Quantification of myocardial deformation in children by cardiovascular magnetic resonance feature tracking: determination of reference values for left ventricular strain and strain rate

Background: The objective assessment of global and regional cardiac function in children has shown to be clinically relevant but is challenging to conduct. Cardiovascular magnetic resonance (CMR) has emerged as a valuable diagnostic modality especially in patients with cardiomyopathy or congenital heart disease. However, data on the normal cardiac deformation in children assessed by CMR is lacking at present. Thus, the aim of this study was to provide reference values for cardiac strain and strain rate in children and adolescents derived from CMR feature tracking (FT) measurements. Methods: In this binational study, eighty children and adolescents (age 0.4–18.0 years, 41 male, 39 female) free from cardiac diseases from two centers underwent CMR in 1.5 T whole-body scanners in supine position. Global peak radial, circumferential and longitudinal systolic strains as well as the corresponding early peak diastolic strain rates were assessed applying FT on short axis as well as 3- and 4-chamber views of standard cine steady-state free precession images. Results: The difference between genders yielded no significance for all assessed strains. Yet, all strains showed a significant parabolic relation to age and an even stronger one to body surface area (BSA). Therefore, BSA-specific reference values were determined using a polynomial regression model. The apical cardiac segments featured significant higher peak circumferential but lower peak radial systolic strains than the midventricular and basal segments (all p < 0.001). Conclusions: The assessment of cardiac deformation by CMR-FT is feasible in children. This is the first CMR study providing specific reference values for FT-derived strain and strain rate in the pediatric age range

P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K+ channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF 20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1β and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care

The transcription factor CREM drives an inflammatory phenotype of T cells in oligoarticular juvenile idiopathic arthritis

Abstract Background Inflammatory effector T cells trigger inflammation despite increased numbers of Treg cells in the synovial joint of patients suffering from juvenile idiopathic arthritis (JIA). The cAMP response element (CREM)α is known to play a major role in regulation of T cells in SLE, colitis, and EAE. However, its role in regulation of effector T cells within the inflammatory joint is unknown. Methods CREM expression was analyzed in synovial fluid cells from oligoarticular JIA patients by flow cytometry. Peripheral blood mononuclear cells were incubated with synovial fluid and analyzed in the presence and absence of CREM using siRNA experiments for T cell phenotypes. To validate the role of CREM in vivo, ovalbumin-induced T cell dependent arthritis experiments were performed. Results CREM is highly expressed in synovial fluid T cells and its expression can be induced by treating healthy control PBMCs with synovial fluid. Specifically, CREM is more abundant in CD161+ subsets, than CD161− subsets, of T cells and contributes to cytokine expression by these cells. Finally, development of ovalbumin-induced experimental arthritis is ameliorated in mice with adoptively transferred CREM−/− T cells. Conclusion In conclusion, our study reveals that beyond its role in SLE T cells CREM also drives an inflammatory phenotype of T cells in JIA