Cardiovascular Toxicology最新文献

Anthracyclines are effective antineoplastic drugs; however, their use is constrained by dose-dependent cardiotoxicity. Vascular endothelial dysfunction is an early independent event in cardiovascular diseases and may precede anthracycline-induced cardiotoxicity. Brachial flow-mediated dilation (FMD) is a non-invasive technique for evaluating vascular endothelial function. We evaluated the evidence on anthracycline-induced vascular endothelial dysfunction in cancer patients and survivors using FMD. Studies measuring FMD in anthracycline-treated active cancer patients or survivors were retrieved from inception to August 2024 using PubMed, Embase, and Scopus. The primary outcome was the difference in FMD between anthracycline-treated patients and healthy controls or baseline. We performed the meta-analysis using a random-effects model and evaluated the certainty in effect estimates. Overall, 18 studies (n = 841 patients) met the inclusion criteria. Compared to the baseline, a non-significant change toward a decline in FMD was observed. However, a significant reduction in FMD was observed in anthracycline-treated patients compared to healthy controls (standardized mean difference (SMD): - 0.6082; 95% CI: - 0.8963 to - 0.3201; p < 0.0001). Subgroup analyses revealed consistent significant reductions in FMD for childhood cancers (SMD: - 0.7189; 95% CI: - 0.9903 to - 0.4476; p < 0.0001), while adult cancers showed no significant difference. No significant publication bias was detected overall for healthy control comparisons. High heterogeneity was observed in the included studies (I² = 81.7808% versus healthy controls and I² = 75.6876% for childhood cancers subgroup analysis). Anthracyclines induce vascular endothelial dysfunction, indicated by lower FMD in cancer patients and survivors, particularly among those with childhood cancers, who might be at risk of long-term cardiovascular complications.

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.

The association between low serum testosterone levels and all-cause mortality in male and female patients with cardiovascular disease (CVD) was investigated. This study extracted data on CVD patients from the National Health and Nutrition Examination Survey (NHANES) database (1999-2000, 2003-2004, 2011-2012, and 2013-2014). The association between low serum testosterone levels (≤ 300 ng/dL) and all-cause mortality in male and female CVD patients was evaluated using univariate and multivariate Cox regression analyses, with hazard ratios (HR) and 95% confidence intervals (CI). A total of 1,177 participants (689 males) with a mean age of 66.01 ± 12.52 years were included in the study. The median follow-up time was 55 (44, 71) months. Low serum testosterone levels occurred in 487 (70.68%) males and 394 (80.74%) females. Additionally, 202 (29.32%) male patients and 94 (19.26%) female patients with CVD were dead. After adjusting for covariates, low serum testosterone levels were associated with an increased risk of all-cause mortality in male CVD patients (HR = 1.48, 95% CI 1.08-2.02, P = 0.013), while the association was not significant in females. Low serum testosterone levels may be associated with an increased risk of all-cause mortality in male CVD patients, but not in female patients.

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.

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.

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.

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.

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.

This study evaluated the occurrence of apatinib-induced hypertension and its impact on the prognosis of patients with solid tumors. A retrospective cohort study with prospective follow-up was conducted on 769 patients treated with apatinib from 2014 to 2021 across three hospitals. Patients were categorized into hypertension and non-hypertension groups. The primary outcome was overall survival (OS), with progression-free survival (PFS) as a secondary outcome. Apatinib-induced hypertension occurred in 33.3% of patients and was associated with significantly longer OS (HR 0.40, 95% CI [0.37-0.48], p < 0.0001) and PFS (HR 0.41, 95% CI [0.35-0.49], p < 0.001). Subgroup analysis confirmed these findings in all cancer types, except for PFS in non-small cell lung cancer. Hypertension may serve as a predictive biomarker for improved anti-tumor efficacy.

Heavy metals were toxic environmental pollutants capable of entering the human body, posing significant risks to human health. Life's Essential 8 (LE8) score is a new comprehensive index constructed for quantifying cardiovascular health (CVH). However, the association between heavy metals mixtures and LE8 appears ambiguous. To investigated the association between heavy metals and cardiovascular health in US population. Urinary heavy metals concentrations (barium, cadmium, cobalt, manganese, molybdenum, lead, antimony, strontium, thallium, tin, tungsten, uranium, cesium) were Ln-transformed and LE8 was consisted of eight metrics. Single and multivariate linear regression, weighted quantile sum (WQS) and Bayesian kernel machine regression models (BKMR) were utilized to assess the association between single and mixed exposure of thirteen heavy metals concentrations and LE8. In 4339 participants from National Health and Nutrition Examination Survey 2007-2018, single urinary heavy metals barium, cadmium, cobalt, lead, antimony, strontium, tin, tungsten, uranium and cesium showed a significant negative association with LE8. WQS models showed heavy metals mixture was negatively associated with LE8 (β = - 2.720, 95% CI - 3.660, - 1.790). BKMR analysis also demonstrated a downward trend of heavy metals mixture and LE8. Both WQS analyzed weights and the conditional posterior inclusion probabilities (condPIP) of BKMR showed that cadmium (37.78%, condPIP = 1.000), barium (24.56%, condPIP = 0.537) and uranium (14.71%, condPIP = 0.646) contributed most for these negative associations. Single and mixed heavy metals, especially cadmium, barium and uranium were negatively associated with LE8 score, a new comprehensive CVH index, predicting an increasing risk of cardiovascular diseases.