% of the total effect. Network toxicology analysis highlighted inflammation-related pathways, including the IL-17 signaling pathway, as key mechanisms linking THM exposure, CVD, and aging. Our study revealed elevated blood TCM and TTHM concentrations are associated with increased prevalence of CVD among U.S. adults aged 45 years and older. Network toxicology and mediation analysis suggest that systemic inflammation may play a mediating role in this relationship.

Although reperfusion therapy can reduce the mortality of myocardial infarction, it results in myocardial ischemia-reperfusion injury (MIRI). The molecular mechanism by which the interferon-γ pathway affects MIRI is unclear, so we addressed this problem by mining transcriptome and single-cell sequencing data. The GSE160516 and GSE83472 datasets, single cell RNA sequencing (scRNA-seq) data of GSE227088 dataset and 182 interferon-γ pathway related genes (IRGs) were retrieved and incorporated into this study. The differentially expressed genes (DEGs) between MIRI and control samples were searched, the candidate genes were obtained by intersecting DEGs with IRGs. The protein-protein interaction (PPI) analysis was utilized for selecting key genes from candidate genes. Moreover, key genes with significant expression and consistent trend in GSE160516 and GSE83472 datasets were selected as biomarkers. The biological functions and regulatory mechanism of biomarkers were investigated by enrichment analysis and predicting the upstream molecules targeting them. Ulteriorly, cell clusters were identified via unsupervised cluster analysis and merged into different cell types by cell annotation. Cell types in which biomarkers observably and differentially expressed were selected as crucial cell types. Finally, cell communication and pseudo-time analysis were implemented based on crucial cell types. Totally 34 candidate genes were searched by overlapping 1,930 DEGs with 182 IRGs. Nine key genes were singled out from candidate genes, of which Myd88 and Trp53 were significantly upregulated in the MIRI samples of GSE160516 and GSE83472 datasets, so they were identified as biomarkers. Besides, they participated in pathways such as ribosome, spliceosome and cell cycle. Myd88 might be simultaneously regulated by mmu-miR-361-3p and mmu-miR-421-3p, and Trp53 could be regulated by Abl1 and Tead2. Totally 25 cell clusters were merged into six cell types, of which three crucial cell types (cardiomyocyte, fibroblast, and macrophage) could interact with each other through receptor-ligand. Pseudo-time analysis revealed states 1, 2, and 5 of macrophages might be associated with MIRI. Two biomarkers (Myd88 and Trp53) related to IRGs in MIRI were mined, providing a reference for elucidating the mechanism of interferon-γ pathway on MIRI.

Biomarkers, such as toenails, are commonly used to investigate the health status of individuals. Nails samples are a useful marker of exposure, as they are easy to collect, store, and represent exposure from 6 to 12 months. There are multiple analytical methods that can be used to extract long-term exposure profiles from toenails including Proton-Induced X-Ray Emission(PIXE) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall goal of this research was to evaluate the level of agreement between the two analytical methods for assessment of different metals in nail samples. Children's nail samples were collected. Nail samples were first analyzed by PIXE and then analyzed by ICP-MS. To compute quantiles for the metal concentrations that had some fully observed and some left-censored concentrations, a reverse Kaplan-Meier estimator was used. Lin's concordance correlation coefficient (CCC) and the Pearson correlation coefficient were calculated to assess agreement between the two methods and to determine the strength of the linear association between the metal concentration measurements obtained under each analytical technique. PIXE and ICP-MS determined similar median concentrations for calcium, copper, potassium, and nickel. However, there were stark differences between other elements. Several elements, such as copper, potassium, and zinc represented strong concordance through use of the CCC. In many studies, scholars want to evaluate how well one measurement can reproduce another, and our paper used several elements to show the degree of reproducibility between the two analytical methods. This can be useful when scholars are determining methods to assess biomarkers in health-related studies.

Fewer studies have focused on the interaction of metal mixtures with hypertension, especially in Chinese community-dwelling elderly. In addition, the relationship between metal exposure and hypertension may be attenuated or strengthened by the presence of multiple chronic diseases in older adults. In this study, inductively coupled plasma mass spectrometry was used to detect the levels of 12 metals in the urine of 693 elderly people in the Yinchuan community. We employed Directed Acyclic Graphs (DAG) to select variables for adjustment in the model. Conditional logistic regression model and restricted cubic spline analysis (RCS) were used to explore the association between and dose-response relationship between metal concentrations in urine and hypertension. Quantile g-computation and Bayesian kernel machine regression (BKMR) to analyze the association of individual urinary metal concentrations and metal mixtures with hypertension risk. Urinary concentrations of 12 metals (vanadium, iron, cobalt, zinc, copper, arsenic, selenium, molybdenum, cadmium, tellurium, thallium, and lead) were higher in the hypertension group than in the non-hypertension group. In the RCS models, the urinary concentrations of vanadium, iron, and lead showed a linear dose-response relationship with hypertension risk. Quantile g-computation analyses showed cadmium contributed the largest positive weights. The BKMR models showed that the positive slope of lead became steep at higher concentrations of urinary iron when the other three metals were at the median. We found that exposure to metal mixtures was associated with the risk of hypertension and a significant positive interaction between urinary iron and lead. Further research is needed to confirm our findings and elucidate the underlying mechanisms of the interaction between metals and hypertension.

Nickel, a transition metal, is ubiquitous in the environment due to both natural processes and anthropogenic activities. While exposure to nickel has been linked to various adverse health outcomes-including genomic damage, allergic reactions, renal disorders, pulmonary fibrosis, carcinomas of the lung and nasal cavities-its cardiovascular toxicity and metabolic implications remain comparatively underexplored. Recently, a series of cross-sectional analyses utilizing data from the National Health and Nutrition Examination Survey (NHANES) have emerged, providing valuable insights into this issue. Based on the literature from PubMed, this review aims to comprehensively, but narratively summarize clinical observations and database analyses derived from human survey datasets, alongside experimental studies conducted on animal models exposed to varying doses of nickel. Current literature suggests a potential association between nickel exposure, primarily indicated by urinary nickel levels, and cardiovascular as well as metabolic disease variables; however, at low doses, inconclusive findings remain even using the same databases, mainly due to the clinical variables differently used in different studies. Experimental research has demonstrated significant toxic effects of exposure to nickel across multiple organs, including the heart and liver, which seemed significantly associated with oxidative stress and damage. Consequently, this review underscores the urgent need for further investigation utilizing both human data and experimental animal models, particularly focusing on low-level nickel exposure, to elucidate the cardiovascular and metabolic consequences of nickel exposure in humans.

Previous studies have inconclusively examined the associations of metals or polycyclic aromatic hydrocarbons (PAHs) with cardiovascular disease (CVD) separately, highlighting the need to explore their combined association with CVD. Based on the 2011-2016 National Health and Nutrition Examination Survey, the association of 12 metals and six PAHs in urine with CVD was analyzed using weighted logistic regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Crucial metals and PAHs were screened, and dose-response, subgroup, interactions, and mediation analyses were conducted. 4306 participants were included, of whom 406 had CVD. Weighted logistic regression showed that cadmium (OR = 1.41, 95% CI 1.11-1.78), tin (OR = 1.63, 95% CI 1.03-2.60), and 1-hydroxypyrene (1-PYR) (OR = 1.40, 95% CI 1.15-1.69) were positively correlated with CVD. These factors also showed a linear relation with CVD. The WQS and BKMR models indicated that the combined association of 12 metals and six PAHs was positively associated with CVD. Cadmium, cesium, tin, uranium, and 1-PYR played critical roles (all weights > 0.050). Subgroup analysis revealed that these substances were mostly positively associated with CVD in young and middle-aged people, smokers, drinkers, and those who were overweight. There was an interaction between tin and smoking status (P for interaction < 0.05). Cadmium and tin mediated 18.40% and 6.90% of the association of 1-PYR with CVD, respectively, whereas the proportions of the mediating effects of 1-PYR in the association of cadmium and tin with CVD were 8.10% and 7.90%, respectively. Overall, higher levels of urinary metals and PAHs mixtures may be associated with higher CVD prevalence. Cadmium, cesium, tin, uranium, and 1-PYR played crucial roles in this association. Cadmium and tin played mediating roles in the association between 1-PYR and CVD. Meanwhile, 1-PYR also played a mediating role in the association between cadmium and tin and CVD.

There is a lack of comprehensive research investigating the relationship between proton pump inhibitors (PPIs) and osimertinib combination therapy concerning cardiotoxicity. We conducted a retrospective analysis of adverse event reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS). In this analysis, we used patients with non-small cell lung cancer (NSCLC) who did not receive osimertinib or PPIs as a control group to assess the association between cardiotoxicity occurrence in patients receiving osimertinib with PPIs and those without PPIs. We employed disproportionality analysis along with both additive and multiplicative models. The reporting odds ratios (ROR) for cardiac events, including torsade de pointes/QT prolongation, cardiomyopathy, cardiac arrhythmias, cardiac failure, ischaemic heart disease, and embolic and thrombotic events, were significantly higher in patients using PPIs with osimertinib (14.11, 9.04-22.04; 4.67, 2.67-8.16; 4.43, 3.17-6.20; 3.67, 2.53-5.34; 2.24, 1.31-3.84; 1.92, 1.43-2.56, respectively) compared to osimertinib alone (4.87, 3.91-6.07; 2.50, 2.02-3.09; 1.59, 1.37-1.84; 2.00, 1.74-2.29; 0.65, 0.50-0.84; 1.01, 0.91-1.11). Our investigation unveiled an elevated risk of cardiotoxicity in NSCLC patients when osimertinib was combined with PPIs, compared to osimertinib monotherapy. Therefore, vigilant monitoring for cardiotoxicity is paramount in NSCLC patients undergoing these combined treatments.

Coronary reperfusion therapy is the most common surgical treatment for myocardial infarction, but it can further induce myocardial ischemia-reperfusion injury (MIRI). Therefore, MIRI following coronary intervention is a challenging clinical issue. This study aims to investigate the involvement of HIF- 1α/BNIP3-mediated mitophagy in the protective effects of Shen-fu Injection (SFI) on MIRI in rats. Key targets and signaling pathways of myocardial MIRI were analyzed using high-throughput transcriptome data from the GSE240842 dataset in the GEO database.To establish the MIRI rat model, the left anterior descending coronary artery was ligated for 30 min, followed by reperfusion for 120 min. Hypoxia/reoxygenation (H/R) in neonatal rat primary cardiomyocytes was induced by oxygen-glucose deprivation for 4 h, followed by reoxygenation for 2 h. Two hours after reperfusion, assessments included myocardial infarction area, CK-MB, CTnI, HE staining, TUNEL, mitochondrial ultrastructure and autophagosomes, HIF- 1α, BNIP3, LC3B-II, LC3B-I protein expression, immunofluorescence, and qRT-PCR. Cardiac function was also evaluated using M-mode ultrasound 2 h after reperfusion. In cardiomyocytes, CCK- 8, EdU cell proliferation levels, scratch assay, mitochondrial membrane potential, ROS levels, cardiomyocyte apoptosis, protein expression levels, and immunofluorescence were assessed 2 h after reoxygenation. Our results indicate that HIF- 1α and BNIP3 are key targets in MIRI. SFI upregulates HIF- 1α expression, promoting moderate mitophagy. This process clears excessively damaged mitochondria, reduces cardiomyocyte apoptosis, and decreases myocardial injury. Additionally, SFI reduces autophagosome accumulation, lowers ROS production, and stabilizes membrane potential. Consequently, the area of myocardial infarction is reduced, and cardiac function is improved. SFI activates the HIF- 1α/BNIP3 pathway to mediate moderate mitophagy, effectively reducing cardiomyocyte apoptosis and alleviating myocardial ischemia-reperfusion injury, thereby protecting cardiomyocytes.

SARS-CoV-2 infections directly or indirectly cause unconscionable vascular events, significantly increasing the morbidity and mortality of COVID-19. Biomarkers associated with cardiac injury often elevate in individuals with COVID-19. Cytokine storm is a mechanism underlying myocardial cell injury caused by SARS-CoV-2 infections. Cell apoptosis in AC16 cells overexpressing structural and helper proteins of SARS-CoV-2 was detected by Western blot, MTT and TUNEL assay. The M protein was determined to play the most pronounced role in inducing apoptosis. Transcriptome sequencing on AC16 cells overexpressing the M protein was performed to screen differentially expressed genes (DEGs), which were further subjected to the gene set enrichment analysis. The regulatory effect of CXCL10 on cell apoptosis of AC16 cells overexpressing M protein was finally explored. Overexpression of M protein significantly increased the Bax/Bcl-2 and cleaved caspase-3/caspase-3(CC3/C3) ratios and the percentage of TUNEL-positive cells in AC16 cells, while markedly reducing cell viability. CXCL10 was the most prominent DEG in AC16 cells overexpressing M protein. Knockdown of CXCL10 partially reversed the increases in the Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratios, the percentage of TUNEL-positive cells, as well as the release of pro-inflammatory cytokines in AC16 cells overexpressing M protein. The M protein of SARS-CoV-2 triggers the production of CXCL10 and apoptosis of myocardial cells.