Altered aortic 3D hemodynamics and geometry in pediatric Marfan syndrome patients

BACKGROUND: Blood flow dynamics make it possible to better understand the development of aortopathy and cardiovascular events in patients with Marfan syndrome (MFS). Aortic 3D blood flow characteristics were investigated in relation to aortic geometry in children and adolescents with MFS. METHODS: Twenty-five MFS patients (age 15.6 ± 4.0 years; 11 females) and 21 healthy controls (age 16.0 ± 2.6 years; 12 females) underwent magnetic resonance angiography and 4D flow CMR for assessment of thoracic aortic size and 3D blood flow velocities. Data analysis included calculation of aortic diameter and BSA-indexed aortic dimensions (Z-score) along the thoracic aorta, 3D mean systolic wall shear stress (WSS(mean)) in ten aortic segments and assessment of aortic blood flow patterns. RESULTS: Aortic root (root), ascending (AAo) and descending (DAo) aortic size was significantly larger in MFS patients than healthy controls (Root Z-score: 3.56 ± 1.45 vs 0.49 ± 0.78, p < 0.001; AAo Z-score 0.21 ± 0.95 vs −0.54 ± 0.64, p = 0.004; proximal DAo Z-score 2.02 ± 1.60 vs 0.56 ± 0.66, p < 0.001). A regional variation in prevalence and severity of flow patterns (vortex and helix flow patterns) was observed, with the aortic root and the proximal DAo (pDAo) being more frequently affected in MFS. MFS patients had significantly reduced WSS(mean) in the proximal AAo (pAAo) outer segment (0.65 ± 0.12 vs. 0.73 ± 0.14 Pa, p = 0.029) and pDAo inner segment (0.74 ± 0.17 vs. 0.87 ± 0.21 Pa, p = 0.021), as well as higher WSS(mean) in the inner segment of the distal AAo (0.94 ± 0.14 vs. 0.84 ± 0.15 Pa, p = 0.036) compared to healthy subjects. An inverse relationship existed between pDAo WSS(mean) and both pDAo diameter (R = −0.53, p < 0.001) and % diameter change along the pDAo segment (R = −0.64, p < 0.001). CONCLUSIONS: MFS children and young adults have altered aortic flow patterns and differences in aortic WSS that were most pronounced in the pAAo and pDAo, segments where aortic dissection or rupture often originate. The presence of vortex flow patterns and abnormal WSS correlated with regional size of the pDAo and are potentially valuable additional markers of disease severity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-017-0345-7) contains supplementary material, which is available to authorized users

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.We thank FPLD2 patients for donating biological samples. We thank the Italian Network for Laminopathies and the European Consortium of Lipodystrophies (ECLip) for support and helpful discussion. We thank Aurelio Valmori for the technical support. The studies were supported by Rizzoli Orthopedic Institute “5 per mille” 2014 project to MC, AIProSaB project 2016 and Fondazione Del Monte di Bologna e Ravenna grant 2015–2016 “New pharmacological approaches in bone laminopathies based on the use of antibodies neutralizing TGF beta 2” to GL. GL is also supported by PRIN MIUR project 2015FBNB5Y.S

Differential flow improvements after valve replacements in bicuspid aortic valve disease: a cardiovascular magnetic resonance assessment

Background Abnormal aortic flow patterns in bicuspid aortic valve disease (BAV) may be partly responsible for the associated aortic dilation. Aortic valve replacement (AVR) may normalize flow patterns and potentially slow the concomitant aortic dilation. We therefore sought to examine differences in flow patterns post AVR. Methods Ninety participants underwent 4D flow cardiovascular magnetic resonance: 30 BAV patients with prior AVR (11 mechanical, 10 bioprosthetic, 9 Ross procedure), 30 BAV patients with a native aortic valve and 30 healthy subjects. Results The majority of subjects with mechanical AVR or Ross showed normal flow pattern (73% and 67% respectively) with near normal rotational flow values (7.2 ± 3.9 and 10.6 ± 10.5 mm2/ms respectively vs 3.8 ± 3.1 mm2/s for healthy subjects; both p > 0.05); and reduced in-plane wall shear stress (0.19 ± 0.13 N/m2for mechanical AVR vs. 0.40 ± 0.28 N/m2 for native BAV, p  0.05), and a similar pattern for wall shear stress. Data before and after AVR (n = 16) supported these findings: mechanical AVR showed a significant reduction in rotational flow (30.4 ± 16.3 → 7.3 ± 4.1 mm2/ms; p < 0.05) and in-plane wall shear stress (0.47 ± 0.20 → 0.20 ± 0.13 N/m2; p < 0.05), whereas these parameters remained similar in the bioprosthetic AVR group. Conclusions Abnormal flow patterns in BAV disease tend to normalize after mechanical AVR or Ross procedure, in contrast to the remnant abnormal flow pattern after bioprosthetic AVR. This may in part explain different aortic growth rates post AVR in BAV observed in the literature, but requires confirmation in a prospective study

Scan–rescan reproducibility of segmental aortic wall shear stress as assessed by phase-specific segmentation with 4D flow MRI in healthy volunteers

Objective: The aim was to investigate scan–rescan reproducibility and observer variability of segmental aortic 3D systolic wall shear stress (WSS) by phase-specific segmentation with 4D flow MRI in healthy volunteers. Materials and methods: Ten healthy volunteers (age 26.5 ± 2.6 years) underwent aortic 4D flow MRI twice. Maximum 3D systolic WSS (WSSmax) and mean 3D systolic WSS (WSSmean) for five thoracic aortic segments over five systolic cardiac phases by phase-specific segmentations were calculated. Scan–rescan analysis and observer reproducibility analysis were performed. Results: Scan–rescan data showed overall good reproducibility for WSSmean (coefficient of variation, COV 10–15%) with moderate-to-strong intraclass correlation coefficient (ICC 0.63–0.89). The variability in WSSmax was high (COV 16–31%) with moderate-to-good ICC (0.55–0.79) for different aortic segments. Intra- and interobserver reproducibility was good-to-excellent for regional aortic WSSmax (ICC ≥ 0.78; COV ≤ 17%) and strong-to-excellent for WSSmean (ICC ≥ 0.86; COV ≤ 11%). In general, ascending aortic segments showed more WSSmax/WSSmean variability compared to aortic arch or descending aortic segments for scan–rescan, intraobserver and interobserver comparison. Conclusions: Scan–rescan reproducibility was good for WSSmean and moderate for WSSmax for all thoracic aortic segments over multiple systolic phases in healthy volunteers. Intra/interobserver reproducibility for segmental WSS assessment was good-to-excellent. Variability of WSSmax is higher and should be taken into account in case of individual follow-up or in comparative rest–stress studies to avoid misinterpretation