Cardiovascular Toxicology最新文献

Cadmium (Cd), a widespread environmental contaminant, induces cardiotoxicity even at low doses through endocrine disruption and oxidative stress. This investigation assessed age-related susceptibility in female albino rats by comparing pre-pubertal (30-day-old) and post-pubertal (60-day-old) animals that were administered CdCl₂ at a dosage of 5.12 mg/kg body weight per day via oral gavage for 15 days. Despite greater Cd accumulation in pre-pubertal rats, post-pubertal animals exhibited heightened cardiac injury. This paradox correlated with impaired induction of metallothionein (MT), enhanced glutathione and vitamin C depletion, and reduced enzymic antioxidants (SOD, CAT, GPx). Concomitantly, altered adrenal function with increased corticosterone (CORT) and reduced estradiol (E2) reflected differential hypothalamic-pituitary-adrenal (HPA) axis responsiveness, further compromising antioxidant defenses. Biomarkers of cardiac function confirmed this vulnerability: increased serum CK-MB and troponin I, electrocardiographic (ECG) abnormalities (ST elevation, QT prolongation, tachycardia), and larger infarct volume. Collectively, these findings demonstrate that post-pubertal susceptibility is driven by reduced MT inducibility and HPA axis-mediated endocrine dysregulation, which amplify oxidative injury and structural remodeling of ventricular myocardium. From a translational standpoint, our findings identify adolescence and early adulthood as critical windows during which females exhibit heightened vulnerability to environmental CdCl₂ exposure. Variations in metallothionein (MT) expression capacity and estradiol levels may serve as informative biomarkers for predicting individual susceptibility. These results also suggest the potential value of targeted interventions such as MT induction, antioxidant therapy, or modulation of hormonal pathways, that merit further investigation. Collectively, the study emphasizes the urgent need for stricter regulation of cadmium exposure, particularly among peripubertal populations, to reduce lifelong cardiovascular risk.

High-density lipoproteins (HDLs) are endogenous nanoparticles critical for cholesterol transport, vascular protection, and immune modulation. Cardiovascular disease (CVD) often induces dysfunctional HDL, driving the emergence of HDL-mimicking nanoparticles (HMNPs)-engineered particles aiming to restore or enhance biological functions. This review details advances in HMNP design, including theranostic platforms and computational engineering, focusing on recent preclinical and clinical results. Key translational barriers such as manufacturing scale, regulatory complexity, population variability, and imaging agent toxicity are discussed, along with future opportunities in multi-target nanoplatforms and computational optimization. HMNPs show promise for advancing cardiovascular care by combining therapeutic and imaging capabilities, offering new hope for heart disease; however, further research is needed to overcome technical and clinical challenges and validate their real-world impact.

Considering the global prevalence of diabetes, diabetic cardiomyopathy (DCM), as a significant diabetes complication, remains a major human challenge; while previous studies have identified ferroptosis as an important underlying mechanism, the unclear regulatory mechanisms hamper the development of therapy for DCM. In this study, we reveal that the expression of the fat mass and obesity-associated protein (FTO) is downregulated in DCM. Overexpression of FTO was found to enhance cardiac function by inhibiting ferroptosis. Mechanistically, acyl - CoA synthetase long - chain family 4 (ACSL4), a key positive mediator of ferroptosis, was identified as a direct target of FTO. The ameliorative effect of FTO was contingent upon the inhibition of ACSL4, and FTO-mediated mitigation of ferroptosis occurs in an ACSL4-dependent manner in DCM. Furthermore, we demonstrate that nicotinamide mononucleotide and sulforaphane can synergistically suppress ferroptosis by targeting distinct pathways, thereby better alleviating cardiac dysfunction. Collectively, our findings uncover an FTO - ACSL4 regulatory axis that plays a crucial role in the pathogenesis of DCM, offering valuable insights for the development of therapeutic strategies against DCM.

Cardiac lymphatics are vital for maintaining tissue-fluid homeostasis and regulating immune response in the heart. Research in recent decades has implicated impaired lymphangiogenesis in the pathophysiology of heart failure following myocardial injury, where it contributes to myocardial oedema, persistent inflammation, and subsequent adverse cardiac remodeling. Growing insight into the molecular aspects of lymphangiogenesis in recent years has opened promising avenues for therapeutic targeting in treating heart failure following myocardial infarction. However, fully harnessing this therapeutic potential requires a deeper understanding of the interactions between the lymphatics and the surrounding microenvironment. Here, we examine how the biology of cardiac lymphatic vasculature offers mechanistic insights for therapeutic targeting in heart failure. In particular, we discuss the mechanism of action underlying the development of cardiac lymphatic vessels. Furthermore, we present an updated synthesis of key signaling pathways, molecular mechanisms, and cellular interactions involved in the intricate cross-talk among cardiac lymphatic endothelial cells, immune cells, and the cardiac extracellular matrix. Overall, we aim to provide a comprehensive framework reflecting current perspectives on how cardiac lymphatic formation is regulated.

Anthracycline-induced cardiotoxicity poses a threat to the long-term heart health of childhood cancer survivors; however, early risk assessment remains challenging due to limited predictive tools. While risk prediction models have been developed for chemotherapy-related hematological toxicity in pediatric cancer patients, research efforts addressing anthracycline-induced cardiotoxicity in this population remain limited. To fill this gap, we conducted a pilot study to develop a risk prediction model for anthracycline-induced cardiotoxicity in children. Using a paired-sample design, we analyzed data collected throughout treatment from 18 children receiving anthracycline-based chemotherapy. Patient demographics, clinical features, and treatment regimen served as input (explanatory) variables, while plasma concentration of high-sensitivity cardiac troponin T was used as the outcome (response), representing anthracycline-induced myocardial injury. Of the initial 33 potential variables, the top 18 were selected based on their importance scores in relation to myocardial injury. This set was further refined to 13 by removing redundancies using the caret package in R to develop a preliminary logistic regression model. A Leave-One-Patient-Out Cross-Validation identified four key predictors for the final model: sex, age at diagnosis, total cyclophosphamide dose (mg), and days since the first anthracycline dose. All were significantly associated with myocardial injury. The final logistic regression model achieved an accuracy of 85%, a sensitivity of 80%, a specificity of 88%, an area under the curve of 0.89, and a Youden's index of 0.68 for predicting myocardial injury risk. These preliminary findings suggest the potential of our predictive model to stratify risk of anthracycline-induced myocardial injury in the pediatric population.

The gut microbiota-derived metabolite phenylacetylglutamine (PAGln) was associated with adverse events in patients with ST-segment elevation myocardial infarction (STEMI). However, the evidence regarding the association between PAGln and culprit plaque characteristics was limited. Here, we aim to investigate the associations between plasma PAGln and culprit plaque characteristics evaluated by optical coherence tomography (OCT) in patients with STEMI. The associations of PAGln level with culprit plaque characteristics were assessed with logistic regression model in 776 patients imaged by OCT at the time of primary percutaneous coronary intervention. The role of PAGln in plaque stability was investigated by bioinformation analysis. Patients in the high plasma PAGln group had a higher prevalence of culprit thin-cap fibroatheromas (TCFA) (37.4 vs. 30.5%, p = 0.001) and CLIMA-defined high risk plaque (37.1 vs. 30.2%, p = 0.001) compared with those in the low PAGln group. In the multivariate logistic analysis, elevated PAGln level remained independently (traditional risk factors) associated with TCFA (OR 1.95, 95% CI 1.29-2.95, p = 0.001) and CLIMA-defined high risk plaque (OR 1.99, 95% CI 1.31-3.02, p = 0.001). Single-cell RNA sequencing results suggested that PAGln-targeted ACE, MME, MMP9 genes enrich macrophages and may be involved in plaque stability in STEMI patients. This study first revealed that PAGln concentrations were significantly associated with the vulnerable plaque independently, and macrophages may be involved in this process.

Knowledge of the proarrhythmic risk of anlotinib among advanced lung cancer (ALC) patients remains lacking. This study was conducted to clarify the characteristics and predictors of new-onset arrhythmias (NOA) and the impact on ALC outcomes after anlotinib treatment. This retrospective study enrolled ALC patients undergoing anlotinib treatment (May 2017-November 2021). NOA was identified using electrograms or Holters, including supraventricular arrhythmias (SVA), QT prolongation (QTP), conduction disorders, and premature contractions. Grades of NOA events were determined with the Common Terminology Criteria for AEs. The predictors of NOA were identified via logistic regression. The Kaplan-Meier method was used to evaluate overall survival. Of 922 eligible patients, NOA occurred in 208 (22.6%), including QTP (n = 120, 57.7%), SVA (n = 16, 7.7%), conduction disorders (n = 49, 23.6%), and premature contractions (n = 59, 28.4%). Grade 3 NOA comprised only QTP. 85.1% NOA events occurred within five months after anlotinib treatment and the median onset time of NOA was 61.9 days (IQR 30.0-120.8). NOA incidence was higher after combined therapy than anlotinib monotherapy (29.9% vs. 10.9%, P < 0.001). The independent predictors of NOA included age, diabetes, and concomitant PD-1 inhibitors and platinum-based agents. NOA had little impact on patients' overall survival. With a non-negligible occurrence, the impact of NOA after anlotinib administration on patients' outcome seemed benign. Age, diabetes, concomitant PD-1 inhibitors and platinum-based agents were independent predictors of NOA. NOA incidence increased with concomitant anti-cancer agents prescription.