Cardiovascular Toxicology最新文献

Peripheral arterial disease (PAD) is becoming more prevalent in the aging developed world and can have significant functional impacts on patients. There is a recent recognition that environmental toxicants such as circulating metals and metalloids may contribute to the pathogenesis of atherosclerotic disease, but the mechanisms are complex. While the broad toxic biologic effects of metals in human systems have been extensively reviewed, the role of non-essential exposure and essential metal aberrancy in PAD specifically is less frequently discussed. This review of the literature describes current scientific knowledge regarding the individual roles several major metals and metalloids play in atherogenesis and highlights areas where a dearth of data exist. The roles of lead (Pb), arsenic (As), cadmium (Cd), iron (Fe), copper (Cu), selenium (Se) are included. Contemporary outcomes of therapeutic trials aimed at chelation therapy of circulating metals to impact cardiovascular outcomes are also discussed. This review highlights the supported notion of differential metal presence within peripheral plaques themselves, although distinguishing their roles within these plaques requires further illumination.

Despite advances in anti-atherosclerotic therapies, residual risk persists in coronary artery disease (CAD). The uric acid to high-density lipoprotein cholesterol ratio (UHR), a metabolic-inflammatory marker, may predict residual risk, but its association with plaque progression remains unexplored. This study investigates the impact of UHR on atherosclerotic plaque burden in CAD patients after treatment. In this prospective cohort study, 118 patients with newly diagnosed CAD undergoing percutaneous coronary intervention were stratified into quartiles by baseline UHR. Intravascular ultrasound assessed plaque burden and characteristics at baseline and 12-month follow-up. Logistic regression and restricted cubic spline models evaluated associations between UHR and plaque progression, adjusting for cardiovascular risk factors. At baseline, the highest UHR quartile (UHR-4) exhibited higher rates of plaque rupture (19.6% vs. 0-8.7%, P = 0.002) and microchannels (56.5% vs. 33.3-55.3%, P = 0.031) compared to lower quartiles. Baseline percent atheroma volume (PAV) was greater in UHR-4 (52.73% vs. 51.04-52.09%, P = 0.006). At follow-up, UHR-4 had a 3.2-fold increased risk of plaque burden > 70% (adjusted RR 3.237, 95% CI 1.156-9.063, P = 0.025), with a linear UHR-plaque burden relationship (P = 0.015). No associations were observed between UHR and minimal lumen area or positive remodeling. Elevated UHR is independently associated with high atherosclerotic plaque burden (> 70%) in CAD patients under guideline-directed therapy after adjusting for traditional risk factors. UHR may serve as a complementary biomarker to existing risk scores, guiding targeted therapies to mitigate plaque vulnerability.

Atherosclerosis is a multifactorial disease influenced by genetic and lifestyle factors (e.g., smoking). The rs1799963 G/A polymorphism in the prothrombin (F2) gene is associated with thrombosis and cardiovascular diseases. However, the interaction between this genetic variant and smoking on the risk of atherosclerosis has not been thoroughly investigated. This study aims to explore the impact of rs1799963 polymorphism-smoking interaction on the risk of atherosclerosis. For this, control (n = 40) and angiographically confirmed atherosclerotic patients (n = 82) were recruited from District Sargodha, Pakistan. All subjects were genotyped for rs1799963 G/A variants by in-house developed tri-ARMS-PCR assay. Statistical analysis was performed to evaluate the interaction between rs1799963 polymorphism and smoking in relation to atherosclerosis risk. Risk of atherosclerosis was increased by the individual effects of F2 rs1799963 G allele [OR 2.96 (95% CI:1.8-8.08) p = 0.034] and smoking [OR 3.9 (95% CI:1.4-10.8) p = 0.008]. Subjects harboring rs1799963 G allele and who were active smokers had ~ 20 times higher risk of atherosclerosis. Synergy index indicated that combined effect of smoking and rs1799963 G allele was higher than their individual effects, which had a positive interaction with atherosclerosis [synergy index = 2.125 (95% CI: 1.66-2.59)]. These findings suggest a strong interaction between F2 rs1799963 polymorphism and smoking for atherosclerosis. The presence of rs1799963 G allele in conjunction with active smoking status greatly increases the risk of atherosclerosis.

As COVID-19 transitions to an endemic stage, its long-term impacts on health, particularly cardiovascular disease (CVD), remain significant. While prior studies have focused on cardiovascular complications following SARS-CoV-2 infection, the question of inherent cardiovascular risk associated with genetic predisposition to COVID-19 has been less explored. This study investigates whether individuals genetically predisposed to COVID-19 may also be at higher risk for CVD, independent of actual infection. Using Mendelian randomization (MR) analysis with data from pre-pandemic, SARS-CoV-2-naive populations, this study assessed the impact of genetic susceptibility to COVID-19 on various CVD outcomes across 18 distinct cohorts. This approach allowed us to simulate COVID-19 predisposition without infection, providing insights into cardiovascular risks associated solely with genetic susceptibility. These findings reveal a significant association between genetic predisposition to COVID-19 and elevated risks for several CVD outcomes, particularly hypertensive heart disease. Notably, individuals with a genetic profile linked to severe COVID-19 (hospitalization-prone) showed a marked increase in risk for hypertensive heart disease. These findings suggest a shared genetic architecture that predisposes individuals to both COVID-19 and cardiovascular risks, irrespective of viral exposure. COVID-19 susceptibility, thus, may act as a "natural stress test," revealing latent cardiovascular vulnerabilities. This connection implies that individuals predisposed to severe COVID-19 may have inherently higher cardiovascular risks, even without SARS-CoV-2 infection. This study highlights the value of COVID-19 susceptibility as a novel marker for assessing CVD risk, enabling timely preventive strategies and mitigating future CVD burden in the post-COVID-19 era. Moreover, this study highlights disease predisposition as a "black box" until clinical onset. While COVID-19 demands an external viral trigger for acute onset, cardiovascular disease unfolds much more slowly, requiring prolonged exposure to detrimental lifestyle and genetic factors. Together, their intersection illustrates how acute environmental triggers and chronic disease processes can converge to influence overall health outcomes.

Ferroptosis is involved in the pathogenesis of diabetic cardiomyopathy (DCM). It has been shown that miR214-3p regulates ferroptosis, but no studies have shown a relationship between miR214-3p and DCM. This study induced glucolipotoxicity cardiomyocytes by treating HL-1 with high glucose and palmitic acid. Under these conditions, intracellular proteins TfR1 and FTH1, involved in Fe²⁺ transport and storage, were significantly elevated, and intracellular Fe²⁺ deposition was increased. The expression of GPX4, a key antioxidant molecule in ferroptosis, was reduced considerably, and the expression of lipid peroxidation-related proteins ACSL4 and COX2 was significantly elevated, with increased intracellular lipid peroxidation. Glucolipotoxicity cardiomyocytes overexpressing miR214-3p showed reduced expression levels of intracellular iron metabolism-related proteins, decreased Fe²⁺ deposition, elevated GPX4 expression, markedly down-regulated expression of ACSL4 and COX2, and reduced intracellular lipid peroxidation. In contrast, glucolipotoxicity cardiomyocytes with knockdown of miR214-3p showed more severe Fe²⁺ deposition and lipid peroxidation. In vivo, DCM mice showed significant cardiac function reduction and myocardial fibrosis. Consistent with the in vitro experiments, the expression level of GPX4 in myocardial tissues of DCM mice was reduced, and the expression of FTH1, ACSL4, and COX2 was significantly elevated. In contrast, DCM mice treated with miR214-3p showed improved cardiac function and alleviated myocardial fibrosis, with up-regulated GPX4 protein expression levels and significantly suppressed FTH1, ACSL4, and COX2 expression. These findings revealed that miR214-3p inhibits ferroptosis to improve DCM.

In recent years, the cardioprotective effects of the volatile anesthetic sevoflurane (SEV) have been confirmed, yet its underlying molecular mechanisms remain incompletely elucidated. Notably, lncRNA LINC00265 has been identified as dysregulated in damaged cardiomyocytes, potentially contributing to disease progression. However, limited research has focused on the interplay between SEV and lncRNA LINC00265. The main objective of this study was to explore the mechanism and role of lncRNA LINC00265 in mediating the cardioprotective effects of SEV against myocardial injury. An in vitro hypoxia/reoxygenation (H/R) model was created in AC16 cells following pretreatment with varying concentrations of SEV. RT-qPCR was used to evaluate the levels of lncRNA LINC00265, miR-370-3p, IL-6, and TNF-α. The concentrations of CK-MB and cTnI were determined using ELISA. Cell viability was evaluated using CCK-8, and apoptosis was quantified by flow cytometry. Additionally, the relationship between lncRNA LINC00265 and miR-370-3p was confirmed using a dual-luciferase reporter assay. Prolonged hypoxia gradually rose in lncRNA LINC00265 levels, which was reversed by SEV pretreatment. SEV pretreatment mitigated H/R-induced decreases in cell viability, increases in apoptosis, and excessive production of IL-6, TNF-α, CK-MB, and cTnI. However, the protective effects of SEV were counteracted by lncRNA LINC00265 overexpression. A negative regulatory relationship between lncRNA LINC00265 and miR-370-3p was discovered. miR-370-3p overexpression mitigated diminished protective effects of SEV by elevated lncRNA LINC00265 in myocardial injury. lncRNA LINC00265 could diminish the protective effects of SEV against myocardial injury by functioning as a sponge for miR-370-3p.

Heart failure (HF) is a clinical syndrome resulting from cardiac overload and injury. The molecular mechanisms underlying ischemic HF remain unclear. Using the GSE116250 and GSE203160 datasets, we screened for differentially expressed genes (DEGs) in ischemic HF, identifying 132 overlapping genes. Through the protein-protein interaction (PPI) network, we screened nine hub genes-SPP1, POSTN, CCN2, FGF7, OGN, BMP2, LUM, TGFB2, and BMP7-that may serve as diagnostic biomarkers for HF. FGF7 and BMP7 expression levels were reduced, while TGFB2, OGN, and CCN2 expression levels were elevated in rat models of left anterior descending coronary artery ligation. Notably, Cell Counting Kit-8 and flow cytometry showed that TGFB2 knockdown promoted viability and inhibited apoptosis in oxygen glucose deprivation-induced H9c2 cells. Western blot analysis further demonstrated that TGFB2 knockdown decreased cleaved Caspase-3/Caspase-3 and Bax protein levels while increasing Bcl-2 protein expression. These findings reveal that TGFB2 knockdown mitigates ischemic HF by suppressing apoptosis, offering novel insights into the fundamental molecular mechanisms underlying HF.

Immune checkpoint inhibitors (ICIs) have demonstrated favorable outcomes in various cancers. However, it has been observed that ICIs may induce life-threatening cardiovascular toxicity. In this study, a meta-analysis was conducted to determine the risk of cardiovascular toxicities in patients exposed to ICIs or in combination with chemotherapy. PubMed, Cochrane Library, and Embase databases were searched from inception to September 24, 2023. This study was conducted in accordance with the PRISMA guidelines. A meta-analysis was conducted on the risk of cardiotoxicity in cancer patients. Data were pooled with a random-effect model. This protocol was registered prospectively in PROSPERO (CRD42023467319). The primary outcome was cardiotoxicity risk in observational studies with ICIs or combined with chemotherapy. The risk factors that affected the occurrence of cardiovascular toxicities were also examined. ICIs or combined with chemotherapy increased the cardiotoxicity risk compared with mono-chemotherapy (OR 1.47; 95% CI 1.05-2.06, p = 0.024). The risk of pericardial disease in cardiotoxic events (OR 1.99; 95% CI 1.23-3.22, p = 0.005) and thromboembolic events (OR 1.34; 95% CI 1.04-1.72, p = 0.025) was significantly increased. Smoking (OR 1.25; 95% CI 1.12-1.39, p < 0.001), previous heart disease (OR 2.01; 95% CI 1.64-2.46, p < 0.001), and lung cancer (OR 1.46; 95% CI 1.26-1.69, p < 0.001) were risk factors worthy of attention. ICIs or combined with chemotherapy show an elevated risk of cardiovascular toxicities. Patients who are smoking, diagnosed lung cancer, and having prior medical history of heart diseases need more attention.

Particulate matter containing environmentally persistent free radicals (EPFRs) is formed when organic pollutants are incompletely burned and adsorb to the surface of particles containing redox-active metals. Our prior studies showed that in mice, EPFR inhalation impaired vascular relaxation in a dose- and endothelium-dependent manner. We also observed that activation of the aryl hydrocarbon receptor (AhR) in the alveolar type-II (AT-II) cells that form the air-blood interface stimulates the release of systemic factors that promote endothelial dysfunction in vessels peripheral to the lung. AhR is a recognized regulator of microRNA (miRNA) biogenesis, and miRNA control diverse signaling pathways. We thus hypothesized that systemic EPFR-induced vascular endothelial dysfunction is initiated via AhR activation in AT-II cells, resulting in a systemic release of miRNA. Using a combustion reactor, we generated EPFR of two free radical concentrations-EPFR_lo (10^16-17 radicals/g particles) and EPFR (10^18-19 radicals/g)-and exposed mice by inhalation. EFPR inhalation resulted in changes in a distinct array of miRNA in the plasma, and these miRNAs are linked to multiple systemic effects, including cardiovascular diseases and dysregulation of cellular and molecular pathways associated with cardiovascular dysfunction. We identified 17 miRNA in plasma that were altered dependent upon both AhR activation in AT-II cells and ~ 280 ug/m³ EPFR exposure. Using Ingenuity Pathway Analysis, we found that 5 of these miRNAs have roles in modulating endothelin-1 and endothelial nitric oxide signaling, known regulators of endothelial function. Furthermore, EPFR exposure reduced the expression of lung adherens and gap junction proteins in control mice but not AT-II-AhR deficient mice, and reductions in barrier function may facilitate miRNA release from the lungs. In summary, our findings support that miRNA may be systemic mediators promoting endothelial dysfunction mediated via EPFR-induced AhR activation at the air-blood interface.

It is widely accepted that cardiac resynchronization therapy (CRT) implantation has anti-arrhythmias effect, though few studies observed a pro-arrhythmias effect in non-responders. Left ventricular reverse remodeling (LVRR) is associated with the inhibitory effect of CRT on ventricular arrhythmias (VAs). Cardiac fibrosis is an important factor that influences LVRR. This study aimed to determine the effects of CRT on VAs, LVRR and cardiac fibrosis, and uncover the underlying mechanism. Eleven dogs underwent rapid right ventricular pacing (RVP) for 4 weeks to develop heart failure, and then were randomly divided into a RVP group (n = 5; RVP for another 4 weeks) and a CRT group (n = 6; biventricular pacing for 4 weeks). Another five dogs were in the control group. Compared with the RVP group, CRT prevented the deterioration in systolic dysfunction and cardiac fibrosis. Ventricular fibrillation threshold was decreased by RVP, which was reversed by CRT, indicating an anti-arrhythmic effect of CRT. Proteomics analysis of myocardia from the dogs showed significant alterations in fibrosis-related signaling pathways by CRT. Metabolomics analysis revealed a metabolic reprogramming of the failure heart conferred by CRT. Integrated analysis of the proteomics and metabolomics identified eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) as the key mediator of CRT. 4EBP1 was downregulated in myocardia from the dogs in the RVP group, which was rescued by CRT. Moreover, overexpression of 4EBP1 diminished transform growth factor (TGF)-β1-induced human CFBs proliferation and synthesis of collagens. CRT regulates fibrosis-related signaling pathways and induces metabolic reprogramming to against cardiac fibrosis and subsequent VAs, potentially through the upregulation of 4EBP1.