Endothelial-mesenchymal transition in human atrial fibrillation

Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation. Methods and results: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n =38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31+ cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen. Conclusions: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling. © 2016 Japanese College of Cardiology

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Ventriculoventricular delay optimization of a cardiac resynchronization device

Cardiac resynchronization therapy (CRT) has become a standard option for patients with severe low cardiac function and mild to severe heart failure. However, its potential has not been maximized to date, as the optimal atrioventricular delay, ventriculoventricular (VV) delay, and tachy therapy settings remain unknown. Here, data from various studies have been used to estimate several CRT settings. Three search words—interventricular interval, VV delay, and interventricular delay with cardiac resynchronization therapy—were entered into PubMed. The methods used to optimize VV delay included ultrasonography, radioisotope diagnosis, scintigraphy, electrocardiography, Swan–Ganz catheterization, and thoracic impedance. Their populations and results were analyzed to identify convincing rules. Methods for VV delay optimization in the literature can be categorized into four patterns. Time and cost were high in several categories. Most studies concluded that their method was effective but no small amount of papers denied individual detailed optimization. There were some population biases in most papers. Individual optimization had a major impact in patients with ischemic heart disease but no significant impact in patients with non-ischemic heart diseases. In summary, CRT is an established therapy, but a well-controlled study is required to find conclusive methods for VV delay optimization

Comparative Efficacy and Safety of Tezepelumab and Other Biologics in Patients with Inadequately Controlled Asthma According to Thresholds of Type 2 Inflammatory Biomarkers: A Systematic Review and Network Meta-Analysis

The anti-thymic stromal lymphopoietin antibody (tezepelumab) has therapeutical potential for inadequately controlled asthma. However, evidence comparing tezepelumab with other biologics is scarce. To address this issue, we performed a network meta-analysis to compare and rank the efficacy of five treatments (tezepelumab, dupilumab, benralizumab, mepolizumab, and placebo) in overall participants and in subgroups stratified by the thresholds of type 2 inflammatory biomarkers, including peripheral blood eosinophil count (PBEC) and fractional exhaled nitric oxide (FeNO). The primary endpoints were annualized exacerbation rate (AER) and any adverse events (AAEs). In the ranking assessment using surface under the cumulative ranking curve (SUCRA) of AER, tezepelumab ranked the highest overall and across subgroups (based on PBEC and FeNO level thresholds). A significant difference was observed between tezepelumab and dupilumab in the patient subgroup with PBEC < 150, and between tezepelumab and benralizumab in overall participants and the patient subgroup with PBEC ≥ 300 and ≥150, respectively. There was no significant difference in the incidence of AAEs in the overall participants between each pair of five treatment arms. These results provide a basis for the development of treatment strategies for asthma and may guide basic, clinical, or translational research

Educational Effects of Simulation and Non-Simulation Training in Airway Management according to Levels of the Kirkpatrick Model: A Systematic Review and Network Meta-Analysis

There is insufficient validation of the effectiveness of simulation-based training (Sim) or non-simulation-based training (non-Sim) for teaching airway management to healthcare professionals within the literature. We thus conducted a network meta-analysis comparing the effectiveness of Sim, non-Sim, and no educational intervention (NI) for airway management. The primary endpoints were knowledge scores (KnS) and behavioral performance scores (BpS) corresponding to assessments at levels 2 and 3 of the Kirkpatrick model, respectively. Effect sizes were expressed as standardized mean differences (Std. MD) and 95% credible intervals (CrIs). Regarding KnS, the educational effects of Sim and non-Sim were significantly improved compared to those of NI (Std. MD [95% CI]: 1.110 [0.903–1.316] and 0.819 [0.209–1.429], respectively); there was no significant difference between Sim and non-Sim. The educational effect of Sim in BpS was significantly improved compared to that of non-Sim and NI (0.850 [0.015–1.691] and 0.660 [0.241–1.076]); there were no differences between non-Sim and NI. Surface under the cumulative rank curve values demonstrated that Sim ranked highest in efficacy for KnS and BpS. This study provides valuable information regarding the educational efficacy of Sim and non-Sim in airway management. Larger randomized controlled trials are needed to confirm these findings

Effectiveness of Therapeutic Monoclonal Antibodies for Asthma Control in Uncontrolled Eosinophilic Asthma-A Meta-analysis of Randomized Controlled Trials-

The overall efficacy of therapeutic monoclonal antibodies （mAbs） for asthma control in patients with uncontrolled eosinophilic asthma remains to be fully characterized. We conducted a meta-analysis of randomized controlled trials （RCTs） to analyze the efficacies of new therapeutic mAbs, such as anti-interleukin （IL）-13 therapies, anti-IL4/13 therapies, and anti-IL-5 therapies, compared with that of a placebo in patients with uncontrolled asthma. This meta-analysis complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses （PRISMA） guidelines. The primary efficacy outcome was asthma control as assessed by Asthma Control Questionnaire （ACQ） scores. Pooled estimates are presented as standardized mean differences （Std MDs） with 95% confidence intervals （CIs）. Seven RCTs of therapeutic mAbs, including anti-IL-13, anti-IL-4/13, and anti-IL-5, met the criteria for study inclusion. The overall Std MD of changes in the ACQ score was −0.31 （95% CI, −0.45 to −0.17; P＜0.0001）. These results strongly indicate that therapeutic mAbs are effective in controlling asthma in patients with uncontrolled eosinophilic asthma