Cardiovascular Toxicology最新文献

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 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.

5-fluorouracil (5-FU), a commonly utilized antitumor agent for the treatment of colon cancer, is linked to an increased risk of cardiovascular diseases. Antihistamines including astemizole (AST) have been reported to present cardiovascular toxicity; however, it remains unclear how 5-FU-mediated cardiotoxicity is affected by AST during the treatment of colon cancer. This study explored the role of AST in 5-FU-induced cardiotoxicity in colon cancer. 5-FU was used to induce cardiotoxicity in cardiomyocytes (HL-1 cells) and BALBc mice, creating in vitro and in vivo models of chemotherapeutic drug-induced cardiotoxicity. In the mice model, we found that the blocking of histamine signal by AST aggravated 5-FU-induced cardiac function injury and cardiac fibrosis. In HL-1 cardiomyocyte cells, the increases of apoptosis and generation of mitochondrial reactive oxygen species (mtROS) were evaluated after the combination treatment of AST and 5-FU. Proinflammatory M1-like-type macrophages were dominant in the AST and 5-FU combination group compared to control groups. The protein expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) was assessed both in vitro and in vivo using Western blot analysis. Clinically, altered Ptgs2 was closely associated with adverse cardiovascular outcomes. Overall, the combination of AST and 5-FU significantly enhanced cardiotoxicity by inducing cardiomyocyte apoptosis, inflammation, and the expression of Ptgs2.

The effect of low-dose ionizing radiation exposure on the risk of cardiovascular disease (CVD) represents a significant concern in the field of radiation protection. The prevailing approach to mitigating the adverse effects of low-dose or low-dose-rate radiation does not currently incorporate the potential risk of CVD, despite the possibility that such risk may be a substantial contributor to overall health hazards. Current evidence suggests a potential association between radiation exposure and CVD; however, the overall findings remain inconclusive. This is particularly due to the uncertainty surrounding the influence of significant non-radiation risk factors on the associations reported in epidemiological studies. It is difficult to discern the underlying connection in observational epidemiology when there is substantial variation in baseline risk factors. The paucity of epidemiological research in this domain is being partially offset by the advancement of multi-omics approaches. These methods assist in identifying radiosensitive targets, comprehending underlying biological processes, and pinpointing biomarkers. This, in turn, fortifies the evidence gleaned from epidemiological studies. In this review, we delve into the body of epidemiological research pertaining to CVD induced by low-dose ionizing radiation and the application of multi-omics techniques. The integration of these two methodologies holds the promise of identifying specific molecules or biological pathways that can be employed to validate endpoints related to radiation risk assessment.

Persistent pulmonary hypertension of the newborn (PPHN) is one of the most common diseases in the neonatal intensive care unit which severely affects neonatal survival. Gut microbes play an increasingly important role in human health, but there are rarely reported how gut microbiota contribute to PPHN. In our study, the metagenomic sequencing of feces from 12 PPHN's neonates and 8 controls were performed to expose the relation between neonatal gut microbes and PPHN disease. Firstly, we found that the abundance of Actinobacteria, Proteobacteria, Bacteroidetes were significantly increased in PPHN compared with controls, but the Firmicutes components was reduced. And some pathogenic strains (like Vibrio metschnikovii) were significantly enriched in the PPHN compared with controls. Secondly, functional annotation of genes found that PPHN up-regulated transmembrane transport, but down-regulated ribosome and ATP binding. Lastly, microbial metabolic pathway enrichment analysis indicated that some metabolic pathway in PPHN were conflicting and contradictory, showed that an abnormally increased metabolism, disturbed protein synthesis and genomic instability in the PPHN neonate. Our results contribute to understanding the changes in the species and function of gut microbiota in PPHN, thus providing a theoretical basis for the explanation and treatment of PPHN.

The advent of heated tobacco products (HTPs) has introduced new variables in the study of nicotine delivery systems and their health implications. Amidst concerns over cardiovascular effects, this study aims to elucidate the acute impact of HTP inhalation on extracellular vesicles (EV) levels in young, healthy individuals. In this controlled, acute exposure study, 23 young, healthy volunteers were subjected to HTP inhalation. EV levels of endothelial and platelet origin were quantified through flow cytometry before and after exposure. Data analysis was performed using multiple measures ANOVA to assess changes in EV concentrations. Our findings reveal a significant increase in EVs of endothelial and platelet origin following short-term HTP inhalation with nicotine. Notably, no significant change was observed in leukocyte- and neutrophil-derived EVs. This increase in EVs suggests acute vascular stress, with peak levels observed 4 h post-exposure. The rise in endothelial and platelet-derived EVs aligns with documented responses to acute vascular injury, paralleling the effects seen with traditional cigarette and e-cigarette use. Despite HTPs being marketed as safer alternatives, our results indicate that nicotine-containing HTPs may still pose significant vascular risks. These findings contribute to the growing body of evidence cautioning against the perceived safety of HTPs and reinforce the importance of regulatory oversight and public health initiatives targeting nicotine delivery technologies. Trial Registrations: ClinicalTrials.gov ID: NCT04824495, registered 2021-01-07.

The role of ferroptosis, an iron-dependent lipid peroxidation regulated cell death pathway, remains obscure during myocardial infarction (MI) recovery. Our study aims to clarify ferroptosis' function in post-MI cardiac recovery, explore the consequences of iron overload and ferroptosis for myocardial remodeling, and assess the effects of Liproxstatin-1 (Lipro-1) treatment on macrophage functionality. Moreover, we examine the potential of Astaxanthin (ASTX), recognized for its antioxidative properties, to mitigate ferroptosis during MI recovery and its subsequent ramifications for myocardial remodeling. Our results demonstrate persistent ferroptosis during MI recovery, marked by decreased Glutathione Peroxidase 4 and increased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Ferroportin 1 alongside elevated lipid peroxidation and iron levels up to D21. We identified a significant correlation between ferroptosis and macrophage activity, noted by the increase in macrophage populations co-expressing GPX4 and ACSL4 markers in the peri-infarct area by D21. Liproxstatin-1 treatment reduced macrophage (CD68 +) counts, promoted M2 polarization decreased inflammation, and improved cardiac function. Myocardial remodeling was improved in Lipro-1-treated rats, as shown by decreased fibrosis and reduced levels of α-SMA, Collagen I, and Collagen III proteins. ASTX treatment also exhibited an inhibiting effect on ferroptosis indicators, and encouraged M2 macrophage polarization, reduced inflammation, and enhanced both cardiac function and myocardial remodeling, mirroring the beneficial effects observed with Lipro-1. In summary, the interactions between ferroptosis, macrophage polarization, and myocardial remodeling are crucial for cardiac function improvement post-MI. Lipro-1 and ASTX emerge as promising therapeutic agents by modulating post-MI ferroptosis and related immune responses.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-sensitive transcriptional factor that enables cells to resist oxidant responses, ferroptosis and inflammation. Here, we set out to probe the effects of NRF2 on cardiomyocyte injury under acute myocardial infarction (AMI) condition and its potential mechanism. Human cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to induce cell injury. qRT-PCR and western blot assays were used to detect the levels of mRNAs and proteins. Cardiomyocyte injury was determined by detecting the levels of lactate dehydrogenase and creatine Kinase MB (CK-MB). Cell apoptosis was investigated by flow cytometry and related markers. Levels of IL-6, IL-10, and TNF-α were measured by ELISA. Cell ferroptosis was assessed by detecting the production of reactive oxygen species (ROS), malonaldehyde (MDA), reduced glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio, Fe + content, and related regulators. The interaction between NRF2 and the suppressor of zest 12 (SUZ12) was analyzed by using dual-luciferase reporter and RNA immunoprecipitation assays. AMI rat models were established for in vivo analysis. NRF2 was lowly expressed in AMI patients and H/R-induced cardiomyocytes. Forced expression of NRF2 reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis. Moreover, NRF2 overexpression improved cardiac function and injury in vivo. Mechanistically, SUZ12 bound to the promoter of NRF2 and promoted its expression. Further functional analyses showed that SUZ12 overexpression reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis, which were reversed by NRF2 silencing. SUZ12-increased NRF2 suppressed H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis in vitro and improved cardiac functions in rats with I/R injury, suggesting the potential cardioprotective effect of NRF2 in cardiac injury during AMI.

The objective of this study is to determine the diagnostic utility of combining homocysteine (HCY), lipoprotein-associated phospholipase A2 (LP-PLA2), and the C-reactive protein-to-albumin ratio (CAR) for carotid atherosclerosis (CAS) and plaque stability in patients with essential hypertension (EH). A total of 280 patients with EH were divided into 2 groups according to ultrasound diagnosis: CAS (n = 106) and non-CAS (N-CAS [n = 174]). The CAS group was further segmented into plaque-stable (n = 50) and plaque non-stable (n = 56) groups. General data were collected for all patients. Risk factors associated with CAS and plaque instability in patients with EH, and the diagnostic utility of HCY, LP-PLA2, and CAR testing alone, or in combination, for assessing CAS and plaque instability were determined. Mean age, systolic blood pressure (SBP), duration of EH, smoking, total cholesterol high-density lipoprotein cholesterol, HCY, LP-PLA2 levels, and CAR were higher in the CAS group than those in the N-CAS group (P < 0.05). SBP, duration of EH, HCY and LP-PLA2 levels, and CAR were independent risk factors for CAS (P < 0.05). In addition, HCY, LP-PLA2, and CAR alone demonstrated significant diagnostic efficacy (P < 0.001) but were inferior to the combined diagnostic utility of the 3 parameters (P < 0.001). HCY and LP-PLA2 levels, and CAR were higher in the plaque non-stable than in the plaque-stable group (P < 0.05). Duration of EH, low-density lipoprotein cholesterol, HCY, LP-PLA2, and CAR independently influenced plaque instability in patients with CAS (P < 0.05). The combined diagnostic utility of HCY, LP-PLA2, and CAR (P < 0.001) was superior to that of each parameter alone and demonstrated more pronounced diagnostic efficacy (P < 0.001). HCY, LP-PLA2, and CAR were independent risk factors for CAS and plaque instability in patients with EH. HCY, LP-PLA2, and CAR demonstrated significant diagnostic efficacy for CAS and plaque instability, and combination of the 3 demonstrated the most pronounced diagnostic efficacy.

Gene therapy has received great attention as a therapeutic approach to improve cardiac function post-myocardial infarction (MI), but its limitation lies in the lack of targeting. This study explored the use of ultrasound-targeted microbubble destruction (UTMD) technique to deliver β-catenin gene to the myocardium, aiming to evaluate its efficacy in preventing cardiac dysfunction post-MI. A cationic microbubble solution containing β-catenin gene pcDNA3.1 plasmid was injected through the tail vein at a rate of 0.6 mL/h, and ultrasound beams were delivered to the heart using GE Vivid 7 Medical Ultrasound System M3s Transducer. Bioluminescence imaging was used to analyze the efficiency of UTMD gene transfection into the myocardium. β-catenin levels were detected by real-time polymerase chain reaction and western blot. Additionally, MI was induced in mice by surgical ligation of the left coronary artery, and cardiac function was evaluated using echocardiography at 14 and 28 days post-surgery. Masson's trichrome staining was employed to determine infarct size. Blood vessel density was also measured. TUNEL assay was used to measure cardiomyocyte apoptosis. Furthermore, mouse cardiac stem cells were isolated using flow cytometry, and Giemsa stain was applied to evaluate the colony adhesion. UTMD delivered the gene to the heart with high efficiency and specificity in vivo. The β-catenin expression was significantly increased in the myocardium (P < 0.01). After MI, the β-catenin group exhibited a notable improvement in the gene therapy-induced neovascularization in the border zone (P < 0.01) and the number and function of cardiac stem cells (P < 0.01), and a significant decrease in cardiomyocyte apoptosis in the heart tissue (P < 0.01). β-catenin gene pre-treated with UTMD can reduce the impact of myocardial injury and promote cardiac self-repair after MI.