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Background The burden of pulmonary disease in children with congenital heart disease (CHD) remains under recognized. Studies have examined children with single ventricle (1V) and two ventricle (2V) heart disease and document a decreased forced vital capacity (FVC). Our study sought to further explore the pulmonary function of children with CHD. Methods A retrospective review was performed of spirometry in CHD patients over a 3 year period. Spirometry data was corrected for size, age, and gender, and analyzed using z-scores. Results The spirometry of 260 patients were analyzed. 31% had 1V (n = 80, 13.6 years (IQR 11.5–16.8)) and 69% had 2V circulation (n = 180, 14.4 years (IQR 12.0-17.3)). 1V patients were found to have a lower median FVC z-score compared to 2V patients (p = 0.0133). The prevalence of an abnormal FVC was 41% in 1V patients and 29% in 2V patients. 2V patients with Tetralogy of Fallot (TOF) and Truncus Arteriosus (TA) had similar low FVC comparable to 1V patients. The number of cardiac surgeries predicted an abnormal FVC in 2V patients except TOF patients. Conclusion Pulmonary morbidity in patients with CHD is common with a decreased FVC noted in 1V and 2V patients. FVC is lower in patients with 1V circulation, however, 2V patients with TOF or TA have similar lung function in comparison to the 1V group. The number of surgical interventions was predictive of FVC z-score in some but not all 2V patients and not predictive in 1V patients suggesting a multifactorial etiology to pulmonary disease in children with CHD.

Soccer athletes frequently experience repetitive head impacts (RHI) during games and practices, which may affect neural integrity over time and lead to altered brain structure. Neck strength is hypothesized to limit the transfer of force to the brain and decrease the effect of RHI on brain structure. The goal of our work was to examine whether greater neck strength is associated with more intact white matter organization (WMO) in collegiate athletes exposed to RHI. Collegiate soccer (n = 17) and limited/non-contact sport (n = 39) athletes were assessed prior to their athletic seasons. Participants completed neck strength assessments using handheld dynamometry in six test positions and diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were calculated for 20 white matter (WM) regions. A multi-variate approach was used to examine the relationship between neck strength and diffusion measures in soccer and limited/non-contact athletes. Neck strength was positively associated with FA and negatively associated with RD across several WM regions in soccer players only. Neck strength was not significantly associated with MD or AD in either group. Greater neck strength was related to more intact WMO in athletes with high exposure to RHI, particularly in regions prone to damage from brain trauma such as the basal ganglia, superior longitudinal fasciculus, and frontoparietal WM. Future studies should examine neck strength as a factor to moderate neural outcomes in athletes with exposure to RHI.

Background: Microcalcifications in the cap of vulnerable plaques contribute to plaque rupture. The mechanism by which microcalcifications form is poorly understood due to the inability to monitor initiating calcification events in vivo. We hypothesized that aggregation of cellular-derived matrix vesicles (MV) within atheroma lead to the formation of microcalcifications. Results: Transmission electron microscopy of ApoE-/- mouse plaques reveals MVs aggregating in regions of disrupted collagen (A). To image aggregation of calcifying MVs, we created a 3D collagen hydrogel system to simulate the atherosclerotic fibrous cap. Conditioned media from calcific human coronary artery smooth muscle cells was added to collagen hydrogels. Confocal microscopy reveals spherical microcalcifications (B, arrows) resembling those previously reported in human plaques. Super-resolution (< 200 nm) microscopy of the collagen hydrogels shows individual MVs aggregating (C, arrows) to form microcalcifications shown by a near-infrared calcium phosphate tracer (D). Scanning electron microscopy combined with x-ray spectroscopy confirms the presence of calcium phosphate mineral within MV aggregates (E, orange color). MV aggregation and calcification size is inversely related to the amount of collagen in our 3D model (p Conclusion: To our knowledge, we are the first to directly visualize aggregation and calcification of MVs in real time. This approach presents a powerful tool to understand the genesis of microcalcifications from nucleating events. Aggregation of MVs within a thinning fibrous cap leads to the formation of microcalcifications, which further destabilize the cap.

Background: Arterial microcalcification predicts cardiovascular events and contributes to plaque rupture. We recently demonstrated that matrix vesicles (MVs) participate in the formation of microcalcifications. Yet, the precise mechanisms by which MVs regulate calcification in atheroma remain unknown. We hypothesized that sortilin 1, a protein associated with arterial calcification in GWAS, promotes calcification via its phosphorylation and recruitment to MVs. Results: We detected sortilin 1 in calcified MVs of human plaques using transmission electron microscopy-based immunogold labeling. Sortilin 1 loading into MVs increased in sortilin 1-overexpressing smooth muscle cells (SMCs), and rose further in MVs derived from calcifying SMCs. Nanoparticle tracking analysis indicated no alteration in MV release. Silencing sortilin 1 reduced tissue non-specific alkaline phosphatase (TNAP) activity within MVs (-45%; p Conclusion: Sortilin 1 promotes MV-mediated vascular microcalcification via Rab11 trafficking and C-terminal phosphorylation. Our data provide mechanistic insight into the correlation between sortilin 1 and calcification and identifies sortilin 1 as a potential therapeutic target to modulate the formation of microcalcifications.

The enzyme prephenate dehydrogenase catalyzes the oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate for the biosynthesis of tyrosine. Prephenate dehydrogenases exist as either monofunctional or bifunctional enzymes. The bifunctional enzymes are diverse, since the prephenate dehydrogenase domain is associated with other enzymes, such as chorismate mutase and 3-phosphoskimate 1-carboxyvinyltransferase. We report the first crystal structure of a monofunctional prephenate dehydrogenase enzyme from the hyper-thermophile Aquifex aeolicus in complex with NAD+. This protein consists of two structural domains, a modified nucleotide-binding domain and a novel helical prephenate binding domain. The active site of prephenate dehydrogenase is formed at the domain interface and is shared between the subunits of the dimer. We infer from the structure that access to the active site is regulated via a gated mechanism, which is modulated by an ionic network involving a conserved arginine, Arg250. In addition, the crystal structure reveals for the first time the positions of a number of key catalytic residues and the identity of other active site residues that may participate in the reaction mechanism; these residues include Ser126 and Lys246 and the catalytic histidine, His147. Analysis of the structure further reveals that two secondary structure elements, beta3 and beta7, are missing in the prephenate dehydrogenase domain of the bifunctional chorismate mutase-prephenate dehydrogenase enzymes. This observation suggests that the two functional domains of chorismate mutase-prephenate dehydrogenase are interdependent and explains why these domains cannot be separated.