Sex differences in leukocyte profile in ST-elevation myocardial infarction patients

BACKGROUND: Whether sex differences exist in the inflammatory response after ST-elevation myocardial infarction (STEMI) remains to be elucidated. We studied leukocyte profiles and their prognostic value in men and women presenting with STEMI. METHODS: From a total of 552 consecutive STEMI patients, blood samples were collected at hospital admission. Linear regression was used to assess the relationship between leukocyte profiles and enzymatic infarct size. Cox regression was used to assess the association between leukocyte profiles and one-year mortality. RESULTS: Women presented with higher lymphocyte counts (2.3·109 cells/L (IQR 1.6-3.1) vs. 1.8·109 cells/L (IQR 1.4-2.5), p = 3.00 ∙ 10-4) and percentages (21.1% (IQR 14.4-28.1) vs. 17.1% (IQR 12.3-24.3), p = 0.004). Lymphocyte to monocyte ratio (LMR) was also higher in women (3.25 (IQR 2.56-4.5) vs. 2.68 (IQR 2.08-3.59), p = 7.28 ∙ 10-7). Higher LMR was associated with lower peak CK-MB (β = -0.27 (95% CI: -0.50, -0.03), p = 0.026), lower peak troponin T (β = -0.45 (95% CI: -0.77, -0.13), p = 0.006) and lower one-year mortality risk (HR 0.35 (95% CI: 0.13, 0.96), p = 0.042). CONCLUSION: At admission for STEMI, women present with higher lymphocyte count and LMR. Higher LMR is associated with smaller infarct size and decreased one-year mortality risk and could be used as a biomarker to predict outcome

FIBROBLAST-SEEDED LUNG EXTRACELLULAR MATRIX (ECM)-DERIVED HYDROGELS AS AN IN VITRO MODEL FOR STROMAL BED IN IDIOPATHIC PULMONARY FIBROSIS (IPF)

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is characterized by aberrant extracellular matrix (ECM) deposition and remodeling, which orchestrates cellular responses to the fibrotic microenvironment[1]. Decellularized lung ECM‐derived hydrogels resemble the mechanical properties[2] of native decellularized tissues, potentially providing a 3D model mimicking native cell‐ECM interactions. We aimed to characterize this 3D human lung microenvironment model, with respect to stiffness and viscoelastic properties, in the presence and absence of primary human lung fibroblasts.Materials & Methods: Lyophilized powders of decellularized IPF and control lung matrices (pool of 6 patients) were pepsin digested, and formed to hydrogels seeded with control primary lung fibroblasts (n = 4 donors), and cultured for 14 days. Stiffness and viscoelastic relaxation were measured by Low‐Load Compression Testing[2] (20% strain).Results: IPF hydrogels were stiffer than controls (1.84 ± 0.33 kPA vs 1.37 ± 0.35 kPA), and became even more stiff when cell‐seeded (1.91 ± 0.37 kPA) in contrast to controls which became softer (1.09 ± 0.27 kPA). Time to reach 100% viscoelastic relaxation was shorter in cell‐seeded compared to native hydrogels for both IPF (19.14 ± 3.17 vs 41.6 ± 37.66 seconds) and control (11.44 ± 6.55 vs 22.21 ± 19.59 seconds).Conclusion: The mechanical properties of the ECM hydrogels were modified by fibroblasts, while in turn the ECM microenvironment altered cellular responses. These data suggest that higher stiffnesses and altered relaxation patterns of the ECM could contribute to the fibrotic response in IPF by instructing the cells. Fibroblast‐seeded ECM‐derived hydrogels can provide more insight on cell‐ECM interactions in IPF.References[1] M. W. Parker et al., “Fibrotic extracellular matrix activates a profibrotic positive feedback loop,” J. Clin. Invest., vol. 124, no. 4, pp. 1622–1635, Apr. 2014.[2] R. H. J. De Hilster et al., “Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue,” Am. J. Physiol. ‐ Lung Cell. Mol. Physiol., vol. 318, no. 4, pp. L698–L704, Apr. 2020

Translational insights from single-cell technologies across the cardiovascular disease continuum

Cardiovascular disease is the leading cause of death worldwide. The societal health burden it represents can be reduced by taking preventive measures and developing more effective therapies. Reaching these goals, however, requires a better understanding of the pathophysiological processes leading to and occurring in the diseased heart. In the last 5 years, several biological advances applying single-cell technologies have enabled researchers to study cardiovascular diseases with unprecedented resolution. This has produced many new insights into how specific cell types change their gene expression level, activation status and potential cellular interactions with the development of cardiovascular disease, but a comprehensive overview of the clinical implications of these findings is lacking. In this review, we summarize and discuss these recent advances and the promise of single-cell technologies from a translational perspective across the cardiovascular disease continuum, covering both animal and human studies, and explore the future directions of the field

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.Peer reviewe

Association of epicardial adipose tissue with different stages of coronary artery disease:A cross-sectional UK Biobank cardiovascular magnetic resonance imaging substudy

Objective: Increased epicardial adipose tissue (EAT) has been identified as a risk factor for the development of coronary artery disease (CAD). However, the exact role of EAT in the development of CAD is unclear. This study aims to compare EAT volumes between healthy controls and individuals with stable CAD and a history of myocardial infarction (MI). Furthermore, associations between clinical and biochemical parameters with EAT volumes are examined.& nbsp;Methods: This retrospective cross-sectional study included 171 participants from the United Kingdom Biobank (56 healthy controls; 60 stable CAD; 55 post MI), whom were balanced for age, sex and body mass index (BMI). EAT volumes were quantified on end-diastolic cardiac magnetic resonance (CMR) imaging short-axis slices along the left and right ventricle and indexed for body surface area (iEAT) and iEAT volumes were compared between groups.& nbsp;Results: iEAT volumes were comparable between control, CAD and MI cases (median [IQR]: 66.1[54.4-77.0] vs. 70.9[55.8-85.5] vs. 67.6[58.6-82.3] mL/m(2), respectively (p > 0.005 for all). Increased HDL-cholesterol was associated with decreased iEAT volume (8 =-14.8, CI =-24.6 to-4.97, p = 0.003) and suggestive associations (P-value = 0.005) were observed between iEAT and triglycerides (beta = 3.26, CI = 0.42 to 6.09, p = 0.02), Apo-lipoprotein A (beta =-16.3, CI =-30.3 to-2.24, p = 0.02) and LDL-cholesterol (beta = 3.99, CI =-7.15 to-0.84, p = 0.01).& nbsp;Conclusions: No significant differences in iEAT volumes were observed between patients with CAD, MI and healthy controls. Our results indicate the importance of correcting for confounding by CVD risk factors, including circulating lipid levels, when studying the relationship between EAT volume and CAD. Further mechanistic studies on causal pathways and the role of EAT composition are warranted

Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data

Background: Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals. Results: We conduct a co-eQTL meta-analysis across four scRNA-seq peripheral blood mononuclear cell datasets using a novel filtering strategy followed by a permutation-based multiple testing approach. Before the analysis, we evaluate the co-expression patterns required for co-eQTL identification using different external resources. We identify a robust set of cell-type-specific co-eQTLs for 72 independent SNPs affecting 946 gene pairs. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into how disease-associated variants alter regulatory networks. One co-eQTL SNP, rs1131017, that is associated with several autoimmune diseases, affects the co-expression of RPS26 with other ribosomal genes. Interestingly, specifically in T cells, the SNP additionally affects co-expression of RPS26 and a group of genes associated with T cell activation and autoimmune disease. Among these genes, we identify enrichment for targets of five T-cell-activation-related transcription factors whose binding sites harbor rs1131017. This reveals a previously overlooked process and pinpoints potential regulators that could explain the association of rs1131017 with autoimmune diseases. Conclusion: Our co-eQTL results highlight the importance of studying context-specific gene regulation to understand the biological implications of genetic variation. With the expected growth of sc-eQTL datasets, our strategy and technical guidelines will facilitate future co-eQTL identification, further elucidating unknown disease mechanisms.</p

Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data

Background: Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals. Results: We conduct a co-eQTL meta-analysis across four scRNA-seq peripheral blood mononuclear cell datasets using a novel filtering strategy followed by a permutation-based multiple testing approach. Before the analysis, we evaluate the co-expression patterns required for co-eQTL identification using different external resources. We identify a robust set of cell-type-specific co-eQTLs for 72 independent SNPs affecting 946 gene pairs. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into how disease-associated variants alter regulatory networks. One co-eQTL SNP, rs1131017, that is associated with several autoimmune diseases, affects the co-expression of RPS26 with other ribosomal genes. Interestingly, specifically in T cells, the SNP additionally affects co-expression of RPS26 and a group of genes associated with T cell activation and autoimmune disease. Among these genes, we identify enrichment for targets of five T-cell-activation-related transcription factors whose binding sites harbor rs1131017. This reveals a previously overlooked process and pinpoints potential regulators that could explain the association of rs1131017 with autoimmune diseases. Conclusion: Our co-eQTL results highlight the importance of studying context-specific gene regulation to understand the biological implications of genetic variation. With the expected growth of sc-eQTL datasets, our strategy and technical guidelines will facilitate future co-eQTL identification, further elucidating unknown disease mechanisms.</p