Mitochondrial C5aR1 signaling is required for proinflammatory macrophage activity during crystal-induced sterile inflammation.
Background and purpose: A significant proportion of ischemic strokes are caused by emboli from unstable carotid artery plaques with intraplaque neovascularization (IPN) as a key feature of plaque instability. IPN is not detectable with conventional Doppler ultrasound.Contrast-enhanced ultrasound (CEUS) can visualize IPN, but it`s use is limited in clinical practice because it requires an intravenous injection of contrast. Superb microvascular imaging (SMI) without contrast uses an algorithm to remove clutter and motion wall artefacts whilst preserving low velocity blood flow signals, enabling visualization of IPN. Our aim was to assess the feasibility of SMI for the detection of IPN.Methods: Thirty-one patients with >50% carotid stenosis were included; twenty-two patients were symptomatic and 9 asymptomatic. All patients underwent conventional carotid ultrasound, CEUS, SMI and blood tests. CEUS and SMI findings were compared and correlated to histological plaque assessments after endarterectomy.Results: There was significant positive correlation between a IPN visual 5-level classification of SMI and a semi-quantitative analysis of CEUS, (p<0.001, r=0.911). Plaques with higher SMI grades had higher numbers of neo-vessels quantified at histology, (p=0.041, r=0.460).Hypoechoic plaques had higher grades of IPN on both CEUS and SMI, (p<0.001). Higher visual IPN counts on SMI were associated with (i) Increased areas of inflammation (p=0.043, r=0,457), (ii) Combined rank scores of granulation tissue, inflammation and lipids (p=0.02, r=0.494) at histology, and (iii) Higher peak-intensity values on quantitative CEUS (p=0.042, r=0.514).
Aims We aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys–Dietz syndrome (LDS). Methods and results We included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys–Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7–10) mm vs. 7 (6–8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001). Conclusion MAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age.
BackgroundLarsen syndrome is a hereditary disorder characterized by osteochondrodysplasia, congenital large-joint dislocations, and craniofacial abnormalities. The autosomal dominant type is caused by mutations in the gene that encodes the connective tissue protein, filamin B (FLNB). Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by arterial aneurysms, dissections and tortuosity, and skeletal, including craniofacial, manifestations. Mutations in five genes involved in the transforming growth factor beta (TGF-β) signaling pathway cause five types of LDS. Stickler syndrome is a genetically heterogeneous arthro-ophthalmopathy caused by defects in collagen, exhibiting a wide specter of manifestations in connective tissue. A rare case is reported that was diagnosed with all these three hereditary connective tissue disorders.Case presentationA 19 year-old, Norwegian male with a clinical diagnosis of Larsen syndrome and with healthy, non-consanguineous parents attended a reference center for rare connective tissue disorders. Findings at birth were hypotonia, joint hypermobility, hyperextended knees, adductovarus of the feet, cervical kyphosis, craniofacial abnormalities, and an umbilical hernia. From toddlerhood, he required a hearing aid due to combined conductive and sensorineural hearing loss. Eye examination revealed hyperopia, astigmatism, and exotropia. At 10 years of age, he underwent emergency surgery for rupture of an ascending aortic aneurysm. At 19 years of age, a diagnostic re-evaluation was prompted by the findings of more distal aortic dilation, tortuosity of precerebral arteries, and skeletal findings. High throughput sequencing of 34 genes for hereditary connective tissue disorders did not identify any mutation in FLNB, but did identify a de novo missense mutation in TGFBR2 and a nonsense mutation in COL2A1 that was also present in his unaffected father. The diagnosis was revised to LDS Type 2. The patient also fulfills the proposed criteria for Stickler syndrome with bifid uvula, hearing loss, and a known mutation in COL2A1.ConclusionLDS should be considered in patients with a clinical diagnosis of Larsen syndrome, in particular in the presence of arterial aneurysms or tortuosity. Due to genetic heterogeneity and extensive overlap of clinical manifestations, genetic high throughput sequencing analysis is particularly useful for the differential diagnosis of hereditary connective tissue disorders.
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