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Item Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity(Springer Nature, 2017-08) Landis, Benjamin J.; Schubert, Jeffrey A.; Lai, Dongbing; Jegga, Anil G.; Shikany, Amy R.; Foroud, Tatiana; Ware, Stephanie M.; Hinton, Robert B.; Pediatrics, School of MedicineThoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.Item Height Versus Body Surface Area to Normalize Cardiovascular Measurements in Children Using the Pediatric Heart Network Echocardiographic Z-Score Database(Springer, 2021) Mahgerefteh, Joseph; Lai, Wyman; Colan, Steven; Trachtenberg, Felicia; Gongwer, Russel; Stylianou, Mario; Bhat, Aarti H.; Goldberg, David; McCrindle, Brian; Frommelt, Peter; Sachdeva, Ritu; Shuplock, Jacqueline Marie; Spurney, Christopher; Troung, Dongngan; Cnota, James F.; Camarda, Joseph A.; Levine, Jami; Pignatelli, Ricardo; Altmann, Karen; van der Velde, Mary; Thankavel, Poonam Punjwani; Chowdhury, Shahryar; Srivastava, Shubhika; Johnson, Tiffanie R.; Lopez, Leo; Pediatric Heart Network Investigators; Pediatrics, School of MedicineNormalizing cardiovascular measurements for body size allows for comparison among children of different ages and for distinguishing pathologic changes from normal physiologic growth. Because of growing interest to use height for normalization, the aim of this study was to develop height-based normalization models and compare them to body surface area (BSA)-based normalization for aortic and left ventricular (LV) measurements. The study population consisted of healthy, non-obese children between 2 and 18 years of age enrolled in the Pediatric Heart Network Echo Z-Score Project. The echocardiographic study parameters included proximal aortic diameters at 3 locations, LV end-diastolic volume, and LV mass. Using the statistical methodology described in the original project, Z-scores based on height and BSA were determined for the study parameters and tested for any clinically significant relationships with age, sex, race, ethnicity, and body mass index (BMI). Normalization models based on height versus BSA were compared among underweight, normal weight, and overweight (but not obese) children in the study population. Z-scores based on height and BSA were calculated for the 5 study parameters and revealed no clinically significant relationships with age, sex, race, and ethnicity. Normalization based on height resulted in lower Z-scores in the underweight group compared to the overweight group, whereas normalization based on BSA resulted in higher Z-scores in the underweight group compared to the overweight group. In other words, increasing BMI had an opposite effect on height-based Z-scores compared to BSA-based Z-scores. Allometric normalization based on height and BSA for aortic and LV sizes is feasible. However, height-based normalization results in higher cardiovascular Z-scores in heavier children, and BSA-based normalization results in higher cardiovascular Z-scores in lighter children. Further studies are needed to assess the performance of these approaches in obese children with or without cardiac disease.Item A novel approach for treating type II endoleaks utilizing contrast-enhanced ultrasound(Elsevier, 2021-06-12) Churchill, Dennis, II.; Motaganahalli, Raghu; LaRoche, Thomas; Ramkaransingh, Jeffrey; Radiology and Imaging Sciences, School of MedicineEndoleaks are a frequent and well-known complication after endovascular repair of aortic aneurysms. An endoleak can lead to increased intrasac pressure, sac enlargement, and potential aneurysm rupture. Type II endoleaks result from retrograde filling of aortic branch vessels and can be treated with surgical, endovascular, or direct percutaneous approaches. Direct percutaneous treatment typically involves embolization of the perfused endoleak cavity typically using a translumbar approach with fluoroscopic guidance. We illustrate a novel image-guided approach for percutaneous transabdominal endoleak treatment using contrast-enhanced ultrasound in combination with fluoroscopy.Item The TRPC6 inhibitor, larixyl acetate, is effective in protecting against traumatic brain injury-induced systemic endothelial dysfunction(Biomed Central, 2019-01-31) Chen, Xingjuan; Taylor-Nguyen, Natalie N.; Riley, Ashley M.; Herring, B. Paul; White, Fletcher A.; Obukhov, Alexander G.; Cellular and Integrative Physiology, School of MedicineBACKGROUND: The incidence of traumatic brain injuries (TBIs) is on the rise in the USA. Concussions, or mild TBIs without skull fracture, account for about 75% of all TBIs. Mild TBIs (mTBIs) lead to memory and cognitive deficits, headaches, intraocular pressure rises, axonal degeneration, neuroinflammation, and an array of cerebrovascular dysfunctions, including increased vascular permeability and decreased cerebral blood flow. It has been recently reported that besides vascular dysfunction in the cerebral circulation, mTBI may also cause a significant impairment of endothelial function in the systemic circulation, at least within mesenteric microvessels. In this study, we investigated whether mTBI affects endothelial function in aortas and determined the contribution of transient receptor potential canonical (TRPC) channels to modulating mTBI-associated endothelial dysfunction. METHODS: We used a model of closed-head mTBI in C57BL/6, 129S, 129S-C57BL/6-F2 mice, and 129S-TRPC1 and 129S-C57BL/6-TRPC6 knockout mice to determine the effect of mTBI on endothelial function in mouse aortas employing ex vivo isometric tension measurements. Aortic tissue was also analyzed using immunofluorescence and qRT-PCR for TRPC6 expression following mTBI. RESULTS: We show that in various strains of mice, mTBI induces a pronounced and long-lasting endothelial dysfunction in the aorta. Ablation of TRPC6 protects mice from mTBI-associated aortic endothelial dysfunction, while TRPC1 ablation does not impact brain injury-induced endothelial impairment in the aorta. Consistent with a role of TRPC6 activation following mTBI, we observed improved endothelial function in wild type control mice subjected to mTBI following 7-day in vivo treatment with larixyl acetate, an inhibitor of TRPC6 channels. Conversely, in vitro treatment with the pro-inflammatory endotoxin lipopolysaccharide, which activates endothelial TRPC6 in a Toll-like receptor type 4 (TLR4)-dependent manner, worsened aortic endothelial dysfunction in wild type mice. Lipopolysaccharide treatment in vitro failed to elicit endothelial dysfunction in TRPC6 knockout mice. No change in endothelial TRPC6 expression was observed 7 days following TBI. CONCLUSIONS: These data suggest that TRPC6 activation may be critical for inducing endothelial dysfunction following closed-head mTBI and that pharmacological inhibition of the channel may be a feasible therapeutic strategy for preventing mTBI-associated systemic endothelial dysfunction.