Cardiovascular Toxicology最新文献

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.

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.

The impact of lead and cadmium exposure on subclinical cardiovascular disease (CVD), indicated by elevated high-sensitivity cardiac troponin (hs-cTnT) and N-terminal pro b-type natriuretic peptide (NT-proBNP) remains uncertain. We analyzed data from participants aged 20 and older, without overt CVD, in the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Elevated lead and cadmium levels were defined as 3.5 μg/dL and 1.0 μg/L (inductively coupled plasma mass spectrometry) and 3.8 μg/dL and 0.9 μg/L (atomic absorption spectrometry), respectively. Elevated hs-cTnT was ≥ 19 ng/L, and elevated NT-proBNP was ≥ 125 pg/mL. Multivariate logistic regression estimated the odds ratios (OR) and 95% confidence intervals (CI) for elevated biomarkers. Among 10,197 participants (mean age 48.8 years; 50.3% female), 5.3% had elevated hs-cTnT and 19.4% had elevated NT-proBNP. Elevated blood lead was associated with increased ORs for elevated hs-cTnT (OR 1.45, 95% CI 1.15-1.84) and NT-proBNP (OR 1.66, 95% CI 1.40-1.97). The corresponding ORs (95% CI) for elevated blood cadmium were 1.33 (1.02, 1.74) and 1.39 (1.18, 1.65). The effect of elevated blood lead on NT-proBNP was particularly pronounced among non-Hispanic Blacks (OR [95% CI], 3.26 [2.24, 4.74]) compared to Mexican Americans (1.46 [0.99, 2.17]) and non-Hispanic Whites (1.31 [1.02, 1.68]) and was stronger in individuals with impaired kidney function (OR [95% CI], 2.31 [1.43, 3.75]) compared to those with normal kidney function (1.44 [1.18, 1.75]). This study first reveals the association between lead and cadmium exposure and subclinical CVD, underscoring the need for targeted preventive measures to reduce cardiovascular risk and improve health outcomes.

With the increasing of PI3K/AKT/mTOR (PAM) inhibitors in cancer therapy, there is a growing need to understand the incidence of cardiovascular events (CVAEs) associated with PAM inhibitors. A systematic search of all randomized clinical trials (RCTs) containing at least one PAM group in electronic databases such as PubMed, ClinicalTrials.gov registry, Embase, Medline, Cochrane Library, and major conferences was performed to extract available CVAEs. The cut-off date was January 31, 2024. Study heterogeneity was assessed using the I² statistic. The risk of CVAEs associated with PAM inhibitors was calculated using Peto OR. The primary outcome was the incidence (95% CI) of PAM inhibitors cardiovascular adverse events in the total population and subgroups. The secondary outcome was the pooled risk of different CVAEs associated with PAM inhibitor exposure in the RCTs. 33 unique RCTs (n = 12,351) were included. The incidence of PAM inhibitors CVAEs of any grade in the intervention group was 48.2%, yielding a combined OR of 2.52 (95% CI 1.82-3.49). The incidence of severe adverse cardiovascular events (≥ grade 3) in the intervention group was estimated at 7.1%, yielding a combined Peto OR of 1.41 (95% CI 1.04-1.93). PAM inhibitors were associated with an increased risk of 5 CVAEs including peripheral edema, lymphoedema, hypercholesterolemia, hypertriglyceridaemia and hyperlipidemia, with higher risks for hypercholesterolemia (Peto OR: 3.27,95% CI 2.61-4.11, P < 0.01; I² = 55.5%, P = 0.06) and hyperlipidemia (Peto OR: 3.53. 95% CI 1.70-7.32, P < 0.01; I² = 19.3%, P = 0.29). This study identified an overall incidence of PAM inhibitors CVAEs and the increased risks associated with PAM inhibitor for five specific CVAEs, not confined to hypercholesterolemia and peripheral edema.

5-Fluorouracil (5-FU) is a chemotherapeutic that is used to treat solid tumors. However, 5-FU is associated with several side effects, including cardiotoxicity. Considering the importance of the intrinsic cardiac nervous system (ICNS) for the heart and that little is known about effects of 5-FU on this nervous system plexus, the purpose of the present study was to evaluate effects 5-FU at a low dose on the ICNS and oxidative and inflammatory effects in the heart in Wistar rats. The rats were divided into two groups: treated and 5-FU (n = 6/group). The control group received saline only. The treated group received the following clinical doses of 5-FU: 15 mg/kg for 4 consecutive days, followed by 6 mg/kg for 4 days alternated with non-treatment days, and finally 15 mg/kg as the last dose on day 14. On day 15, the rats were euthanized and underwent thoracotomy. The atria were used for histological analysis, and the ventricles were used for biochemical analysis. The results showed an increase in neuronal density and a decrease in ganglionic and neuronal area in the ICNS. Furthermore, tissue inflammation was observed, indicated by an increase in proinflammatory factors and the enzymatic activity of myeloperoxidase and n-acetyl-glucosaminidase. Oxidative stress was also observed, confirmed by a reduction of endogenous antioxidant defenses and the presence of lipoperoxidation. Treatment with 5-FU also caused cardiac atrophy and fibrosis. These findings indicate that cardiotoxicity is present with 5-FU treatment and affects the morphometric aspects of the ICNS.

Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.

Dihydromyricetin (Dih), a naturally occurring flavonoid, has been identified to exert a protective effect against ischemia/reperfusion injury. However, the detailed mechanisms remain unclear. Here we investigated the biological role of Dih in preventing hypoxia/reoxygenation (H/R) injury in cardiomyocytes. The results showed that Dih protected cardiomyocytes against H/R-induced apoptosis, as proved by improved cell viability and decreased lactate dehydrogenase (LDH) release, cell apoptosis percentage, and caspase-3/7 activity. H/R-induced oxidative stress in cardiomyocytes was also prevented by Dih with increased activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and decreased levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Treatment with Dih prevented H/R-induced increase in the activities of myocardial enzymes aspartate aminotransferase (AST), creatine kinase-MB (CK-MB), and creatine kinase (CK). miR-34a expression was upregulated after H/R stimulation, which could be attenuated by Dih pretreatment. Besides, miR-34a overexpression attenuated the protective effects of Dih against H/R-caused increase in apoptosis, oxidative stress, and myocardial enzyme activities. Next, we demonstrated that Notch1 was a target molecule of miR-34a. Notch1 overexpression reversed the role of miR-34a in regulating the cardioprotective effect of Dih on H/R injury. These observations indicated that the cardioprotective effect of Dih against H/R injury was mediated by the miR-34a/Notch1 signaling. Dih may be a candidate agent for improving the clinical efficacy of cardiac ischemia/reperfusion injury treatment.

The rapid development and deployment of mRNA and non-mRNA COVID-19 vaccines have played a pivotal role in mitigating the global pandemic. Despite their success in reducing severe disease outcomes, emerging concerns about cardiovascular complications have raised questions regarding their safety. This systematic review critically evaluates the evidence on the cardiovascular effects of COVID-19 vaccines, assessing both their protective and adverse impacts, while considering the challenges posed by the limited availability of randomized controlled trial (RCT) data on these rare adverse events. In adherence to PRISMA 2020 guidelines, we conducted a systematic review using the Scopus database, incorporating articles published from January 2020 to July 2024. Our search included terms related to COVID-19 vaccines and cardiovascular conditions. We selected relevant studies from case-control studies, cohort studies, and clinical trials, while excluding descriptive analyses, cross-sectional studies, and conference reports. Case reports were also included due to the limited availability of extensive RCT data on the rare cardiovascular adverse events associated with COVID-19 vaccines. Of the 6037 articles initially screened, 410 were assessed in detail and 175 studies were ultimately included. The review identified a variety of cardiovascular adverse effects associated with COVID-19 vaccines. mRNA vaccines were primarily linked to myocarditis and pericarditis, particularly in younger males, with lower cardiac risks compared to COVID-19 infection. Adenoviral vector vaccines were associated with thrombosis and thrombocytopenia. Inactivated vaccines had fewer severe cardiovascular reports but still presented risks. Takotsubo cardiomyopathy was most commonly observed following mRNA vaccination. Case reports provided valuable additional insights into these rare events, highlighting clinical presentations and potential risk factors not fully captured by larger epidemiological studies. This review reveals a nuanced cardiovascular risk profile for COVID-19 vaccines, with mRNA vaccines linked to rare myocarditis and pericarditis in young males and a higher incidence of Takotsubo cardiomyopathy in females. Adenoviral vaccines show a notable association with thrombosis. Despite these risks, the benefits of vaccination in preventing severe COVID-19 outcomes outweigh the potential complications, underscoring the importance of continued surveillance, case report documentation, and personalized risk assessment. The inclusion of case reports was critical, as they provided valuable real-world data that complemented the findings from large-scale studies and RCTs.

Doxorubicin (DOX) is a remarkable chemotherapeutic agent, however, its adverse effect on DOX-induced cardiotoxicity (DIC) is a rising concern. Recent research has identified carvacrol (CAR), an antioxidant and anti-inflammatory agent, as a promising natural compound for protecting against DIC. This study aims to investigate the potential cardioprotective effects properties of CAR in vitro and in vivo. The cardioprotective effect of CAR was assessed by pretreating H9c2 cells with non-toxic CAR for 24 h, followed by co-treatment with DOX (10 μM) for an additional 24 h. The cell viability was determined using an MTT assay. For the in vivo study, male Sprague-Dawley rats (200-250 g) were randomly divided into three groups: control, cardiotoxicity (DOX), and treatment (CAR + DOX) groups. CAR (50 mg/kg, BW) was administered orally to the CAR + DOX groups for 14 days. Then, a single dose of DOX (15 mg/kg/i.p, BW) was administered on day 15 for DOX and CAR + DOX groups. The rats were allowed to recover for 3 days before being sacrificed. Our results demonstrated that DOX (10 µM) significantly reduced H9c2 cell viability by 50% (p < 0.0001), and CAR (0.067 µM) protected H9c2 cells from DIC (p = 0.0045). In the rat model, CAR pretreatment effectively mitigated DOX-induced reductions in systolic pressure (p = 0.0007), pulse pressure (p = 0.0213), hypertrophy (p = 0.0049), and cardiac fibrosis (p = 0.0006). However, the pretreatment did not alter the heart function, oxidative stress, and antioxidant enzymes. In conclusion, our results indicate that CAR could potentially serve as an adjuvant to reduce cardiotoxicity by ameliorating myocardial fibrosis and hypertrophy.

Doxorubicin (DOX) is an important drug used in the treatment of many malignancies. Unfortunately DOX causes various side effects, with cardiotoxicity being the most characteristic. Risk factors for DOX induced cardiotoxicity (DIC) include cumulative dose of DOX, preexisting cardiovascular diseases, dyslipidemia, diabetes, smoking, along with the use of other cardiotoxic agents. Development of DIC is associated with many pathological phenomena - increased oxidative stress, as well as upregulation of ferroptosis, apoptosis, necrosis, and autophagy. In DIC expression of many microRNAs is also deregulated. In order to avoid cardiotoxicity and still use DOX effectively DOX derivatives such as epirubicin were synthesized. Nowadays a new liposomal form of DOX (L-DOX) appeared as an alternative to conventional treatment with greatly reduced cardiotoxicity. L-DOX can be divided into two groups of substances - pegylated (PLD) with increased solubility and stability, and non-pegylated (NLPD). Many metaanalyses, clinical along with preclinical studies have shown L-DOX treatment is associated with a smaller decrease of left ventricular ejection fraction (LVEF) and other heart functions, but efficacy of this treatment is comparable to the use of convenctional DOX.