Cardiovascular Toxicology最新文献

Acute heart failure is a critical and life-threatening complication that occurs during the treatment of solid tumors in children. It has a high mortality rate, poses treatment challenges, and also affects the overall prognosis of tumor treatment. Currently, there are limited clinical diagnostic and treatment data in this area. To understand the characteristics and outcomes of acute heart failure in children with solid tumors during the treatment process, share treatment experiences, and provide management strategies for monitoring, treatment, and prevention. Five representative cases of children with solid tumors were selected to summarize the clinical features, auxiliary examination data, individualized treatment plans, and treatment effects during the occurrence of acute heart failure. The possible triggers and time points for the onset of acute heart failure in children with solid tumors were analyzed, along with treatment responses and influencing factors. All five cases of children with solid tumors exhibited symptoms of acute heart failure after chemotherapy, with heart functions staging from class II to class IV. Most cases occurred during the bone marrow suppression period after chemotherapy, with a noticeable increase in heart rate during the early stages of heart failure. Those using anthracycline drugs did not reach the internationally recommended maximum cumulative dose. Two children with heart function class IV altered their tumor treatment plans to completion, and one child with heart function class IV and concurrent renal dysfunction had chemotherapy interrupted. All children received oral anti-heart failure treatment and nutritional myocardial therapy. Two children with heart function class II returned to normal after oral medication; three children with heart function class IV received intravenous vasoactive agents during the acute phase of heart failure, followed by regular reinforcement in the later stage. The heart function improved in all three cases (heart function class IV), with one case returning to normal, one case with slow recovery in non-compaction cardiomyopathy gradually approaching normalcy, and one case with only mild improvement in heart function despite concurrent renal dysfunction. Children with solid tumors are susceptible to acute heart failure during the bone marrow suppression period and an increased heart rate serves as an early warning signal. Active anti-heart failure treatment is effective. For severe cases, regular intravenous administration of vasoactive agents during the maintenance period can promote the recovery of heart function, with renal dysfunction emerging as a significant factor influencing poor recovery of heart function.

Post-myocardial infarction (MI) cardiac remodeling ultimately causes heart failure. We explored how CUG-binding protein Elav-like family member 1 (CELF1) affected post-MI cardiac remodeling. Mice underwent MI induction by left anterior descending artery (LAD) ligation and short hairpin-CELF1, overexpressing-flavin-containing monooxygenase 2 (FMO2) lentivirus and transforming growth factor-β1 (TGF-β1) treatments. Mouse cardiac fibroblasts were cultured in vitro, followed by fibrosis induction with TGF-β1. Left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricular end-systolic volume were tested by ultrasound cardiography. Heart weight/body weight was determined. CELF1 and FMO2 mRNA levels, pathologic changes, collagen deposition and myocardial fibrosis of cardiac tissues, cardiomyocyte area, myocardial apoptosis, and myocardial CELF1, FMO2, collagen I, fibronectin, and elastin levels were assessed by RT-qPCR, HE, Masson, WGA, TUNEL staining, and immunohistochemistry. CELF1-FMO2 interaction was confirmed using RNAct database and RIP assay. The biotinylated GU-rich element of FMO2 mRNA-CELF1 binding and mRNA stability were assayed by RNA pull-down and actinomycin D assays. LAD ligation induced cardiac remodeling [cardiac enlargement, myocardial tissue damage, increased myocardial collagen fiber tissues, poor cardiac function, cardiomyocyte hypertrophy, myocardial apoptosis, and extracellular matrix (ECM) deposition]. CELF1 was up-regulated in post-MI mouse myocardial tissues. CELF1 silencing up-regulated FMO2 and improved previously-mentioned conditions in MI mice, which were partially reversed by inducing ECM deposition. CELF1 down-regulated FMO2 and promoted FMO2 mRNA decay through interaction with FMO2 and FMO2 mRNA 3'UTR, respectively. FMO2 overexpression improved ECM deposition and cardiac remodeling in MI mice. CELF1 facilitates post-MI cardiac remodeling through FMO2 inhibition.

The cardiovascular and pulmonary disease risks of the use of electronic nicotine delivery systems (ENDS) are uncertain. We recently showed that ENDS solvent-derived aerosol (propylene glycol and vegetable glycerin, PG:VG) exposure induced a transient receptor potential ankyrin-1 (TRPA1)-dependent endothelial dysfunction (ED) in healthy female mice. As thermal degradation of PG:VG generates aldehydes, we hypothesized that acrolein (AC), a constituent of ENDS-derived aerosol and a known TRPA1 agonist, was responsible, in part, for the observed TRPA1-dependent pulmonary and vascular effects of PG:VG. To test this, female wild-type (WT) and TRPA1 null mice were exposed by inhalation to either filtered air or AC alone, and biomarkers of exposure and of harm were measured. Compared with their genotype-matched air control group, JUUL Virginia Tobacco (VT), PG:VG, and AC alone exposures (6 h) significantly increased urinary levels of the AC metabolite, 3-hydroxypropyl mercapturic acid (3HPMA), in both female WT and TRPA1 null mice. AC exposures at 1 and 3 ppm led to the rapid onset and reversal (upon cessation) of 'respiratory braking' in female WT but not in TRPA1 null mice indicating a TRPA1 dependence. As AC stimulated TRPA1-dependent respiratory braking, we measured urinary monoamines and their metabolites after exposure as a proxy of nervous system activation. In WT mice, AC exposure suppressed levels of dopamine, metanephrine, serotonin (5HT), and 5HT metabolite (5HIAA), whereas in TRPA1 null mice only 5HT was equally suppressed by AC. To assess vascular effects, mice were exposed for 4 days to Air or AC (6 h/day, 1 ppm), and aortic function was measured ex vivo. Although endothelial-dependent relaxation was similar in air control and AC-exposed mice, aortic sensitivity to an NO donor was enhanced significantly and equally by AC in both WT and TRPA1 null mice reflective of a TRPA1-independent and compensatory effect. Collectively, AC exposure at a level present in ENDS aerosols stimulated both TRPA1-dependent and -independent pulmonary, vascular, and systemic effects. These data suggest that ENDS use may increase cardiovascular and pulmonary disease risk, in part, via AC present in ENDS-derived aerosols yet independent of either nicotine or flavorants. The level of AC present in ENDS aerosols should be lowered to an amount where it does not induce biomarkers of vascular, pulmonary, and systemic harm to mitigate potential long-term disease risk.

Systemic inflammatory response index (SIRI), is associated with prognosis in coronary artery disease (CAD), heart failure (HF), and acute myocardial infarction. This study investigated the relationship between SIRI and non-dipper hypertension. The study retrospectively included a total of 254 naive, newly diagnosed hypertensive individuals based on ambulatory blood pressure monitoring (ABPM), containing 166 dippers (DHT) and 88 non-dippers (NDHT). The SIRI value of all patients was calculated based on neutrophil, monocyte, and lymphocyte counts. The average age of study population was 50.7 ± 9.4 years old, and the male ratio was 68.5%. Compared with DHT, patients in the NDHT group had higher SIRI, monocyte to HDL-C ratio (MHR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), and neutrophil count, while high-density lipoprotein cholesterol (HDL-C) and lymphocyte count were lower (p < 0.05). The left ventricular mass index (LVMI) was higher in the NDHT group (p < 0.05). Multivariate logistic regression analysis showed that SIRI, LVMI, and HDL-C were independent predictor factors for NDHT. ROC curve analysis determined the optimal SIRI cut-off value for predicting NDHT diagnosis to be 2.41 (sensitivity 69.3%, specificity 64.5%, area under the receiver operating characteristic curve, 0.743; p < 0.001). The AUC values obtained for SIRI, MHR, NLR, PLR, HDL-C, and LVMI parameters in the ROC curve analysis were compared pairwise. The results demonstrated that SIRI's discriminative capacity in predicting NDHT was superior to all other indices. SIRI is an independent and significant predictor factor for NDHT and is superior in predicting NDHT diagnosis compared with HDL-C, MHR, LVMI, NLR, and PLR.

Smoking, secondhand smoke exposure, and alcohol consumption are significant risk factors that contribute to an increased global burden of cardiovascular diseases. However, the casual relationship between smoking, passive smoking, alcohol consumption, and atrial fibrillation (AF) remains uncertain. Conventional observational studies are difficult to draw conclusion on high-quality causality. To elucidate the association between smoking, secondhand smoke exposure, alcohol consumption, and AF, we conducted this two-sample Mendelian randomization (MR) analysis. Smoking encompasses current tobacco smoking, ever-smoked, and light smokers, with light smokers being defined as at least 100 smokes in lifetime, as well as secondhand smoke exposure, which is characterized by workplace had a lot of cigarette smoke from other people smoking: Often. Alcohol consumption encompasses diagnoses-secondary ICD10: Z72.1 Alcohol use and the frequency of alcohol intake. Genetic variants associated with smoking and alcohol consumption were obtained from the IEU Open GWAS project and subsequently selected as instrumental variables (IVs). The corresponding variants associated with AF were also retrieved from the IEU Open GWAS project. The primary MR method utilized was the inverse-variance weighted (IVW). To assess the robustness of our results, multiple supplementary methods were utilized, including the weighted median (WM), MR-Egger regression, MR-PRESSO, MR-Egger intercept test, and the leave-one-out method. A reverse MR analysis was also conducted to determine the potential existence of reverse causality. Genetic predictions indicate a causal relationship between active smoking (current tobacco smoking, P_-val = 0.019, OR: 1.413, 95% CI = 1.058-1.888; ever smoked, P_-val = 0.049, OR: 1.355, 95% CI = 1.001-1.834; light smokers, P_-val = 0.001, OR: 1.444, 95% CI = 1.154-1.806) and AF. No causal association was found between secondhand smoke exposure, alcohol consumption phenotypes, and AF. Additionally, the reverse MR analysis did not reveal any evidence of reverse causality from AF to active smoking. This study provides MR evidence supporting a causal association between active smoking and AF. The significance of smoking cessation is underscored by its potential to prevent or mitigate the risk of AF. Furthermore, the impact of secondhand smoke exposure and alcohol consumption on AF, as well as the causality among these factors, warrants further investigation.

Macrolides are associated with cardiovascular toxicity risk. However, data on their cardiovascular toxicity profiles beyond QT prolongation are limited, and differences in the profiles among various macrolide antibiotics remain unclear. We investigated the cardiovascular toxicity profiles of different macrolides using VigiBase, a global database of individual case-safety reports. Disproportionality analysis was performed using VigiBase, the WHO Pharmacovigilance database, from 1968 to December 2023. Associations between five macrolides (erythromycin, clarithromycin, azithromycin, josamycin, and roxithromycin) and adverse events (20 cardiovascular toxicities and diarrhea as a positive control) were predicted using the reporting odds ratio. Reported outcomes were evaluated for suggested drug-adverse event associations. Among the 36,129,107 reports analyzed, azithromycin was the most commonly used macrolide, followed by erythromycin, clarithromycin, roxithromycin, and josamycin. Diarrhea was frequently reported among users. Azithromycin use was associated with hypertension, cardiac valve disorders, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, torsade de pointes/QT prolongation, cardiac conduction disorders, heart failure, and hemorrhage-related laboratory abnormalities. Erythromycin and clarithromycin use were also associated with cardiac valve disorders, ventricular tachyarrhythmias, torsade de pointes/QT prolongation, and cardiac conduction disorders. The rates of caused/prolonged hospitalization in azithromycin-related hypertension, heart failure, and bleeding-related laboratory abnormality were 46%, 45%, and 50%, respectively. Each of the macrolide antimicrobials was associated with various cardiovascular toxicities, including Cardiac valve disorder, shock, and QT prolongation. Notably, azithromycin was associated with an increased frequency of reported hypertension and heart failure, distinguishing it from the other drugs. These results highlight the importance of considering the cardiovascular toxicity profile of individual macrolide antibiotics when prescribing them.

Cancer therapy-induced cardiotoxicity remains a significant clinical challenge, limiting the efficacy of cancer treatments and impacting long-term survival and quality of life. NADPH oxidases, a family of enzymes that are able to generate reactive oxygen species (ROS), have emerged as key players in the pathogenesis of cardiotoxicity associated with various cancer therapies. This review comprehensively examines the role of NADPH oxidases in cancer therapy-induced cardiotoxicity, elucidating the underlying mechanisms and exploring potential therapeutic approaches. We discuss the structure and function of NADPH oxidases in the cardiovascular system and their involvement in cardiotoxicity induced by anthracyclines and ionizing radiation. The molecular mechanisms by which NADPH oxidase-derived ROS contribute to cardiac injury are explored, including direct oxidative damage, activation of pro-apoptotic pathways, mitochondrial dysfunction, vascular damage, inflammation, fibrosis, and others. Furthermore, we evaluate therapeutic strategies targeting NADPH oxidases, such as specific inhibitors, antioxidant therapies, natural products, and other cardioprotectors. The review also addresses current challenges in the field, including the need for isoform-specific targeting and the identification of reliable biomarkers. Finally, we highlight future research directions aimed at mitigating NADPH oxidase-mediated cardiotoxicity and alleviating cardiovascular side effects in cancer survivors. By synthesizing current knowledge and identifying knowledge gaps, this review provides a rationale for future studies and the development of novel cardioprotective strategies in cancer therapy.

Cardiotoxicity, a severe side effect of cytotoxic drugs like doxorubicin (DOX), can lead to cardiomyopathy and heart failure, significantly impacting patient prognosis. This study investigates the molecular mechanisms of DOX-induced cardiotoxicity and explores isoquercitrin (IQC) as a potential therapeutic agent. RNA-sequencing analysis revealed 7855 dysregulated genes in DOX vs. Control and 3853 in DOX + IQC vs. DOX groups. Functional enrichment analysis of upregulated genes in the DOX vs. Control group highlighted cytokine-cytokine receptor interaction and calcium signaling pathways as significant immune-related KEGG pathways. Immune genes were shortlisted based on inflammatory functions, followed by protein-protein interaction analysis and hub gene identification. This process revealed IL6, IL1B, IL10, CCL19, CD27, CSF1R, ADRB2, GDF15, TNFRSF10B, and PADI4 as the top 10 interacting immune hub genes. Validation in the DOX + IQC vs. DOX group showed that IQC downregulated CCL19, IL10, PADI4, and CSF1R genes. Computational drug design techniques, including virtual screening and molecular dynamic simulations, identified promising targets for IQC. These targets were experimentally validated using RT-qPCR in AC16 cell lines under four conditions: control, DOX, low dose DOX + IQC, and high dose DOX + IQC. The study demonstrates that IQC significantly reduces inflammation and oxidative stress in human AC16 cardiomyocyte cell line by downregulating inflammatory and stress pathways induced by DOX. It concludes that CCL19 and PADI4 are crucial immune biomarkers for treating DOX-induced cardiotoxicity using IQC, providing insights into potential therapeutic strategies using plant-based compounds to mitigate the cardiotoxic effects of DOX in cancer treatment.

Ring finger protein 146 (RNF146) participates in regulating ferroptosis and ferroptosis is involved in myocardial ischemia/reperfusion injury (MI/RI). However, the effects and mechanisms of RNF146 in MI/RI are still unclear. TTC, H&E, IHC, DHE stainings, and echocardiography technology were used to determine the myocardial infarction area, pathological injury, level of RNF146, ROS, and cardiac function parameters, respectively. CCK-8 was employed to determine the cell viability. The corresponding kits, RT-qPCR, and western blot were adopted to determine the levels of CK-MB, LDH, Fe²⁺, MDA, ROS, gene expression levels of RNF146 and death-associated protein kinase 1 (DAPK1), protein expression levels of RNF146, DAPK1, GPX4, FTH1, and ACSL4. Co-immunoprecipitation, cycloheximide tracking, and ubiquitination assays to investigate the relationship between RNF146 and DAPK1. Ferroptosis occurred in mice with MI/RI and inhibiting ferroptosis could alleviate MI/RI. Moreover, the expression of RNF146 is down-regulated in MI/RI, and overexpression of RNF146 can inhibit H/R-induced ferroptosis of cardiomyocytes. Mechanistically, RNF146 promotes ubiquitination and degradation of DAPK1. In addition, the effects of overexpressed RNF146 in alleviating MI/RI were effectively reversed by overexpressing DAPK1. This study demonstrated that RNF146 alleviates MI/RI by facilitating the ubiquitylation-mediated degradation of DAPK1 to reduce ferroptosis.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for efficient and cost-effective treatments to decrease the risk of CVD. The sigma-1 receptor (S1R) plays a role in the development of cardiac hypertrophy, heart failure, ventricular remodeling, and various other cardiac diseases. Preclinical studies have shown that S1R activation has considerable beneficial effects on the cardiovascular system, and this knowledge might contribute to informing clinical trials associated with the prevention and treatment of CVDs. Therefore, the objective of this review was to investigate the mechanisms of S1R in CVD and how modulation of pathways contributes to cardiovascular protection to facilitate the development of new therapeutic agents targeting the cardiovascular system.