European Journal of Clinical Investigation最新文献

Introduction: Coronary artery disease (CAD) is a main cause of morbidity and mortality. The effectiveness of coronary revascularization in chronic coronary syndromes (CCS) is still debated. Our recent study showed the superiority of coronary revascularization over optimal medical therapy (OMT) in reducing cardiovascular (CV) mortality and myocardial infarction (MI). The recent publication of the ORBITA-2 trial suggested superiority of percutaneous coronary revascularization (PCI) in reducing angina and improving quality of life. Therefore, we aimed to provide an updated meta-analysis evaluating the impact of PCI on both clinical outcomes and angina in CCS.

Methods: Relevant studies were screened in PubMed/Medline until 08/01/2024. Randomized controlled trials (RCTs) comparing PCI to OMT in CCS were selected. The primary outcome was CV death. Secondary outcomes were MI, all-cause mortality, stroke, major bleeding and angina severity.

Results: Nineteen RCTs involving 8616 patients were included. Median follow-up duration was 3.3 years. Revascularization significantly reduced CV death (4.2% vs. 5.5%; OR = .77; 95% CI .62-.96, p = .02). Subgroup analyses favoured revascularization in patients without chronic total occlusions (CTOs) (p = .052) and those aged <65 years (p = .02). Finally, a follow-up duration beyond 3 years showed increased benefit of coronary revascularization (p = .04). Secondary outcomes analyses showed no significant differences, except for a lower angina severity in the revascularization group according to the Seattle Angina Questionnaire (SAQ) (p = .04) and to the Canadian Cardiovascular Society (CCS) classification (p = .005).

Conclusions: PCI compared to OMT significantly reduces CV mortality and angina severity, improving quality of life in CCS patients. This benefit was larger without CTOs, in patients aged <65 years and with follow-up duration beyond 3 years.

Background: Dyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first-time presentation of chest pain and on-target LDL-C levels and intermediate FRS/ESC-Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re-event rate up to 6 years follow-up.

Methods: Blind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil-to-Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission.

Results: cTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL-6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(-) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL-6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re-event rate at follow-up.

Conclusions: Inflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re-event rate over a follow-up period of up to 6 years.

Background: With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes.

Methods: We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR.

Results: Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet.

Conclusion: These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation.

Objective: This study investigates the association between a new insulin resistance indicator, the triglyceride-glucose (TyG) index, and the risk of macrosomia.

Design: This is a prospective cohort study.

Methods: This study included 1332 women who delivered at Peking University International Hospital between October 2017 and August 2019. Participants were divided equally into three groups based on the TyG index. Logistic regression and restricted cubic spline (RCS) analyses were used to evaluate the relationship between the TyG index and macrosomia and conducted subgroup analyses. The TyG index's ability to predict macrosomia was assessed using the receiver operating characteristic (ROC) curve.

Results: Multivariable logistic regression analysis revealed that the TyG index is an independent risk factor for macrosomia (Odds ratio [OR] 1.84, 95% confidence interval [CI] 1.02-3.30, p < .05). RCS analysis indicates that the risk of macrosomia increases with the rise of the TyG index (p for nonlinearity <.001) when the TyG index is >6.53. Subgroup analysis showed a synergistic additive interaction between the TyG index and gestational diabetes mellitus (GDM) of macrosomia. The area under the ROC curve for the predictive model was 0.733 (95% CI 0.684, 0.781), with a sensitivity of 76.4% and specificity of 66.9%. Incorporating the TyG index alongside traditional risk factors notably enhances macrosomia prediction (p < .05).

Conclusions: The TyG index independently predicts macrosomia, and exhibits an additive interaction with GDM in its occurrence. Integrating the TyG index with traditional risk factors improves the prediction of macrosomia.

Trial registry: Clinical trials. gov [NCT02966405].

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID-19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID-19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro-inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored.

Zhou Y, Chen J, Li S, et al. Prognostic implication of lipidomics in patients with coronary total occlusion undergoing PCI. Eur J Clin Invest. 2022;52(11):e13826.

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Background: Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium.

Methods: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28).

Results: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β-HSD1/11β-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including 'inflammatory response', 'IFN-γ response' and 'IL6/JAK/STAT3 signalling'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state.

Conclusions: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.

Background: The impact of chronic oral anticoagulant (OACs) use on long-term post-discharge outcomes after coronavirus disease 2019 (COVID-19) hospitalisation remains unclear. Herein, we compared clinical outcomes up to 2-years after COVID-19 hospitalisation between patients on vitamin K antagonists (VKAs), direct-acting OACs (DOACs) and no OAC therapy.

Methods: Data from TriNetX, a global federated health research network, were used. Adult patients on VKAs, DOACs or no OAC therapy at diagnosis of COVID-19 between 20 January 2020 and 31 December 2021, who were hospitalised for COVID-19, were included. The primary outcomes were all-cause mortality, ischaemic stroke/transient ischaemic attack (TIA)/systemic embolism (SE) and the composite of intracranial haemorrhage (ICH)/gastrointestinal bleeding, at 2 years after COVID-19 hospitalisation.

Results: We included 110,834 patients with COVID-19. Following propensity score matching (PSM), we identified a decreased mortality risk in DOAC-treated patients compared to the no OAC cohort (RR .808, 95% CI .751-.870). A higher risk of ischaemic stroke/TIA/SE was observed in VKA users compared to DOAC users (RR 1.100, 95% CI 1.020-1.220) and in VKA users compared to patients not taking OAC (RR 1.400, 95% CI 1.140-1.720). VKA use was associated with a greater risk of ICH/gastrointestinal bleeding than DOAC users (RR 1.198, 95% CI 1.066-1.347), while DOAC users had a lower risk compared to no OAC-treated patients (RR .840, 95% CI .754-.936).

Conclusion: COVID-19 patients taking prior DOACs were associated with lower long-term mortality risk and ICH/gastrointestinal bleeding than patients not taking OAC. Compared to patients on DOACs, VKA users were associated with higher risks of mortality, ischaemic stroke/TIA/SE and ICH/gastrointestinal bleeding.

Background: An individual's genetic fingerprint is emerging as a pivotal predictor of numerous disease- and treatment-related factors. Single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes play key roles in an individual's exposure to a malignancy-associated risk, such as Aflatoxin B1 (AFB1)-induced hepatocellular carcinoma (HCC).

Aim: This study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1-induced HCC.

Materials & methods: A set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years' worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1-induced HCC, including older but significant data.

Results: Variations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio-activation, thus influencing an individual's vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1-epoxide adducts in HCC patients.

Discussion: CYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio-activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most.

Conclusion: Polymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1-induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk-assessment, diagnosis, and treatment.

Aims: This study aimed to explore how incorporating shared decision-making (SDM) can address recruitment challenges in clinical trials. Specifically, it examines how SDM can align the trial process with patient preferences, enhance patient autonomy and increase active patient participation. Additionally, it identifies potential conflicts between SDM and certain clinical trial aspects, such as randomization or blinding, and proposes solutions to mitigate these issues.

Materials and methods: We conducted a comprehensive review of existing literature on patient recruitment challenges in clinical trials and the role of SDM in addressing these challenges. We analysed case studies and trial reports to identify common obstacles and assess the effectiveness of SDM in improving patient accrual. Additionally, we evaluated three proposed solutions: adequate trial design, communication skill training and patient decision aids.

Results: Our review indicates that incorporating SDM can significantly enhance patient recruitment by promoting patient autonomy and engagement. SDM encourages physicians to adopt a more open and informative approach, which aligns the trial process with patient preferences and reduces psychological barriers such as fear and mental stress. However, implementing SDM can conflict with elements such as randomization and blinding, potentially complicating trial design and execution.

Discussion: The desire for patient autonomy and active engagement through SDM may clash with traditional clinical trial methodologies. To address these conflicts, we propose three solutions: redesigning trials to better accommodate SDM principles, providing communication skill training for physicians and developing patient decision aids. By focussing on patient wishes and emotions, these solutions can integrate SDM into clinical trials effectively.

Conclusion: Shared decision-making provides a framework that can promote patient recruitment and trial participation by enhancing patient autonomy and engagement. With proper implementation of trial design modifications, communication skill training and patient decision aids, SDM can support rather than hinder clinical trial execution, ultimately contributing to the advancement of evidence-based medicine.